Pilot Study Awardees
Pilot Study Awards Recipients
Each year we support multiple pilot studies with $75,000 each to pave the way for new avenues of ovarian cancer research and to expand our understanding of the disease.
Pilot Study Awards Recipients
Each year we support multiple pilot studies with $75,000 each to pave the way for new avenues of ovarian cancer research and to expand our understanding of the disease.
Pratip K Bhattacharya, PhD
M.D. Anderson Cancer Center
Houston, TX, United States
2019 Rosser Family Pilot Study Award
Research in Focus: Early detection of ovarian cancer
Development of Platelet-based Metabolic Biomarkers for Ovarian Cancer
Ovarian cancer is the fourth leading cause of cancer deaths in women. The disease is often diagnosed at an advanced stage as there are no reliable early detection methods. Therefore, there is a critical unmet need for biomarkers that can confidently and easily predict the biological behavior of ovarian cancer to improve early detection, determine how aggressive tumors are, and monitor their response to treatment. Dr. Bhattacharya proposes that a solution may be found in blood platelets—circulating colorless disk-shaped cell fragments, found in large numbers in blood that are involved in clotting. Research has shown that platelets in a cancer-free person contain a different compilation of information, stored in molecules called RNA, than platelets in a person with cancer. These tumor “educated” platelets have recently generated interest for their potential in diagnosing cancer. Dr. Bhattacharya hypothesizes that tumor-educated platelets from patients with ovarian cancer will show a different metabolism compared with platelets from healthy volunteers, and will identify this changed metabolism by a simple, easy, and inexpensive method called NMR spectroscopy on blood samples. This technique, if successful, would be used along with information from imaging information. This method would be of enormous interest because of its ease of accessibility, potential use as metabolic biomarker for ovarian cancer detection, and ability to bypass the need for invasive biopsies.
Caroline Ford, PhD
University of New South Wales
2019 James A. Harting Pilot Study Award
Research in Focus: Novel therapies to treat ovarian cancer
Shock and ROR! Inhibiting ovarian cancer metastasis with targeted therapies in an organotypic model of ovarian cancer
In order to improve survival in ovarian cancer, we need to further study the molecular changes at the root of the disease to identify key cellular pathways that are responsible for the start and progression of cancer. Dr. Ford and colleagues have recently identified two genes, ROR1 and ROR2 that are abnormally expressed at high levels in ovarian cancer. By silencing the genes, they can dramatically block ovarian cancer cell migration and invasion, key processes needed for cancer cells to spread to other parts of the body. Dr. Ford and colleagues have also shown that when cancer cells become resistant to chemotherapy, targeting the ROR genes can re-sensitize them to the effects of chemotherapy drugs. ROR1 and ROR2 are not found in non-cancer cells so they are attractive targets for therapeutic interventions. Dr. Ford and colleagues will use a unique 3D model of ovarian cancer to determine the potential of ROR1 and ROR2 as cancer drug targets. They will target the RORs using two different approaches with the 3D model: 1) use nanoparticles to deliver gene silencing molecules and (2) use an antibody, called cirmtuzumab, which specifically targets ROR1 and has previously shown to be effective in other cancer types. A positive outcome from this study will progress much needed individualized therapy for ovarian cancer patients and increase survival.
Cecil Han, PhD
Washington DC, United States
2019 Pilot Study Award
Research in Focus: Understanding the biological processes that cause ovarian cancer
Understanding and Targeting Mitochondrial Heterogeneity in Ovarian Cancer
High grade serous ovarian cancers are very complex and variable, making them difficult to treat. One source of this variability may be in the mitochondria, a cellular component known as the “powerhouse”, of ovarian cancer cells. Studies have shown that the variability in mitochondria of ovarian cancer cells can influence how tumors grow, metastasize, and respond to treatment. We do not yet understand how variation in mitochondria might impact these key cancer characteristics. Dr. Han and colleagues recently showed that the USP13 protein may play an important role in how mitochondria in ovarian cancer cells may affect cancer growth and progression. The USP13 protein is barely present in non-cancerous ovary or fallopian tube tissue, but is present at high levels in ovarian cancers. High expression of USP13 in ovarian cancers is associated with poor survival. Dr. Han has shown that if USP13 is blocked, ovarian cancer cells die and tumor growth is dramatically suppressed. The mitochondria of these cells with blocked USP13 are also dysfunctional, indicating that the effect of USP13 on cancer cells may be through its action on mitochondria. In this study, Dr. Han and colleagues will use a mouse model that has high expression of USP13 in fallopian tubes to understand the role of the protein in regulating mitochondria and how this process may contribute to cancer initiation and progression. Future plans for this work would be to develop a specific USP13 inhibitor to treat tumors with high USP13 expression. A better understanding of the underlying biological processes may also help identify additional targets to overcome metastasis and chemotherapy resistance in high grade serous ovarian cancer.
Lana Kandalaft, PhD
University Medical School, Lausanne (CHUV)
2019 Dearborn Family Pilot Study Award
Research in Focus: Novel therapies to treat ovarian cancer
Development of personalized cancer vaccination strategies in ovarian cancer
As ovarian cancer lacks specific symptoms, most patients are diagnosed at an advanced stage whereby treatment response is poor. One option for treatment is to activate the patient’s own immune system using individually tailored vaccines to fight off ovarian cancer. The immune system can be stimulated into action by antigens—substances present on the surface cells. As cancer cells divide rapidly, they accumulate many gene mutations along the way which can serve as antigens. These gene mutations can be unique to the patient (private neoantigens) or present in different patients with the same or different type of cancers (shared tumor antigens). Studies have shown that the unique, private neoantigens are more effective than shared tumor antigens in activating the immune system, resulting in complete tumor regression and long-term remission. Sophisticated genome-sequencing and algorithms are used for identifying tumor neoantigens that may be effective for a patient. However these procedures can take around 6 months and are unsuitable for advanced stage patients. To address this issue, Dr. Kandalaft will use a mouse model to investigate the feasibility of personalized vaccines. Personalized vaccines would comprise of a patient’s own dendritic cells and whole tumor tissue mixture prepared in the clinic, and then be infused into the patient to activate the immune system to seek out and kill cancer cells based on their tumor neoantigen expressions. The major advantage is that the patient’s whole tumor mixture can encompass all tumor neoantigens present in the cancer. Patients would be treated immediately with the vaccine without the need to identify neoantigens. The vaccine preparation method is straightforward and potentially useful in other cancer types as well.
Adam R Karpf, PhD
University of Nebraska Medical Center
Omaha, NE, United States
2019 Pilot Study Award
Research in Focus: Understanding the biological processes that cause ovarian cancer
Oncogenic collaboration between Cyclin E1 and FOXM1 in high-grade serous ovarian cancer
High-grade serous ovarian cancer is the most common form of ovarian cancer, the most deadly gynecologic malignancy. One of the most important characteristics of HGSOC is genomic instability – when DNA (genome) of cells acquires a lot of mutations and other kinds of abnormalities. Genomic instability is a driving force for the development and evolution of tumors and chemotherapy resistance, and leads to poor patient outcomes. We currently have an incomplete understanding of the underlying causes of genomic instability in ovarian cancer. Dr. Karpf will investigate whether two proteins, cyclin E1 and FOXM1, collaborate to promote genomic instability and cancer formation in ovarian cancer. Both cyclin E1 and FOXM1 have been shown to be present in very high levels in high grade serous ovarian cancer. Dr. Karpf and his colleagues will examine how the level of cyclin E1 and/or FOXM1 in fallopian tube cells effects the genomic instability of cells and the ability of the cells to become cancerous. They will also study the molecular details of how the two proteins interact to bring about these cancer-associated changes. By increasing our understanding of the mechanisms that cause high-grade serous ovarian cancer, this study may lead to new avenues for early detection and treatment of this disease. Importantly, ovarian cancers that result of the mechanism described by Dr. Karpf may be especially vulnerable to treatment with a new class of drugs (e.g. ATR, CHK1, and WEE1 inhibitors) currently being tested for effectiveness in treating ovarian cancer patients.
Christopher J. Kemp, PhD
Fred Hutchinson Cancer Research Center
Seattle, WA, United States
2019 Sequoyah Electric Pilot Study Award
Research in Focus: Novel therapies to treat ovarian cancer
Preclinical advancement of combination therapy targeting BAZ2A and EZH2 in ovarian clear cell carcinoma
Ovarian cancer accounts for over 14,000 deaths in the United States every year. Although ovarian cancer has several subtypes, patients have been treated almost in the same way. Precision medicine is a treatment approach in which drugs target abnormal genomic changes unique to each cancer. Dr. Kemp is focusing on clear cell carcinoma of the ovary (OCCC), a rare but chemotherapy-resistant subtype. Up to 60% of OCCC have mutations in the ARID1A gene. Recent studies have shown that ARID1A-mutated OCCC can be targeted with inhibitors of the EZH2 protein. Dr. Kemp has shown that growth of ARID1A-mutated OCCC can also be blocked by inhibiting the BAZ2A protein. Importantly, when inhibitors for EZH2 and BAZ2A are combined, they kill ARID1A-mutated OCCC cells even more effectively than either drug alone. In this study, Dr. Kemp and colleagues will test the effectiveness and tolerability of GSK2801, a BAZ2A inhibitor, as a combination therapy with EZH2 inhibitors using a mouse model of OCCC. They will also investigate how BAZ2A interacts with EZH2 to kill cancer cells in OCCC cells from patients. This study is the first demonstration that BAZ2A is a candidate therapeutic target for OCCC. The completed result will provide key evidence to move this drug combination forward to a clinical trial.
Keren Levanon, MD/PhD
Sheba Medical Center
Ramat Gan, Israel
2019 Pilot Study Award
Research in Focus: Prevention of ovarian cancer & understanding the biological processes that cause ovarian cancer
Microbiome profiling unveils metabolic vulnerabilities of BRCA mutated ovarian cancer
Recent studies have shown that fallopian tubes and other genital track tissues that were previously thought to be sterile actually contain bacteria. These bacteria are believed to cause chronic inflammation which can lead to cancer in the affected tissue. Dr. Levenon and colleagues believe that the microbiome, or the collection of different bacteria, in the fallopian tubes may play a key role in both the initiation and progression of high grade serous ovarian cancer. Their preliminary studies have also found that the composition of bacteria in ovarian tumors differs in tissues from individuals with BRCA mutations and those without BRCA mutations. In this study, Dr. Levenon and colleagues will examine the bacterial composition of high grade serous ovarian cancers and normal fallopian tube tissue from women with different hormone status (premenopausal vs postmenopausal), age, and BRCA status (BRCA mutation vs no BRCA mutation). They will also study some of the metabolic characteristics of the bacteria to understand how they may be “feeding” or contributing to cancer formation. This work may fuel further investigation to define women who are at high risk for ovarian cancer, and impact prevention and identification of novel targets for therapy.
Sachdev Sidhu, PhD
University of Toronto
Toronto, Ontario, Canada
2019 Pilot Study Award
Research in Focus: Novel therapies to treat ovarian cancer
Targeting Ephrin receptors with antibody-drug conjugates to design novel treatments for ovarian cancer
Alterations in certain proteins located on the surface of cells, known as receptor proteins, can lead to the formation of tumors. These receptor proteins represent attractive targets for the development of new treatments. Dr. Sidhu and colleagues are investigating receptors of the EPH protein family as new targets for therapy as they are often deregulated in ovarian cancer, contributing to cancer development and metastasis. Dr. Sidhu and colleagues have done a comprehensive survey of ovarian cancer cells to determine which members of the EPH receptor family are present in ovarian cancer cells and identify the best ones to target when developing new treatment strategies. The goal of this study is to use protein engineering to design novel biological molecules called synthetic antibodies that bind to EPH receptors. These antibodies will bind ovarian cancer cells to deliver a “payload” of anti-cancer drugs inside the cancer cells. At the end of this study, Dr. Sidhu and colleagues will have generated candidate therapies that can be further tested in cellular and animal models, with the ultimate goal of designing more effective ovarian cancer therapies.
Amy Patrice Skubitz, PhD
University of Minnesota – Twin Cities
Minneapolis, MN, United States
2019 Cookie Laughlin Pilot Study Award
Research in Focus: Early detection of ovarian cancer
Validation of a multi-protein classifier for detecting early stages of ovarian cancer
Early detection of ovarian cancer is needed to increase patient survival by identifying the disease when it is most treatable. However, there is currently no blood test sensitive and specific enough to screen women in the general population. Although many proteins have been reported to be present at higher levels in the blood of women with ovarian cancer, no single protein has been sufficient to detect early stages of cancer. Dr. Skubitz and colleagues hypothesize that that multiple proteins need to be combined into one clinical blood test in order for the test to successfully identify women with ovarian cancer. They have screened hundreds of blood samples from healthy women and women with ovarian cancer on Proseek® Multiplex Oncology II plates. These plates use the latest technology to simultaneously determine the levels of 92 cancer-related proteins in one drop of a patient’s blood. By performing complex statistical analyses, Dr. Skubitz and colleagues have identified several proteins as potential biomarker candidates for ovarian cancer detection. In preliminary studies, they combined multiple candidate biomarkers into a mathematical formula that allows them to discriminate between blood from healthy women versus women with ovarian cancer. In this study, they will validate their biomarker formula by testing blood samples from 88 women with early stages of ovarian cancer and 264 healthy women on Oncology II plates. The goal of this study is to develop a test to detect ovarian cancer in its earliest, most treatable stage.
Wa Xian, PhD
University of Texas Health Science Center at Houston
Houston, TX, United States
2019 Pilot Study Award
Research in Focus: Understanding and overcoming resistance to chemotherapy
Resistant Cancer Stem Cell Profile in Multi-Site Metastasis of HGSC
Even though ovarian cancer is typically detected very late, advances in surgery and chemotherapy have resulted in remarkable responses in most patients such that cancer is essentially undetectable at six months. However, a frustratingly large number of these patients will see a return of this disease against which chemotherapy is less effective. There is now increasing evidence that this recurrent disease is the result of a very small number of cancer cells in the original cancer that are somehow “different”. Therefore, the most pressing problem in ovarian cancer today is understanding how to kill this very small number of resistant cells. To meet this challenge, Dr. Xian and colleagues have very recently developed a technology that may permit us to identify these rare, resistant tumor cells soon after the patient is diagnosed with ovarian cancer. In particular, they can grow these rare resistant cells in a test tube so that they can use powerful techniques to determine at a molecular level how they are different and thereby identify drugs that specifically kill them before they have a chance to multiply and result in the recurrence of ovarian cancer. This study aims to determine the existence of these resistant cells in both primary and metastatic tumors of a patient, and identify drugs that specifically target these changes in these cells. Dr. Xian’s ultimate aim is to more effectively prevent clinical relapses and ultimately provide curative therapies for patients.
Hui Zong, PhD
University of Virginia
Charlottesville, VA, United States
2019 Pilot Study Award
Research in Focus: Prevention of ovarian cancer
Efficacy testing for ovarian cancer prevention at pre-malignant stages with a novel mouse model
Prevention remains the ultimate goal for successful management of cancer. Identifying cancer prevention strategies is challenging due to the large population required to run a clinical trial and the amount time it takes to reach the endpoint needed to have results. There is also heightened scrutiny for tolerability and safety for preventative drugs, since they would be used in a relatively healthy population. However, animal models provide an opportunity to devise the most promising preventative regimens to guide clinical trials. In this study, Dr. Zong and colleagues propose to use a new ovarian cancer mouse model that permanently tracks mutant cells from the earliest time points through cancer development to test how effective different compounds may be for cancer prevention. Dr. Zong’s study should lead to promising data regarding these compounds as potential chemo-preventatives and help identify important principles to design highly informative clinical studies for ovarian cancer prevention.
Gianpietro Dotti, M.D.
The University of North Carolina at Chapel Hill
Chapel Hill, NC, United States
Project: Targeting B7-H3 in Ovarian Cancer
Research Area: Immunotherapy, CAR-T Cell Therapy
Ovarian cancer is an aggressive type of tumor for which no effective therapy is currently available when the disease comes back after chemotherapy and surgery. This has prompted Dr. Dotti to develop a strategy in which the immune system will be used to target ovarian cancer cells. An important job of the immune system is to attack and destroy abnormal cells in our bodies. Some abnormal cells are able to escape from being recognized by the immune system and cancers develop. T cells are white blood cells that are part of the immune system that can identify and attack abnormal cells. Recent advances in cancer treatments are using the immune system T cells to attack cancers. Dr. Dotti and his colleagues are developing a new way to attack ovarian cancer by modifying a person’s own immune system T cells to re-direct them to specifically kill tumor cells. The modified T cells can recognize a tumor antigen called B7-H3 that they found on most ovarian cancer cells. An antigen is a substance on a cell that can be the target of an immune system response. The modified T cell therapy is referred to as “B7-H3.CAR T cells”. Additionally, they will use novel drugs to attack some other cells within the tumor to further increase the activity of the B7-H3.CAR T cells. Dr. Dotti will do experiments in mice and, if promising, this approach will be used clinically in women with ovarian cancer later on.
Steven M Jay, Ph.D.
University of Maryland-College Park
College Park, MD, United States
Project: Engineering HER3-targeted ovarian cancer therapy
Research Area: Novel Therapy
The presence of the HER3 protein on the surface of ovarian cancer cells is associated with worse survival outcomes; therefore, blocking the pro-cancer activity of the HER3 protein may improve survival. Dr. Jay’s lab has developed a new approach to interfere with the function of HER3 using small proteins arranged in a specific configuration. These small protein molecules effectively reduce the growth of ovarian cancer in animals on their own. However, based on what we know from experience with current treatments and the effectiveness of similar biologic therapies, it’s expected these molecules will be used in the clinic as part of a drug conjugate, when the proteins are physically bound to a chemotherapy drug, or combination therapy approach. In this study, Dr. Jay’s lab plans to test the therapeutic potential of their approach in combination with common chemotherapy drugs used to treat ovarian cancer. In addition, Dr. Jay’s group will gauge the potential of creating drug conjugates with chemotherapy drugs and the small proteins to further enhance therapeutic effectiveness of their approach. This strategy is fundamentally different than other HER3-targeted therapies currently in clinical trials and could lead to a novel candidate for clinical trials.
Pamela K Kreeger, Ph.D.
University of Wisconsin-Madison
Madison, WI, United States
Project: Role of P-selectin in transcoelomic spread of ovarian cancer
Research Area: Cancer Biology, Novel Therapy
In high grade serous ovarian cancer, metastasis or spread of the cancer occurs when tumor cells break away from the primary tumor, float through the fluid in the abdominal cavity, and attach to the lining of tissues in the abdomen to form new metastases. Blocking tumor cell attachment could slow or stop the development of additional metastases and improve patient outcomes and quality of life. Dr. Kreeger’s lab has analyzed the role of a population of immune system cells, called the alternatively-activated macrophages, in this process. Through their experiments, they have determined that these macrophages produce a substance called MIP-1ß that increases the level of another protein called P-selectin on the cells that line the abdominal cavity. In a bioengineered experimental model Dr. Kreeger tested, the P-selectin protein allows tumor cells to attach and ‘stick’. Excitingly, there are already drugs that are approved by the Federal Drug Administration to inhibit the receptor for MIP-1ß or in clinical trials to inhibit P-selectin. While these drugs were developed for diseases other than cancer, they could potentially be used to control metastasis in ovarian cancer. In this project, Dr. Kreeger will validate that P-selectin promotes metastasis in mouse models of high grade serous ovarian cancer in order to move forward with pre-clinical testing of those drugs and ultimate translation to the treatment of patients in the clinic.
John Liao, M.D., Ph.D.
University of Washington
Seattle, WA, United States
2018 JAMES A. HARTING PILOT STUDY AWARD
Project: Development of a vaccine to prevent serous tubal intraepithelial carcinoma
Research Areas: Prevention, Cancer Vaccine, Treatment, Immunology
High grade serous ovarian cancer does not originate in the ovary, as once thought, but on the fallopian tube. Precancerous fallopian tube cells (called serous tubal intraepithelial carcinoma or STIC) can go through a series of malignant changes and metastasize to the ovary and develop into what we know as high grade serous ovarian cancer. As an innovative treatment strategy, Dr. Liao proposes to develop a vaccine that would target the development of STIC which, if eliminated, could ultimately prevent the development of high grade serous ovarian cancer. Dr. Liao and colleagues work on developing vaccines that stimulate a strong response by T-cells of the immune system to kill tumor cells. T-cells only come into tissues if there is something that is not normally present there. The proteins that are different and present in larger than usual amounts are called antigens and identified by T-cells. Dr. Liao’s group has already identified several antigens present in large amounts in STIC compared to normal fallopian tube tissue. Dr. Liao will determine which antigens might be best to include in a vaccine by testing which antigens can promote growth of fallopian tube cells. Targeting those antigens that promote the progression of the cancer would potentially have the most impact on eliminating the tumor. Dr. Liao and colleagues have already made a vaccine targeting three identified STIC antigens. They will immunize mice that are likely to develop STIC and test if they can prevent it. Data generated through this project would be the basis of a fully developed multi-antigen STIC, and consequently high grade serous ovarian cancer, prevention vaccine.
Dan Peer, Ph.D.
Tel Aviv University
Tel Aviv, Israel
Project: Developing a novel therapeutic modality to chemo-resistance epithelial ovarian cancer.
Research Areas: Novel Therapy, Chemotherapy Resistance
Chemotherapy resistance is one of the biggest challenges for the treatment of epithelial ovarian cancer. One promising method to reliably test new anticancer drugs and understand response to chemotherapy is to develop 3-dimentional (3D) models known as spheroids from patient tumor cells. Dr. Peer and colleagues have developed a unique collection of over 20 spheroid 3D models from epithelial ovarian cancer patients who either responded or did not respond to chemotherapy. Using spheroids established from patients, Dr. Peer found increased amounts of several proteins that associated with resistance to chemotherapy. In this study, Dr. Peer proposes to develop a laboratory platform which uses engineered personalized nanoparticles that contain molecules called siRNAs, which reduce expression of some of these proteins, combined with chemotherapy. This will allow Dr. Peer to test if and how well cancer spheroids can be killed with this therapy approach. siRNA based treatment may uncover mechanisms that help us understand how the tumor progresses and responds to chemotherapy. The work may set the groundwork for developing novel and more effective treatments of epithelial ovarian cancer based on precision nano-medicine.
Angela Russo, Ph.D
University of Illinois at Chicago – UIC
Chicago, IL, United States
2018 MARLYS CHENEY PILOT AWARD
Project: Characterization and targeting the markers of stemness altered during ovarian cancer pathogenesis using WNT inhibitors
Research Areas: Cell Biology, Stem Cells, Tumor Microenvironment
High-grade serous ovarian cancer is the most common type of ovarian cancer with the highest mortality rate. The lethal nature of these tumors is mainly due to the difficulty in detecting the disease at early stages when it is more treatable. Reduced amounts or absence of a protein called PTEN in fallopian tube cells is enough to lead to formation of a tumor and growth of tumor cells in the abdominal cavity. Dr. Russo’s research will aim to identify the cellular pathways that are turned on when this critical PTEN protein is lost in fallopian tube in order to identify early targets during the development of ovarian cancer. Dr. Russo’s preliminary experiments show that changes in a cellular pathway that involves the WNT protein and changes in “stemness” (giving ordinary cells properties of stem cells that have the potential of changing into many different kinds of cells) are involved in this process. Dr. Russo has shown that inhibiting function of WNT pathways with a drug called LGK-974 can reduce cancer cells from colonizing in the ovary. Importantly, the LGK-974 drug is in clinical trial for pancreatic and breast cancer, but not ovarian cancer. This work may set the ground work a potential approach for treating ovarian cancer patients with this drug. In this study, Dr. Russo aims to extend the use of the WNT inhibitors alone and in combination with chemotherapy drugs to test if the treatment blocks tumor metastases. Additionally, Dr. Russo will identify changes in cancer stem cells markers during ovarian cancer progression and determine whether WNT inhibitors reduce the expression of these markers. This work may help provide evidence to stratify the use of WNT inhibitor therapy based on the amount of PTEN expression and the make-up of cancer stem cell markers expressed in cancer cells.
Alice Soragni, Ph.D.
University of California, Los Angeles
Los Angeles, CA, United States
2018 LYNDA’S FUND PILOT STUDY AWARD
Project: p53 aggregation in pre-malignant ovarian cancer lesions
Research Area: Cancer Biology
p53 is a crucial tumor suppressor protein that prevents damaged cells from becoming cancerous. In order to divide uncontrollably, cancer cells often inactivate p53 by mutating it, as in the majority of ovarian cancer cases. Some mutations may loosen the structure of the p53 protein. In this process, a sticky segment of the p53 protein can stick to other p53 proteins to form clumps causing a large number of the proteins to aggregate together. p53 mutations are present in pre-cancerous cells in the fallopian tube and in early cancerous lesions. Dr. Soragni will test if the collection of the mutated p53 proteins in aggregates can be found in early stage ovarian cancer tissues and see if the presence of these aggregates is different in normal and precancerous tissues. She will also test if a drug known to target these kinds of aggregates can prevent benign precancerous tissues in mice from becoming malignant. If successful, Dr. Soragni’s work will help us understand the role of p53 aggregates in the progression of ovarian cancer from benign to a malignant state and provide a potential block to the process.
Emanuela Grassilli, Ph.D.
Università degli Studi di Milano-Bicocca (University of Milano – Bicocca)
Project: p65BTK as an actionable target in ovarian cancer
Research Area: Novel Therapy
Dr. Grassilli proposes to test treatment of ovarian cancer with drugs that target a protein called p65BTK which is expressed by ovarian cancer cells. She recently identified p65BTK as a protein that is present at high levels in colon cancer and showed that the function of the protein can be blocked by a drug called Ibrutinib to kill those cancer cells. Her initial studies showed that in colon cancer and some lung cancer cells, Ibrutinib could kill even cells that are resistant to currently used chemotherapy drugs. Dr. Grassilli also did initial studies in ovarian cancer cells and showed that they too can be killed by this method. In the Rivkin-funded study, Dr. Grassilli will expand on this work to understand how this treatment might work, both on its own and when combined with currently use chemotherapy, in the context of different genetic backgrounds commonly seen in ovarian cancer. She will also study how response to the drug changes in ovarian cancer cells that express different levels of p65BTK, the target protein of Ibrutinib.
Shannon Hawkins, M.D., Ph.D.
Indianapolis, IN, United States
Project: Dissecting the role of ARID1A in ovarian cancer using a 3D bio-assembled model of the endometriotic tumor microenvironment
Research Areas: Cancer Biology
Endometriosis, growth of uterus tissue outside the uterus, effects 5 million women in the US and is associated with a 50% increase in the risk of ovarian cancer. Interestingly, women with endometriosis at the time of ovarian cancer diagnosis have a better prognosis because of the specific kinds of ovarian cancers they tend to have. Dr. Hawkins’ study will determine the effects of an important tumor suppressor gene, called ARID1A, in an innovative cellular model of endometriosis-associated ovarian cancer, in order to develop new treatments. Dr. Hawkins will use a method called the Kenzan method which places balls of cells (spheroids) onto a tiny microneedle (Kenzan in Japanese), allowing for the construction of complex living structures similar to building with Lego blocks. The spheroids secrete material and fuse together forming constructs of ovarian cancer within an “endometriotic tumor microenvironment”. The study will test the specific cellular and molecular contributions of ARID1A both in this endometriotic tumor microenvironment and in the tumor itself. The unique 3D model allows the testing of interactions between cells of the tumor and tumor microenvironment, the molecular landscape on a cell-specific level, and the inflammatory molecules involved. These studies will lead to improved drug targets for ovarian cancer for women with endometriosis.
Alvaro Monteiro, Ph.D.
H. Lee Moffitt Cancer Center & Research Institute
Tampa, FL, United States
Project: Tackling PARP inhibitor resistance through functional proteomics
Research Areas: Chemotherapy Resistance
There has been significant progress in ovarian cancer treatment especially with the development and approval of PARP inhibitor drugs. Despite this progress, a sizable percentage of patients do not respond or stop responding to PARP inhibitor treatment. Dr. Monteiro proposes to apply a novel approach to understand resistance to PARP inhibitors that may either be present from the start or develop during treatment. Dr. Montiero and colleagues believe that tumors with defects in BRCA1 or BRCA2 that do not respond to PARP inhibitors will show significant changes in both protein complexes that interact with the PARP inhibitor drug and in other modifications on proteins. They will look for these changes both in ovarian cancer cells and in frozen tissues from tumors to identify markers of PARP inhibitor resistance and to identify new targets for rational combination therapies that can overcome resistance. If successful, the results of this project may extend the benefits of PARP inhibitor therapy to a significantly larger segment of ovarian cancer patients, identify patients who would not benefit from PARP inhibitors so that alternative therapies can be explored earlier, and find potential targets for combination therapy to reverse or bypass PARP inhibitor resistance.
Susan J Ramus, PhD
The University of New South Wales (UNSW)
Project: Genetic susceptibility to non-high grade serous ovarian cancer
Research Areas: Prevention, Genetics
Ovarian cancer consists of five distinct types of cancers that have different clinical characteristics, patient outcomes, and even begin in different nearby organs. They have different changes in the DNA of the tumor cells which affect the biology of tumor. Most research focuses on the common subtype called high grade serous. Very few studies focus on the 35% of women who have “non-high grade serous” types, resulting in decreased opportunities for those women. Genetic changes in genes, such as BRCA1 and BRCA2, are important in high grade serous cases, allowing better treatment options, family testing, and preventive surgery. While research continues to uncover new genes linked with high grade serous, little is known about genes linked with non-high grade serous ovarian cancer. Dr. Ramus will use large numbers of non-high grade serous cases, from an international collaboration, to identify similar types of genes, in this understudied ovarian cancer subtype. She and her colleagues will identify a group of 30 genes from available data and look for differences between 2,000 non-high grade serous cases and 1,000 healthy individuals without cancer. Understanding the genetics of non-high grade serous ovarian cancer can have significant clinical impact for women affected by those cancers and may lead to opportunities for prevention and improved treatment.
2017 James A. Harting Pilot Study Award
Many ovarian cancer patients experience distress for years after their diagnosis, even during periods of remission and stable disease. Studies have shown that changes in the nervous system and inflammatory responses associated with chronic stress may promote cancer growth and metastasis. Therefore, interventions that reduce stress in patients have physical health implications in addition to providing social and emotional support. Dr. Andersen’s study will look at how a meditation-based intervention called “Building Personal Resilience” (BPR), tailored for ovarian cancer patients who have just completed chemotherapy, impacts health measures associated with cancer outcomes such as Heart Rate Variability (HRV). Dr. Andersen will also look at biochemical changes that may be associated with successful BPR intervention. This work will lay the foundation for a larger study that will not only improve the quality of life of ovarian cancer survivors, but may also have a direct impact on their physical health.
PARP inhibitors are a promising class of drugs for the treatment of ovarian cancers with defects in the BRCA1 or BRCA2 genes. However, drug resistance to PARP inhibitors poses a significant challenge for clinicians. Dr. D’Andrea’s group has recently shown that in cancer cells with BRCA2 mutations, PARP inhibitor resistance can be caused by decreased abundance of a protein called EZH2. Lower levels of EZH2 protect newly made DNA by reducing the recruitment of another protein called MUS81, that can chew up newly made DNA. Protection of newly made DNA has been shown by Dr. D’Andrea and others to lead to resistance to PARP inhibitors and cisplatin, first-line therapy for ovarian cancer. This study will allow Dr. D’Andrea to better understand how reduced expression of EZH2 leads to PARP inhibitor resistance and determine how common this phenomenon is in resistant ovarian cancer samples from patients. Understanding how PARP inhibitor resistance works is necessary to develop better therapies and to more effectively predict tumor response to treatment.
High dose of Ascorbate, or Vitamin C, administered through the bloodstream has been suggested to have anti-tumor properties when given in combination with chemotherapy and/or radiotherapy. This concomitant treatment strategy has shown promise in early clinical trials of ovarian cancer. When administered intravenously, a much higher concentration of ascorbate can reach the tumor than is possible if taken orally. The highly concentrated ascorbate causes reactive oxygen molecules to form and build up in the tumor cells, and these reactive oxygen species are the principal mediator of DNA and protein damage in cells. Their accumulation can lead to cell death, particularly when concurrently exposed to chemotherapy. Dr. Hempel proposes that ovarian cancer cells may be especially sensitive to ascorbate treatment because they contain higher levels of reactive oxygen precursors already, and the treatment will have a cascading effect turning all of these molecules into the harmful reactive species. Furthermore, the environment surrounding ovarian tumors may be conducive to this therapy because the balance of molecules in the fluid of the abdominal cavity makes it easier for the reactive oxygen molecules to form inside of the cancer cells. Dr. Hempel and colleagues will determine if ovarian cancer is indeed a good candidate for ascorbate combination therapy. The results of their work will inform the development of a clinical trial in late stage ovarian cancer patients.
Though patients with mutations in the BRCA1 gene respond better to cisplatin and PARP inhibitors than patients without mutations, resistance to these drugs remains a major obstacle for the successful long-term treatment of ovarian cancer. Dr. Johnson’s group recently showed that cancer cells with certain BRCA1 mutations are able to produce an alternative version of the BRCA1 protein that makes them resistant to PARP inhibitors and cisplatin. This phenomenon likely applies to almost 30% of all known mutations in the BRCA1 gene. Cells rely on a protein complex called the splicesome to make this version of BRCA1. Dr. Johnson wants to use drugs, known as splicesome inhibitors to block the function of the splicesome and prevent this resistance-causing variant from being produced with the aim of preventing the associated drug resistance. If successful, splicesome inhibitors may provide the means to combat resistance in a subset of patients with BRCA1 mutations.
The ovarian cancer environment in the abdominal cavity is quite complex, as cancer cells exist among cancer progenitor cells and immune cells in the ascites fluid. The physical stress from fluid movement and interactions with other cells likely influence the growth and drug response of ovarian cancer cells. Dr. Mehta has developed a much needed bioreactor model that mimics the cellular complexity and mechanical stresses experienced by ovarian tumor cells. Dr. Mehta will use this model to study how cancer progenitor cells interact with other cancer cells in the tumor environment and control the response of immune cells in order to evade chemotherapy and promote metastasis. She will also study how fluid flow dynamics impact both response to chemotherapy and metastasis of ovarian tumors. This work will provide an important model to efficiently and effectively test new drugs and immunotherapy approaches for the treatment of ovarian cancer.
HE4 is a protein that is highly overproduced in ovarian cancer cells and secreted into the bloodstream and serves as a biomarker for the presence of ovarian cancer. However, HE4 is also causally linked to tumorigenesis by promoting enhanced growth, blood vessel formation, resistance to chemotherapy, and successful bypass of the immune response. Therefore, Dr. Moore proposes that HE4 is a novel therapeutic target for ovarian cancer. Preliminary studies in Dr. Moore’s laboratory have demonstrated that blocking HE4 slows tumor growth and increases efficacy of chemotherapy. However, a small molecule inhibitor, or pharmacologic drug, that can block HE4 in humans is lacking. Dr. Moore will undertake the task of designing and testing a new drug that will inhibit HE4 and consequently treat ovarian tumors. This innovation has the potential to increase survival and quality of life in women with ovarian cancer.
2017 Pape Family Pilot Study Award
Women with inherited mutations in the BRCA1 and BRCA2 genes have a greatly increased risk of developing high-grade serous ovarian cancer (HGSOC). This type of cancer starts as a lesion in the fallopian tube, and these lesions almost always contain cells with a mutation in a gene called TP53, which is commonly mutated in many types of cancers. Dr. Risques and colleagues recently reported the important discovery that mutations in TP53 are common in normal tissue as well and that these mutations are more abundant in older women with mutations in the BRCA1 and BRCA2 genes. They concluded that mutations in TP53 accumulate in normal tissue during the aging process, and that their increased frequency might be associated with the development of cancer. Based on these findings, Dr. Risques hypothesizes that women with BRCA1 and BRCA2 mutations have more TP53 mutations in their fallopian tubes than other women. Remarkably, Dr. Risques has also been able to find these TP53 mutations without invasive surgery to study the fallopian tubes. She can find the frequency of TP53 mutations in a patient from collecting blood samples. In this study, Dr. Risques will determine if women with the BRCA1 and BRCA2 mutations carry more TP53 mutations in their blood, and whether this correlates with greater risk of developing ovarian cancer. If this proves true, sampling TP53 mutations in the blood could be an extremely easy, non-invasive way to determine a patient’s risk of developing ovarian cancer.
More than 80% of patients with high-grade serous ovarian cancer (HGSOC) develop resistance to treatment and eventually succumb to their disease. The need to develop new treatments for this form of ovarian cancer is dire. About 65% of ovarian cancers have increased production of a protein called Cyclin E that drives cell division leading to uncontrolled tumor growth. These cancers are among those resistant to current chemotherapy options. Dr. Simpkins and colleagues have discovered a promising new drug combination that kills these cells. Cancer cells with increased Cyclin E accumulate damage to their DNA when it is being replicated (copied), and as a result, they rely heavily on proteins that help pause the replication process and repair the damage to the DNA. Two such proteins are ATR and Wee1. Dr. Simpkins proposes to exploit this weakness in cancer cells with increased Cyclin E to our advantage for ovarian cancer treatment. By blocking ATR and Wee1 from helping the cells repair their DNA, the cancer cells accumulate so much damage that they eventually die. In this study, Dr. Simpkins will find out more about how this drug combination works to kill the cancer cells and test this treatment in mice. Her findings may lead to clinical trials of a new treatment for this aggressive ovarian cancer using already existing chemotherapies.
The majority of ovarian cancers recur 18-24 months after first responding to chemotherapy. Residual cells hide out in the abdominal cavity and often become unresponsive to current chemotherapy when they grow back. Dr. Telleria researches therapies that would be administered chronically after chemotherapy to prevent recurrence. A class of drugs called antiprogestins is not currently used in ovarian cancer treatment, but Dr. Telleria has demonstrated that these agents block growth of ovarian cancer cells even after the cells become resistant to standard chemotherapy. Antiprogestins work by allowing abnormal proteins to accumulate in a part of the cell called the endoplasmic reticulum (ER) causing stress to the cell. Dr. Telleria hypothesizes that he can cause more stress and quicker cell death by treating with a proteasome inhibitor in combination with the antiprogestin drug. The proteasome inhibitor would prevent the breakdown and recycling of abnormal proteins in the cell, leading to faster and more dramatic build up of defective proteins and killing the cancer cell. If further testing proves successful, this therapy could be used as a long-term treatment to turn a fatal recurring cancer into a survivable disease.
Angiogenesis, the process of forming a new network of blood vessels from existing ones, is a central hallmark of cancer. In order for a tumor to grow, it must have the blood flow necessary to feed its rapidly dividing cells. A gene called VEGF (vascular endothelial growth factor) is involved in the process of angiogenesis and is often over-abundant in cancer cells. Therefore, researchers developed drugs to inhibit VEGF in an attempt to limit tumor growth. Unfortunately, these therapies have been less than successful because cancers quickly become resistant to the drug, especially ovarian cancers. Dr. Wen previously discovered that the protein p130cas is abundant in ovarian tumor cells, and that it is required for cells to become resistant to anti-VEGF therapy. Therefore, in this study, Dr. Wen and colleagues will try to determine why blocking p130cas stops tumor angiogenesis and evaluate the therapeutic potential of targeting p130cas as a new strategy for treating ovarian cancer. Dr. Wen has collaborated with an expert in nanoparticle drug delivery to develop a biodegradable nanoparticle that will block p130cas and remain circulating in the blood for a long period of time. She will test the efficacy of this particle at inhibiting growth of ovarian tumors in mice that are resistant to VEGF therapy. If successful, this would be an important new strategy for overcoming resistance to anti-angiogenic treatments for ovarian cancer.
Scientists are actively working to find new therapies for ovarian cancer as resistance to current therapies, including PARP inhibitors and cisplatin, poses a major problem in the clinic. One promising approach is to develop strategies that activate the patient’s normal immune system and inflammatory response to fight cancer. Dr. Yull is proposing to use a class of drugs known as BET (Bromodomain and Extraterminal) inhibitors that can modify the normal cells surrounding the tumor for therapeutic benefit. BET inhibitors are thought to have an anti-tumor effect by blocking genes that promote tumor growth in tumors and immune cells. Dr. Yull will test the effects of BET inhibitors alone and in combination with PARP inhibitors on immune cells known as macrophages and on cells in the environment of the tumor using a cancer mouse model. If effective, this innovative strategy has the potential to provide a new tool to combat this deadly disease.
When diagnosed early, ovarian cancer has an excellent prognosis, but current imaging methods for detecting ovarian cancer have not yet yielded the hoped-for benefit. Standard clinical magnetic resonance scanners produce images of poor quality, with low resolution and limited information content. However, magnetic resonance spectroscopy (MRS) could potentially reveal metabolic features of ovarian cancer that would reliably distinguish ovarian cancer from benign ovarian lesions. Dr. Belkic will be optimizing MRS for ovarian cancer detection using her advanced signal processing method, the fast Padé transform (FPT), which has already been shown to dramatically improve resolution and generate high-quality MRS data to detect ovarian cancer.
Dr. Chefetz-Menaker recently demonstrated that chemotherapy resistant ovarian cancer stem-like cells (CSC) can be identified by a protein activity known as ALDH. The expression of ALDH in CSC allows a unique opportunity to develop therapeutics specifically targeting CSC, which are thought to be the cells involved in recurrence. Dr. Cheftez-Menaker has developed novel ALDH inhibitors which appear to induce ovarian CSC cell death via a necroptotic mechanism, which will be explored in this study to expand the understanding of ALDH inhibition-induced necroptosis and provide critical pre-clinical studies for a potential novel CSC targeted therapeutic to prevent recurrent disease.
Granulosa cell tumors of the ovary arise due to dysfunction of the granulosa cells, which are support cells in the ovary, involved in ovulation and production of hormones. Dr. Chu will determine if using therapeutic drugs that act on critical cell signaling pathways, involving key genes for cell survival, will render these tumors more sensitive to chemotherapy. By identifying and manipulating unusual and distinctive patterns of key cell survival genes, he can develop tools for better prognostic indicators and potential new targets for granulosa cell tumor treatments.
Early detection of ovarian cancer represents the best hope for mortality reduction and long-term disease control. Dr. Facciabene’s preliminary data indicate that developing ovarian cancer induces change in the microorganisms found in the gut, also known as the gut microbiome. Previously, controlled studies have demonstrated the existence of skin and saliva microbiome signatures in breast and pancreatic cancer, respectively. Dr. Facciabene hypothesizes that using a combination of next-generation sequencing (NGS) and metagenomics analysis, a sensitive and specific screening test for ovarian cancer can be developed through the analysis of the gut microbiome.
BRIP1 gene has recently been recognized as an ovarian cancer susceptibility gene, based primarily on discovery of mutations that result in a truncated, or shortened, BRIP1 protein that no longer functions properly. Most genetic variation in the BRIP1 gene, however, does not lead to a shortened form of the protein, but some variants may still lead to protein dysfunction. Dr. Goodfellow will determine which BRIP1 gene variants have disrupted BRIP1 protein function and mostly likely could result in the development of ovarian cancer by developing mouse strains carrying defective Brip1 genes to study how certain mutant proteins lead to ovarian tumors. Together, these studies will allow for new approaches to prevent and treat ovarian cancer.
Normal cellular growth is regulated by a process called replication checkpoint. Most ovarian cancers contain the tumor suppressor p53 that is mutated and therefore interferes with proper replication checkpoint function. Dr. Lin’s preliminary data uncovered a novel activity in mutant p53 that is responsible for replication checkpoint defects. By performing a large-scale compound screen, he has identified novel compounds that target the checkpoint defect. Dr. Lin will now test the antitumor activity of two active compounds in ovarian cancer to see if p53 can be targeted to restore replication checkpoint functions that would inhibit cancer growth.
To understand how cancers grow and spread within patients, it is essential that researchers have realistic and simple animal models that accurately recreate the mutations seen in the DNA of human cancers. Dr. McNeish will use a new technique, called CRISPR/Cas9 gene editing, to alter the DNA in a mouse model of ovarian cancer, specifically creating mutations seen in human high grade serous ovarian cancer. This new mouse model will used to identify key abnormalities in the DNA of tumor cells that drive changes in the environment surrounding the tumor, especially the interactions with the immune system.
Regulatory T (Treg) cells are part of the immune system and have been shown in ovarian cancer to suppresses immune cell activity and prevent the immune system from fighting ovarian cancer cells. Dr. Obermajer has shown that another type of immune system cell called T helper 17 (Th17) cells can be converted into Treg cells by the presence of myeloid-derived suppressor cells. She will identify the steps needed to convert Th17 cells into Treg cells and determine whether it is possible to do the reverse conversion of Treg cells into Th17 cells because Th17 cells have a strong anti-tumor activity that can be harnessed to fight ovarian cancer.
Mesothelial cells line the abdominal cavity and play an important role in ovarian cancer metastasis. These mesothelial cells in the presence of ovarian cancer tumors are deprived of oxygen (hypoxic) and, as a result, produce components of the hypoxia inducible factor (HIF) signaling pathway that allow them to “talk” to ovarian cancer tumor cells and promote metastasis. By targeting mesothelial cells in the treatment of ovarian cancer, Dr. Rankin hopes to interrupt the signals that promote metastasis and limit the spread of ovarian cancer cells throughout the patient’s body.
Early detection remains the best approach for successful treatment of cancer, including ovarian cancer, as patients with early stage cancer have the best chance of survival. There is an urgent need to identify specific biomarkers for early detection and to understand the earliest time points in cancer progression to guide effective clinical intervention. Dr. Slack-Davis is developing a novel mouse model for ovarian cancer that can immediately and permanently track individual cells, at the time of the earliest genetic mutations that eventually lead to ovarian cancer. By knowing the earliest genetic mutations, early detection biomarkers can be developed to indicate the presence of ovarian cancer.
Since majority of the ovarian cancer cases are detected at later stages, novel therapeutic approaches are critically needed to improve the overall survival rates. Targeted delivery of therapeutics where drugs can be delivered specifically to the cancer cells without causing damage to normal cells is a promising approach to treat ovarian cancer. Dr. Thiviyanathan will develop a new class of affinity molecules that can recognize the cancer cells. He will use multifunctional nanoparticles made up of RNA to attach the affinity molecules to act as homing devices to deliver the therapeutic drugs to the cancer cells.
A key clinical problem in the management of advanced ovarian cancer is tumor resistance to traditional platinum drugs and to newer drugs that inhibit the PARP protein (PARPi). Dr. Wilson will investigate an innovative approach to improve the effects of platinum drugs and PARPi. He has shown that the TR3 protein, which kills ovarian cancer cells, is reduced in tumors resistant to these platinum and PARPi drugs. By activating TR3 function in ovarian cancer cells that are being treated with platinum drugs and PARPi, he hopes to improve drug response and benefit a large number of women with advanced disease.
PARP inhibitors are among the most promising class of targeted therapeutics for the treatment of ovarian cancer. Patients with mutations in BRCA genes and some patients with sporadic cancers are particularly sensitive to this class of drugs, presumably because of defects in their cells to repair DNA damage. Heat Shock Protein 90 (HSP90) is a molecular chaperone that helps stabilize and regulate the activity of several essential proteins required for DNA damage repair. Based on its role in regulating these essential proteins, Dr. Connolly will test whether inhibition of HSP90 will sensitize tumor cells to PARP inhibition through further preventing DNA damage repair from taking place in ovarian cancer cells, making PARP inhibitors more efficient at killing ovarian cancer cells.
High-grade serous ovarian cancer is strikingly similar to triple negative breast cancer as both can be particularly aggressive cancers and are likely to recur. Dr. Das has found that these two diseases are also similar on the molecular level as both types of cancer cells have a defect in a tumor suppressor gene called p53 and express a cell signaling protein called estrogen receptor beta (ERp). This project will analyze how the protein made by the defective p53 gene works in concert with ER) to influence aggressive cancer growth and therapeutic resistance. Dr. Das will examine ovarian cancer cell lines as well as 400 patient tumors to gain a fundamental understanding of how these proteins drive the progression of ovarian cancer over time.
Targeted agents such as poly-ADP ribose polymerase (PARP) inhibitors are actively being tested alone or in combination with chemotherapy or radiotherapy as promising treatments for ovarian cancer. However, not all patients will respond to and benefit from these therapies. Dr. Lin’s project is to test whether a new imaging technique using a Positron Emission Tomography (PET) tracer for PARP inhibitors can light up areas of known ovarian cancer as well as inform on PARP1 protein activity in tumor biopsies of patients. Developing a non-invasive method to image ovarian cancer patients with tumors exhibiting high PARP1 protein activity would allow better selection of patients for PARP inhibitor therapy by matching the right therapy to the right patient.
Ovarian cancer cells are genetically unstable. A deletion of the gene MTAP, which is involved in methionine metabolism, is found in 3-15% of ovarian tumors. As a result, affected ovarian cancer cells have lost a functional enzyme for metabolizing old proteins which is needed to build new proteins. Dr. Shlomi’s project will identify metabolic “back up” pathways that enable ovarian cancer cells to adapt and continue living despite losing a critical enzyme. Genetic and pharmacological inhibition of these back up pathways would be very useful in targeting and killing surviving cancer cells. He will use the latest technologies including mass spectrometry and computational genome-scale metabolic network modeling approaches to identify the best ways to inhibit the back up pathways.
Recent clinical studies have found that ovarian cancer patients with Th17 lymphocyte infiltrates in tumors enjoy a markedly longer overall survival, suggesting that Th17 cells play a protective role against ovarian cancer. Dr. Cannon designed an innovative approach to dendritic cell vaccination that activates a Th17 T cell response against ovarian cancer, raising the exciting prospect of dendritic cell vaccine clinical trials to stimulate Th17 immunity. However, ovarian tumor associated myeloid cells suppress anti-tumor immunity stimulated by dendritic cells. This project will determine the mechanisms of immune suppression and test drugs that have the potential to alleviate suppression and boost the efficiency of dendritic cell vaccination.
The primary aim of Dr. Hanchette‘s project is to discover whether high rates of ovarian cancer occurrence in the United States correspond with the locations of pulp and paper mills. An association between the two has been reported, using state rates, and is of concern because of the effluents released by the industry. She plans to explore this potential ovarian cancer-paper mill relationship using smaller units of geography, such as counties, which would provide a better approximation of exposure. Dr. Hanchette will use geographic information system (GIS) software for mapping, visualization, spatial statistics, and environmental modeling of pollutants.
Paclitaxel is used extensively for the treatment of ovarian cancer. The overall goal of this project is to test the efficacy and toxicity of a novel paclitaxel drug delivery system, capable of selectively targeting ovarian cancers and thereby increasing tumor cell kill without enhancing toxicity. Dr. Howell has developed a unique dendrimer that can carry paclitaxel and can be loaded with folates so that it binds very tightly to the folate receptors that are present in large amounts in most ovarian cancers, thus increasing the amount of drug that gets into the tumor.
Ovarian cancer is associated with a high degree of heterogeneity (meaning the tumors differ from patient to patient), highlighting the importance of developing individualized treatment. Changes in the levels of the growth factors belonging to the Transforming Growth Factor (TGF-β) family, specifically Inhibin, are frequently found in ovarian cancer. In addition, loss of the receptor for Inhibin on the surface of ovarian cancer cells, namely Type III TGF-β receptor, is also frequently observed. The goal of Dr. Karthikeyan‘s project is to evaluate the pre-clinical feasibility of specifically targeting Inhibin so that it will interact with one class of receptors and not another in order to prevent Inhibin‘s ability to promote tumor growth and metastasis, thereby improving personalized treatment strategies for ovarian cancer.
Next-generation sequencing of single cancer cells identified from the blood of ovarian cancer patients can potentially guide treatment decisions, identify recurrence early, and lead to earlier and more accurate diagnosis of the disease. Dr. Kuhn will use a “fluid biopsy” to extract rare tumor cells (also known as circulating tumor cells or CTCs) that travel in the blood far away from the main tumor. He will obtain genetic information from cells captured at multiple time points over the course of the disease to investigate if certain genetic markers correspond to the patient‘s cancer status. This will lay the foundation for guiding treatment decision at every clinical visit.
Platinum-based chemotherapy is prevalently used for the treatment of ovarian cancer. The prognosis for patients with platinum-resistant ovarian cancer is extremely poor, and new treatments for this disease are urgently needed. Dr. Nawrocki‘s preliminary data indicate that protein degradation may be an essential process that is required for resistance to platinum-chemotherapy as its inhibition reverses cisplatin resistance in ovarian cancer models. The goal of this project is to define the mechanisms by which protein degradation regulates chemosensitivity. He hypothesizes that protein turnover is required for the development of resistance to platinum chemotherapy and that it can be targeted to improve overall survival.
Patients with late stage clear cell ovarian carcinoma have poorer survival rates than the more common high-grade serous ovarian carcinomas. Current therapies are not effective for this aggressive cancer. Dr. Wong‘s preliminary data suggests that targeting the mTOR pathway, which is frequently activated in cancers and also implicated in cell growth, protein synthesis, invasion, and cell metabolism, is a promising strategy to treat clear cell ovarian carcinomas. He hypothesizes that it will be more effective to kill the cancer cells if both the mTOR and c-Myc pathways are targeted. In this project, he will use a pre-clinical mouse model to investigate the efficacy of combining two inhibitors, one for each pathway, in treating clear cell ovarian carcinoma.
Tumors have elaborate suppressive mechanisms against host immune system to enhance their survival. Ovarian tumors highly express a protein called CD73 that limits anti-tumor immune response in order to promote tumor growth. Dr. Zhang‘s recent research demonstrates that CD73 may serve as an emerging immune target for ovarian cancer treatment. In this project, he will evaluate the efficacy of CD73 blockade with an FDA-approved drug as a novel means to enhance ovarian cancer immunotherapy. He hopes open the door for the rapid translation of these preclinical findings into the clinic for effective ovarian cancer treatment.
Despite advances in treatment, almost 80% of ovarian cancer patients suffer disease recurrence and succumb to the disease within 5 years of diagnosis. Cancer stem cells are a small population of drug resistant tumor cells that survive chemotherapy treatment. These cells are capable of initiating new tumor growth and therefore contribute to ovarian cancer recurrence. Dr. Ahmed will utilize novel and known methods to isolate circulating cancer stem cells from the ascites (tumor fluid) of ovarian cancer patients before and after chemotherapy treatment to identify targets which support cancer stem cell survival and chemotherapy resistance.
Failure to understand key mechanisms contributing to the onset of high-grade serous ovarian cancer represents a barrier to diagnosis and treatment of this fifth-leading cause of death among American women. One of the likely factors promoting the disease is lesions in transcription elongation Cdk12/CycK complex, whose recurrent mutations have been identified. By generating human primary cell-based model cell lines containing these mutations, Dr. Barboric will examine the possible tumor suppressor function of Cdk12/CycK complex as well as its target gene regulatory circuitry, of which perturbations may be critical for the onset and maintenance of ovarian cancer.
Recent comprehensive genomic analyses of patient samples have revealed the virtually unstudied cyclin-dependent kinase 12 (Cdk12) as a novel player in ovarian tumorigenesis. Dr. Blazek has already determined that Cdk12 maintains genome stability via the transcriptional regulation of key DNA-damage response genes, including BRCA1, ATR, and FANCI, identifying this kinase as a potential tumor suppressor. However, the precise molecular mechanisms leading to Cdk12-dependent ovarian tumorigenesis are unknown. The goal of this project is to attain an initial molecular understanding of these deregulations, which could eventually lead to the development of novel therapeutic approaches for ovarian cancer.
Tumors contain thousands of DNA alterations, making it difficult to identify the causal factors of the disease. This proposal applies high-throughput screening approach to assess 500 genes for their ability to promote tumor growth. Dr. Cheung identified GAB2 as a potent cancer-causing gene whose copy number is abnormally increased in 36% of primary ovarian tumors. He will investigate the signaling mechanisms underlying its cancer-causing effect and evaluate the efficacy of rational targeted agents in treating advanced patient-derived primary ovarian tumors in mice. Credentialing novel cancer-causing genes represents the first crucial step towards developing more effective targeted therapy for treating ovarian cancers.
Tumor suppressor proteins are natural cellular defense mechanisms against cancer because they keep tumor-causing proteins under control by promoting their degradation. OPCML is such a tumor suppressor; however, it is inactive in most cases of ovarian cancer. Dr. Gabra’s project aims to develop treatment for ovarian cancer by restoring OPCML presence in cancerous cells in the ovaries. In this entirely novel therapeutic approach, non-infectious virus-like particles will be used as vehicles to deliver the OPCML protein to cancer cells. Viroprotein therapy is very promising for cancer because it bypasses the clinical limitations of gene therapy. It also holds a great potential to be developed as therapy for many other types of cancer.
The Lounsbury/Francklyn labs have discovered a role for the enzyme threonyl tRNA synthetase (TARS) in promoting blood vessel growth (angiogenesis) in ovarian cancer. These studies led to the characterization of a selective TARS inhibitor that reduces angiogenesis in a living system. Dr. Lounsbury’s project is a pre-clinical study to determine the impact that TARS inhibition has on an animal model of ovarian cancer. Furthermore, this study will determine if TARS levels are elevated in blood samples from patients with ovarian cancer. The results of this study may thus identify a new target for both treatment and diagnosis of ovarian cancer.
The spreading of cancer cells from the primary ovarian tumor to distant organs within the abdomen is the most critical step in ovarian cancer. Yet it remains the least understood aspect of the disease. Using unique and clinically relevant experimental models, including primary human cells, that replicate the early steps of metastatic tumor formation in patients, Dr. Mitra will investigate a novel mechanism of gene regulation that promotes metastasis. This will improve our understanding of the regulation of this key step and will help us to develop novel and effective therapies for ovarian cancer.
Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies. Despite aggressive treatment, recurrence is common with poor survival. Dr. Said has recently reported the loss of expression of the tumor suppressor of the glycoprotein SPARC in advanced OvCa. However information about its tissue-specific regulation is elusive. Our overall objective is to understand the regulation of SPARC in OvCa by inflammation. The central hypothesis is that the inflammatory micro-environment of OvCa inactivates SPARC expression and promotes disease progression. The proposed studies are likely to generate important new clinically relevant mechanisms and biomarkers for targeted therapies.
G129R, a molecular antagonist to tumoral PRLR, robustly inhibits tumor growth through formation of excessive autophagosomes in ovarian cancer cells. Dr. Wen will explore the regulatory mechanism of G129R-induced autophagy in ovarian cancer cells and therapeutically evaluate the potential for G129R in treatment of epithelial ovarian cancer. This project will also determine the effect of G129R in tumorigenic properties of ovarian cancer stem cells, which are tightly associated with the recurrence of ovarian cancer. The expected outcomes will generate preclinical evidence for G129R as a novel chemotherapeutic drug and for promoting suicidal autophagy as a therapeutic strategy against ovarian cancer.
The heterochronic pathway orchestrates the timing of cell divisions and fates during development. Its core elements, LIN28 and the microRNA let-7, form bistable switches via a double-negative regulatory loop. Dr. Zhang has previously reported that let-7 is downregulated in epithelial ovarian cancer and functions as a critical tumor suppressor. A systematic review shows that let-7 is the microRNA that is most frequently and significantly associated with outcomes in ovarian cancer. Importantly, let-7 replacement therapy has been successfully tested in preclinical animal models. Thus, Dr. Zhang proposes that reconstruction of the heterochronic pathway is a novel strategy for epithelial ovarian cancer treatment.
Better understanding of molecular mechanisms contributing to the onset of high-grade serous ovarian cancer will advance improvements in diagnosis and treatment. Dr. Barboric will investigate the deregulation of a novel transcription elongation kinase Cdk12/CycK, whose recurrent mutations have been identified recently. Using newly developed epithelial ovarian model cell lines harboring these mutations and systems biology approaches, this project will reveal how mutated Cdk12/CycK kinase perturbs gene expression programs and interactions with its associated factors, giving insight into deregulated biological processes that underlie the genesis of ovarian cancer.
Small Cell Carcinoma of the Ovary (SCCO) is a lethal form of ovarian cancer striking young women and girls (average age at diagnosis is 23 years). Dr. Cunliffe hypothesizes that the very early onset and highly aggressive nature of SCCO suggests a consistent underlying genetic lesion, and thus a potential therapeutic vulnerability. The project’s objective is to identify the full spectrum of molecular changes associated with SCCO to define clinically actionable targets. In addition, she proposes to develop preclinical laboratory models of SCCO to enable future studies designed to confirm mechanisms of targeted drug sensitivity, and accelerate translation of discoveries into to clinical practice.
Immunotherapy theoretically should be effective for ovarian cancer but only has modest effects because of ovarian cancer-related immune dysfunction. Dr. Curiel will use a well-established pre-clinical mouse model to test rationally designed combinations of agents that should be synergistically useful to treat OC based on known and hypothesized mechanisms of action of selected agents and targets. Agents used are FDA-approved or already in human trials, speeding translation. The current project combines the two most effective cancer immunotherapies known based on preliminary data – anti-PD-1 and anti-B7-H1 – to test for synergy in improving immune responses against ovarian cancer.
Millions of ovarian cancer survivors live with residual symptoms of impaired thinking and impaired memory severe enough to interfere with basic activities of daily living and work. However, very little is known about how to treat problems in cognition. Pharmacologic interventions have only been modestly helpful, if at all, and not all patients desire or are able to take medications. Dr. Gray will examine the ability of a 7-week cognitive rehabilitation intervention to improve memory and thinking abilities in ovarian cancer survivors. In addition, the project will measure changes in brain activity patterns from the treatment using neuroimaging.
Acquired chemoresistance, in which patients whose tumors initially respond to cisplatin ultimately relapse with drug-resistant disease, is a major factor in the low survival rate among ovarian cancer patients. To address this clinical problem, it is absolutely necessary to understand the molecular and genetic changes that drive the development of chemoresistance and allow ovarian cancer cells to survive in the presence of cisplatin. Dr. Hooks’ lab has shown that RGS proteins are suppressed in chemoresistance and control cell sensitivity to cisplatin. The goal of the project is to test the hypothesis that RGS proteins control cell survival by two complementary pathways. The long-term benefit of this work will be to guide efforts to reverse the amplification of ovarian cancer cell survival.
Immunosuppression that prevails in ovarian tumor microenvironment is the main reason for the recurrence of disease in ovarian cancer patients. Blockade of suppressor cells and/or immune inhibitory networks during vaccination has great chance at reducing recurrence among patients. PD-1/B7-H1 axis is a major inhibitory pathway in ovarian cancer. This pathway is known to negatively regulate anti-tumor T cells but Dr. Karyampudi’s recent study shows that PD-1+ dendritic cells mediate immunosuppression in ovarian cancer. This project will aim to understand these dendritic cells in order to develop successful vaccination strategies aimed at targeting PD-1/B7-H1 axis in ovarian cancer.
Stem-like cancer cells are thought to play a key role in both chemoresistance and relapse, both of which can occur following treatment of advanced ovarian cancer. Stem-like cancer cells are maintained and supported by niches enriched in immune cells. Dr. Kryczek’s project will document the role of myeloid-derived suppressor cells in regulating genetic and epigenetic mechanisms which stabilize and maintain stem-like cancer cells. Myeloid-derived suppressor cells massively infiltrate the ovarian cancer tumor environment (primary and metastatic tumor as well as peritoneal fluid) and utilize distinct signaling pathways, thereby contributing to the opposing biological functions that promote stability and survival of stem-like cancer cells.
The CDK inhibitor p27KIP1 is traditionally viewed as a tumor suppressor by inhibiting cell cycle progression. However, the cytosolic mislocalized p27KIP1 can induce ovarian cancer cell invasion. Dr. Lin has shown that these opposing effects are regulated through the interaction of p27KIP1 with the adaptor protein TRIP6, which is expressed at high levels in ovarian cancers. TRIP6 cooperates with AKT to promote the oncogenic effect of cytosolic p27KIP1 but regulates growth factor-induced nuclear p27KIP1 degradation to promote cancer cell proliferation. This project aims to elucidate the novel mechanisms and consequences of these regulations to find better strategies for ovarian cancer therapy.
Dr. Nanjundan proposes that endometriosis, an inflammatory gynecological disease, is a “precursor lesion” leading to the development of endometrioid/clear cell ovarian cancers. Although less frequent relative to serous ovarian cancers, often the prognosis is worse. This project will investigate whether “autophagy,” a survival mechanism which could be activated in response to iron (a product of heme elevated in endometriotic cysts), is involved in the transition from endometriosis to ovarian cancer.
Cancer cells that are able to perform homology-directed repair (HDR) can be resistant to PARP inhibitor therapeutics, which are purposefully designed to cause DNA damage. Many ovarian cancers apparently lack the HDR pathway, and hence are likely to be sensitive to PARP inhibitor therapy. Dr. Stark has found that HDR-deficient cells show biomarkers for unstable DNA. This project will determine whether these biomarkers for unstable DNA can identify individual ovarian cancers that have lost the HDR pathway, and hence are likely to be responsive to PARP inhibitor therapy. Accurately identifying ovarian cancer patients that will likely respond to PARP inhibitor will accelerate the development of this promising therapeutic approach.
Dr. Abbott’s work is focused on discovering new tumor-specific targets on the surface of cancer cells. Tumor-targeted therapy regimens will have less toxic side effects to normal tissues, and lead to a better quality of life for patients. This project is based on a recent discovery of a unique type of carbohydrate (glycan) found on proteins that cover the surface of ovarian tumor cells and not normal ovarian cells. The membrane receptors that help this glycan stick to the surface of tumor cells will be identified and subsequently used for the development of tumor-targeted therapeutics in the future.
Around 70% of women diagnosed with ovarian cancer have advanced disease and the prognosis is very poor. Treatment for ovarian cancer consists of surgery followed by chemotherapy. One of the contributing factors to the poor prognosis for advanced ovarian cancer is due to tumor cells becoming resistant to chemotherapy. This project aims to understand how a new overexpressed gene (ARID3B) is regulated in ovarian cancer and how different forms of this gene contribute to chemoresistance. These studies will further the understanding of genes that are involved in ovarian cancer and chemoresistance in order to better treat ovarian cancer patients.
Too little is known about the genetic lesions responsible for ovarian cancer tumor initiation, and uncertainty remains over the specific cell or cells of origin. Data emerging from The Cancer Genome Atlas (TCGA) on the many genomic alterations in serous ovarian carcinoma has delivered a treasure trove of new candidates for investigation, but discerning which gene alterations are critical early events in cancer pathogenesis, how tumors evolve to their highly aggressive state, and which pathways represent the best therapeutic targets will require a large scale collaborative research effort. Animal models developed in Dr. Dinulescu’s lab, which accurately recapitulate the human disease, constitute great tools for defining the key roles that ovarian cancer cells in the ovarian surface epithelium and distal fallopian tube play in tumor initiation and resistance to chemotherapy. Furthermore, they provide us with unique, relevant in vivo systems in which to screen novel molecularly targeted therapies as they become available.
Women carrying mutations in the breast-cancer associated 1 or 2 (BRCA1/2) genes are at higher risk for developing epithelial ovarian cancer. BRCA1/2 play critical roles in repairing DNA and helping genes avoid mutation. Interestingly, BRCA1/2 is not functioning optimally in cases of sporadic epithelial ovarian cancer, and BRCA2 and Aurora A interact in cells to regulate genomic stability. Dr. Do will test the hypothesis that Aurora A and BRCA1/2 interact to mediate DNA repair and cell growth. An Aurora A kinase inhibitor and a PARP inhibitor will be tested as therapies for ovarian cancer.
Understanding of epithelial ovarian cancer development is critical for designing effective diagnostic and therapeutic approaches. During recent years it has become increasingly clear that cancers may arise from stem and progenitor cells. However, the location of the stem cell compartment of the ovarian surface epithelium that give rise to cancer cells remains unknown. Dr. Nikitin will explore a newly identified stem cell compartment in the ovary and determine properties of these stem cells and their contributions to epithelial ovarian cancer.
Adoptive immunotherapy is extremely effective for triggering tumor regression in patients with malignant melanoma. To develop adoptive T-cell therapy for epithelial ovarian cancer, we have created a chimeric immune receptor (CIR) that redirects the immune system against alpha-folate receptor, a protein on the surface of 90% of epithelial ovarian cancer cells. In designing this therapy, other strategies that will be taken into account including promoting growth and survival of the body’s own immune cells to fight ovarian cancer. The results of Dr. Powell’s work will provide preclinical data essential for clinical development.
No one knows what microenvironmental interactions control ovarian cancer metastasis. Getting this crucial information requires a fresh look from a new perspective. Recently Dr. Rinker-Schaeffer’s lab made a novel connection between ovarian cancer metastatic colonization and structures on the omentum (tissues in the abdomen) that contain immune cells and are called milky spots. It is suspected that cancer cells take advantage of milky spots to promote their own survival and growth. This project will identify interactions between omental immune cells and cancer cells that can be targeted in combination with current therapies in order to suppress metastatic growth, improve quality of life, and extend disease-free survival.
Adoptive immunotherapy can induce cancer regression but rarely results in cure. We have infused HER2-specific Th1 cells in breast cancer patients, and 50% of patients had a partial or complete response to the treatment. Dr. Salazar hypothesizes that Th1/Th17 immune cells that can recognize tumor cells can have enhanced therapeutic efficacy. This project will determine the optimal conditions to grow these multifunctional immune cells in the lab in order to enhance their ability to identify and target cancer cells using IGFBP2. Results from this project will lead to a phase I study of adoptive immunotherapy in ovarian cancer after priming with an IGFBP2 vaccine.
The molecular basis underlying the range of ovarian cancer patient responses to chemotherapeutic agents is poorly understood. This project will address the urgent need to stratify ovarian cancer patients for therapy and enhance currently available treatment strategies. Recently, Dr. Sawicki’s lab discovered that the stress response protein, HuR, can mediate therapeutic efficacy of gemcitabine and a PARP inhibitor, two drugs currently used to treat ovarian cancer, by rapidly binding and regulating cancer-associated mRNA transcripts. Therefore, HuR may serve as both a potential predictive marker for drug efficacy and a promising target for therapeutic manipulation for the treatment of epithelial ovarian cancer.
The function of kinases is to turn proteins on and off in cells. Aurora A kinase is one such kinase whose levels increase early in ovarian cancer and are associated with poor prognosis. By identifying the proteins that Aurora A kinase turns on and off in ovarian cancer cells that are not affected in normal cells, Dr. Shah can design drugs to inhibit Aurora A kinase from doing its job and reverse the cascade of proteins that are involved in progression of ovarian cancer. Safer drugs can be developed which target only ovarian cancer cells while avoiding normal cells.
The origins of ovarian cancer are poorly understood but most cancers seem to arise from the surface layer of cells on the ovary or the fallopian tube. Ovarian surface epithelial cells have the ability to develop into ovarian cancer subtypes that fall into two broad categories: low-grade and high-grade. Previous work shows that changes in a protein, PAX2, occur in the earliest cancerous structures in both ovaries and fallopian tubes. Dr. Vanderhyden’s lab has developed methods to isolate both ovarian and fallopian tube cells from mice and will determine how changes in PAX2 contribute to the early stages of ovarian cancer.
Women who inherit a mutation in the BRCA1 gene have a 40% risk of developing ovarian, tubal, or peritoneal cancer. Dr. Walsh is seeking to shed light on genetic and molecular events that lead to tumor development in some women in this high-risk population but not in others. A significant difference in the genetic sequence of the PARK2 gene distinguishes BRCA1 mutation carriers that do develop cancer from those who do not develop cancer. This project will further investigate PARK2, which is mutated in other cancers and has a tumor suppressor function, by looking at its role in the biology of BRCA1-associated gynecologic cancer development.
High grade papillary serous carcinoma may arise from serous tubal intraepithelial carcinoma in the fallopian tube. MiR-182 is a small RNA molecule that is significantly overexpressed in both types of carcinomas. Dr. Wei hypothesizes that miR-182 overexpression is a critical and early molecular change in papillary serous carcinoma. He will use normal fallopian tube secretory epithelial (FTSE) cell lines to investigate whether adding miR-182 in large amounts will result in tumors and whether miR-182 causes tumors via target genes BNC2 and MTSS1 known to be involved in papillary serous carcinoma. The results will provide a new marker in early detection and a potential therapeutic target for PSC.
While platinum-based drugs continue to be the foundation of therapy for ovarian cancer, chemoresistance remains the main challenge for effective management of recurrent disease. The development of new therapeutic strategies to combat ovarian cancer is needed. This study will examine the therapeutic potential of Bmi-1, a polycomb group (PcG) gene, in ovarian cancer and chemoresistance. Bmi-1 plays a key role in regulating the ability of normal stem and progenitor cells to grow. This group showed that ovarian cancer cell lines and tumor tissue have a higher Bmi-1 expression than normal ovary cells. They also found that a micro-RNA that regulates Bmi-1 when present in sufficient quantities is less abundant in ovarian cancer. Finally, they showed that reducing Bmi-1 in cancer cells made the cell less able to grow and susceptible to chemotherapy. Bmi-1 potentially plays a key role in mediating drug resistance in ovarian cancer. As such, Dr. Bhattacharya and her team will evaluate the clinical significance of Bmi-1 in ovarian cancer by comparing gene expression to stage/grade and outcome and determine the benefit of targeting Bmi-1 in disease progression in a mouse model.
While effector lymphocytes are known to mediate anti-tumor immune responses, regulatory T cells (Tregs) have recently been found to promote tumor progression in ovarian cancer patients. Perforin and granzyme B are cytotoxic molecules previously known to be utilized by effector lymphocytes to kill tumor cells. However, Dr. Cao’s recent studies suggest that Tregs utilize the perforin/granzyme B pathway to suppress anti-tumor immune responses. Therefore, Dr. Cao and his team will study ovarian cancer patients and mouse models to characterize the contribution of this pathway in effector lymphocyte-mediated anti-tumor immunity vs. Treg-facilitated tumor progression, and to dissect the mechanisms of granzyme B-dependent Treg function.
An exciting new hypothesis in ovarian cancer biology is that tumor development is driven by cancer stem cells, which are resistant to standard chemotherapies and consequently responsible for the high rate of tumor relapse seen in patients. Animal models, which accurately recapitulate the human disease, used in Dr. Dinulescu’s laboratory constitute great tools for defining the key roles that ovarian cancer stem cells play in tumor initiation and resistance to chemotherapy. Furthermore, they provide her team with unique, relevant systems in which to screen novel nanotechnology-based therapies specifically targeting ovarian cancer stem cells that show increased efficacy and lower toxicity than currently available chemotherapy drugs.
Ovarian cancer is an important cause of death and inherited susceptibility accounts for a substantial fraction of this cancer. Moreover, advances in knowledge of hereditary forms of cancer have led to insights into the more common, non-hereditary forms. Technological innovation is a key to the generation of knowledge and has recently brought revolutionary changes in the ability to study cancer. Here, Dr. Foulkes and his team will harness the power of “deep sequencing” to discover mutations that are important in ovarian cancer. This pilot study could lead to important discoveries that will help us in our struggle to better understand this often fatal disease.
Based on his previous work and recent results, Dr. Xiaolong He hypothesizes that microRNA miR-124 may function as a tumor suppressor. In this study, two specific aims are proposed to strengthen the hypothesis. Aim 1 is to examine the levels of miR-124 in human ovarian tumors and thus establish the clinical relevance of this hypothesis. Aim 2 will explore why miR-124 is reduced in ovarian cancer cell lines. Should Dr. He’s hypothesis ultimately prove correct and supported by experimental results, it will have a significant impact on our understanding of how ovarian cancer develops and likely lead to new approaches to treat this fatal disease.
CTR2 has shown to be a particularly attractive target against which to develop a drug that both inhibits tumor growth and sensitizes to platinum drugs. In this project, Dr. Howell will establish a robust assay to evaluate the function of CTR2 that can be used to identify molecules that can serve as the starting point for subsequent structure-activity studies and refinement of structure to produce a lead compound for pre-clinical testing. Dr. Howell’s group feels that this can be achieved by first screening to find molecules that enhance cisplatin toxicity, then conducting a secondary screen that directly measure the cellular uptake of cisplatin and its interaction with DNA. The specific aims are to 1) establish a primary assay that detects a CTR2-specific increase in the toxicity of a low concentration of cisplatin and 2) establish a series of secondary screens that quantify the CTR2-dependent cellular accumulation of cisplatin and its ability to damage DNA.
Currently, post-operative chemotherapy for patients with sporadic and BRCA-associated ovarian cancers includes treatment with taxanes and platinum. However, there is an indication that patients with BRCA-associated cancers respond less favorably to taxanes. Dr. Orsulic has identified that a target of taxanes, TUBB4, is upregulated in BRCA1-deficient cells. She and her team will test the hypothesis that TUBB4 plays a role in modulating cell chemosensitivity to paclitaxel. The results of this project will impact the use of taxanes as standard of care for patients with advanced ovarian cancer and allow for the better identification of patients who are less likely to benefit from this drug.
In preliminary studies, Dr. Lieber’s laboratory has identified new markers for ovarian cancer ovca stem cells. In this new study, his team will continue to address the concept of ovarian cancer stem cells and the phenotypic plasticity of ovarian cancer cells. Dr. Lieber proposes that various subsets of ovca stem cells exist that may alter phenotype depending on external factors (such as chemotherapy). He will be using a new approach to determine whether tumors arise from a single progenitor cell by tracking lentiviral intergration sites in primary ovarian tumors grown in mice with and without cisplatin treatment. This study will expand his team’s search for cancer stem cell markers and their attempt to track single cancer stem cells in tumors after transplantation into mice, and will contribute to a better understanding of treatment resistance of ovarian cancer.
Preliminary results have led to the hypothesis that TR3 is a marker of chemotherapy-induced apoptosis and a potential therapeutic target in ovarian cancer. In this study, three aims will be investigated by Dr. Wilson and his team. First, knockdown studies will be done to determine if TR3 is mechanistically involved in the tumor cell response to HDAC inhibitors or DNA-damaging agents. In the second aim, mitochondrial translocation will be assessed using immunoflourescence and subcellular fractionation. Lastly, TR3 expression will be correlated with response to therapy in both cultured cell lines and in human ovarian cancer specimens. Results will provide a valuable extension of Dr. Wilson’s work to determine the utility of TR3 as a biomarker and therapeutic target for future treatment of ovarian cancer.
It has been estimated that 44% of ovarian cancer patients use Complementary and Alternative Medicine (CAM). While many CAM treatments are safe, several that may be commonly used are contra-indicated during active conventional treatment. Dr. Anderson’s study seeks to conduct a cross-sectional survey of 300 women in treatment that would include detailed analyses of women’s stage of disease and use of conventional and CAM treatments. This would allow exploration of issues associated with counter-indicated CAM use by ovarian cancer patients.
Nuclear Factor kappa B (NF-kB) is a family of proteins that regulate the levels of genes involved in cell growth and survival and are present in many different types of cells. Dr. Annunziata’s research completed under a MRC Scientific Scholar Award found that NF-kB signaling was active in a defined group of ovarian cancer and importantly these cancer cells stopped growing when treated with a drug that blocked NF-kB activity. This study will test the hypothesis that NF-kB activity in ovarian cancer is caused by changes in key NF-kB regulator proteins.
Women with a higher number of ovulations throughout their lifetime, without breaks due to pregnancy or oral contraceptives, have increased ovarian cancer risk. Dr. deFazio’s study aims to identify the genes that participate in the ovulation process in normal cells and become dysregulated and contribute to the development of ovarian cancer. Identifying these genes could help identify high risk women who can be targeted for screening and prevention strategies.
Cancers adopt diverse strategies for immune evasion to safeguard their survival. The activating immunoreceptor NKG2D and its tumor-associated ligand MICA are key components in the human lymphocyte defense against cancer. Dr. Spies has discovered that solid tumors including ovarian cancer paradoxically express NKG2D. Preliminary data support the idea that NKG2D complements the presence of MICA in a stimulatory loop that may promote tumor survival. Validation of this model may advance knowledge of ovarian cancer development and malignancy and thus impact approaches to therapy.
Recent data suggest that many presumed ovarian or peritoneal carcinomas may actually arise in the fallopian tubes (FT). If true, early detection of ovarian carcinoma should focus on viewing and sampling the FT. A new technology has been developed at the University of Washington, providing high resolution, small size and flexibility needed to enter and transverse the FT. Dr. Swisher’s study will provide pilot data from eightwomen to demonstrate that FT imaging in high risk women is safe and effective and could be performed in an out-patient setting.
Overcoming platinum-resistance in ovarian cancer patients remains a great challenge. Recently, histone deacetylase (HDAC) inhibitors are being used to minimize resistance. HDAC6 may confer the cisplatin-resistance by down-regulating a DNA repair complex. Dr. Zhang will investigate three aspects by which HDAC inhibitors sensitize cisplatin resistant ovarian cells and may identify HDAC6 as a therapeutic target for platinum-resistance in ovarian cancer.
PAPP-A is a protein that has been shown to reduce tumor incidence and burden. Using a PAPP-A mouse model, Dr. Boldt will examine the development of growth of ovarian cancer and the immune response. The results will provide insight into the role of PAPP-A in ovarian cancer and may indicate it as a potential target for developing therapy.
This study will examine ovaries removed during prophylactic (preventative) surgery, before ovarian cancer is discovered or suspected. The hypothesis is that aberrant DNA methylation can be detected in the blood of women prior to the onset of clinical symptoms. Researchers will examine changes in DNA to establish a biomarker panel that would identify the development of ovarian cancer at the earliest possible time.
Folate-receptors are relatively absent in normal tissues but overexpressed on cancer cells. Therefore, folate-receptor targeted contrast agents have the potential to provide cancer specific imaging. By targeting these receptors so they will appear vividly in magnetic resonance imaging (MRI), this study seeks to improve the ability to diagnose ovarian cancer with a new imaging technique.
Mesothelin is a plasma membrane antigen expressed in significantly high levels in mesothelioma and ovarian cancer patients. This study will test the hypothesis that ovarian cancer cells are biologically dependent on the expression of mesothelin for their survival. The results will provide a suitable basis for evaluating mesothelin silencing as a treatment strategy against ovarian cancer.
With over 80 genes and 200 transcripts implicated in the development of ovarian cancer, there are little similarities among ovarian cancer. It is the goal of this study to identify those genes that are singularly critical to the genesis of the disease which therefore hold promise for therapy, diagnosis and prognosis.
This study aims to improve a woman’s prognosis by adding a therapeutic vaccination to encourage the body to mount an anti-tumor response using the secreted growth regulatory protein TGFβ (transforming growth factor). Dr. Hellstrom has shown that a mouse tumor engineered to inhibit TGFβ becomes effective as a vaccine and here will study similarly engineered human ovarian cancer towards developing a therapeutically effective vaccination.
T helper cells (Th), a sub-group of white blood cells, play a crucial role in inflammatory responses and autoimmune diseases, but are poorly understood in human pathology. By using our well-established human ovarian cancer model, we propose to map out the basic knowledge of the nature of IL-17+ T cell in human ovarian cancer. Our project will lay a conceptual framework by which Th17 biology may be used to develop new strategies to treat human cancers.
Protein growth factors belonging to the transforming growth factor beta (TGFβ) superfamily, which include bone morphogenic proteins (BMPs), influence the growth, motility, and invasive potential of ovarian cancer cells. Blocking of these pathways may produce a more epithelial-like or “non-cancer-like” cell. These studies will test whether blocking BMP interactions in the cell will lead to reducing tumor burden in patients and shed light on the molecular mechanisms underlying BMP pathways.
MicroRNAs are a recently discovered class of genes, important for regulation of critical proteins in the cell. We have identified a family of p53-regulated microRNAs (p53 is a protein central to many of the cell’s anti-cancer mechanisms) that are found at reduced levels in human epithelial ovarian cancer. Our preliminary results indicate that re-expression of these microRNAs reduces proliferation, adhesion-independent growth and tumorigenicity of ovarian cancer cells.
Immune cell migration into ovarian cancer is an important way in which the tumor is recognized as abnormal and killed by the immune system. Ovarian cancer tumors produce high amounts of a protein called SDF-1, thereby preventing immune cells to protect the body against the disease. This proposal aims to block the production of SDF-1 by ovarian cancer and thereby allow immune cells to eradicate the tumor.
Platinum compounds are key drugs for the treatment of ovarian cancer and often help patients gain initial remission. However, some patients do not respond, called “primary platinum resistance.” To understand why this happens, we will analyze ovarian tumors with primary platinum resistance in patients with BRCA1/2 mutations. Our study may clarify why the resistance occurs and eventually lead to the establishment of a strategy to overcome this problem.
This project will compare global gene expression patterns across human and a novel genetically engineered mouse model of epithelial ovarian cancer in order to identify relevant molecular pathways and candidate genes that are essential for ovarian cancer development. This unique approach of cross-species comparisons should lead to the discovery of early markers of detection and novel therapeutic targets for drug development that are much needed for this disease.
A well-studied growth regulator in the development of ovarian cancer is the “oncogene” known as ErbB3/HER-3. There are several naturally-occurring variants of ErbB3 which are difficult to distinguish by currently available methods. We believe that developing accurate and specific tests for each ErbB3 variant will allow physicians to make predictions about the aggressiveness of a given ovarian tumor, whether the tumor will respond to a given treatment, and whether the patient will relapse following treatment.
Low-grade ovarian serous carcinomas (OSCs) appear to be a continuum from borderline tumors, and is often resistance to chemotherapy. The possible progression from borderline tumor to low-grade OSC will involve the acquisition of the ability to invade or destroy the underlying tissues. In this study, we will test a set of highly expressed genes (potential therapeutic targets) to determine their involvement in the invasive characteristics of low-grade ovarian cancer.
Ovarian cancer, like all cancer, is a disease of gene malfunctions. This study will look at a gene known to control cancer cells (PIK3CA) and the proteins it interacts with. These proteins hold potential for being therapy targets for treating ovarian cancer.
This study seeks to determine whether a simple urine test for a protein called Bcl-2 may serve as a new biomarker for detection of ovarian cancer.
This study seeks to find a blood-based DNA pattern (as opposed to a single specific target) that could be used to detect ovarian cancer early.
TRIP6 is a novel molecule that helps make cancer cells immortal, thus allowing cancer to grow uncontrolled. This study will determine if silencing TRIP6 can increase the effectiveness of chemotherapy.
This study will look at a family of genes (STAT3) and their impact on the process of cell death. With a greater understanding the role of STAT3, researchers hope to improve bevacizumab, a known therapy for ovarian cancer.
This study will confirm the expression and activity of two important enzymes and investigate the effects of inhibiting these enzymes. The results will provide information regarding their role in ovarian cancer and have an impact on screening, surveillance and treatment strategies for patients.
It is believed that the vascular cell adhension molecule-1 (VCAM-1) aids in the adhesion and spreading of ovarian cancer in the abdomen and beyond. By defining the role of VCAM-1, this work could lead to a target for treatment possibilities.
Dr. Yee is studying a new technique to treat women with late stage ovarian cancer. T cells are collected from patients and responder cells are enhanced. These are given back to the patient, where the patient’s immune system should recognize these cells and use them to fight the cancer.
γ synuclein (gamma synuclein) is a protein that may shuttle other proteins which promote the growth and spread of cancer. This study will identify these protein promoters and assess whether γ synuclein could be used in screening.
Epithelial ovarian cancer is the leading cause of death among gynecological cancers. We will actively discover, identify and validate disease biomarkers associated with early disease. The data collected from these key preclinical studies will be instrumental in designing successful clinical trials involving novel, molecularly targeted therapies and screening means for early detection. This work will allow us to test the efficacy of targeted therapies in ovarian cancer, improve the chemotherapies currently used, and better understand the mechanism of tumor chemoresistance. A sustained research effort in the areas of screening and treatment will dramatically improve the prognosis of ovarian cancer patients, as has been proven in other women’s cancers, such as breast and cervical cancers.
Telomerase is an enzyme that maintains and protects the ends of chromosomes, the telomeres. While telomerase is constrained in many normal adult cells, a majority of cancers appear to depend on active telomerase for their growth, making this enzyme an attractive target for new anti-cancer therapies. Two telomerase targeting methods have been developed in the laboratory of our collaborator, Dr. Elizabeth Blackburn. Both of these approaches, hairpin siRNA and MT-TER, singly and in combination have been shown to block growth of a variety of cancer cell lines in vitro. The goal of this study is to test the efficacy of these telomerase-targeting approaches in a nude mouse model of human ovarian cancer with ascites and intraperitoneal carcinomatosis developed in our laboratory. Ultimately we hope these new methods will decrease human ovarian cancer burden and ascites and lengthen survival for women with this disease.
The most significant cause of death and illness related to ovarian cancer is its propensity to spread in the abdomen. However, the mechanisms responsible for spread are not known. We discovered that an enzyme called transglutaminase 2 (TG2) is present at high levels in ovarian tumors, in abdominal fluid recovered from patients with cancer and in ovarian cancer cells. We also found that this protein facilitates the spreading and adhesion of ovarian cancer cells to the extra-cellular matrix by modulating the function of beta integrins. We hypothesized by modulating tumor cell interaction with the microenvironment TG2 regulates the process of intra-peritoneal metastasis and the response to chemotherapy. In this proposal we will evaluate the physical and functional interaction between TG2 and integrins in ovarian cancer cells and tumors. This interaction may ultimately alter the way ovarian cancer cells respond to chemotherapy. If TG2 alters sensitivity to chemotherapy, the next step will be to test inhibitors of TG2 in conjunction with chemotherapy.
The risk of developing ovarian cancer increases rapidly in the peri- and post-menopausal periods, when ovulation ceases but the reproductive gonadotropin hormones are elevated. These gonadotropins can induce expression of certain enzymes which stimulate an inflammation-like condition that may cause changes in ovarian morphology and may promote cancer. To understand the relationship between menopause and ovarian cancer risk, these studies will investigate in the Wv mouse model, which mimics postmenopausal biology, the importance of ovulation and cyclooxygenase-1 enzyme expression on ovarian cancer development. We will also evaluate the potential to use pharmacological inhibitors of cyclooxygenases to reduce ovarian cancer risk.
Using NY-ESO-1, a previously discovered antigen, Dr. Cassian Yee and Dr. Naomi Hunder, both of Fred Hutchinson Cancer Research Center, are using a new technique to treat patients with late stage ovarian cancer. T cells are collected from eligible patients and responder T cells are enhanced. These are given back to the patient through IV, where the patient’s immune system will recognize these cells and use them to fight the existing cancer.