Bridge Funding Award

Federal funding for research is tighter than ever, and often researchers do not get funded on their first try with a new proposal. The purpose of Bridge Funding is to allow researchers to produce data needed to substantiate their proposal resubmission to federal funding agencies for a promising new research project. In order to be competitive, resubmitted proposals must include solid data and address the concerns of expert reviewers. The Rivkin Center provides interim funding of up to $30,000 for six months to researchers who have submitted to the National Institutes of Health (NIH) or an original proposal to the Department of Defense (DoD) pertaining to ovarian cancer and who were not funded but received a score close to the funding threshold. With more data, ovarian cancer researchers stand a better chance of being successfully funded with a stronger, resubmitted proposal.

This award category was launched in 2014 with a lead gift from Margaret Sherman.

Rosana Risques, PhD
University of Washington

Research in focus: Early Detection of Ovarian Cancer

Development of a multi-gene uterine lavage test for ovarian cancer detection
Ovarian cancer is deadly because it is usually detected at advanced stage. Survival for advance stage ovarian cancer is only 25%, compared to 90% for early stage cancer, which indicates that ovarian cancer can be cured if detected early. Dr. Risques’s goal is to develop a test for ovarian cancer detection based on the identification of tumor mutations in uterine lavage—a simple, 5-minute procedure that washes the uterus with a saline solution. Dr. Risques and colleagues have demonstrated that, in women with ovarian cancer, tumor mutations can be identified in the lavage DNA using an ultra-accurate sequencing method called Duplex Sequencing (DS). However, DS is inefficient and requires large amounts of DNA. In addition, their preliminary studies only sequenced a single gene (TP53). To overcome these limitations, Dr. Risques and colleagues developed CRISPR-DS which is faster, simpler, and requires 10 times less DNA than standard DS. They propose to sequence lavage DNA with a CRISPR-DS gene panel including the 9 most common mutated genes in the 5 different subtypes of ovarian cancer. With the Rivkin Bridge Funding award, Dr. Risques will demonstrate of the need of sequencing of genes in addition to TP53 and the ability of the method to detect early cancers. These analyses will take us a step closer to a much needed clinically applicable test for ovarian cancer detection.

Adam Karpf, PhD
University of Nebraska
2018 Kirwin-Hinton Bridge Funding Award

Rhno1 in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most common and deadly form of ovarian cancer, accounting for about 25,000 cases and 15,000 deaths in the United States every year. New and improved therapies are critically needed for HGSOC. Drugs targeting proteins that respond to “stress” during DNA replication have shown promise, with some being tested in clinical trials for several types of cancers.

Dr. Karpf’s research project focuses on a protein called Rhno1, which is also involved in this stress response process. Early studies have shown that increased amounts of Rhno1 are found in high-grade serous ovarian cancer and are associated with lower survival in patients. In lab experiments, increased Rhno1 levels have been shown to promote the growth and survival of ovarian cancer cells.

In this Bridge Funding Award study, Dr. Karpf will develop two different kinds of mouse models in which Rhno1 function or levels are changed to understand how change in Rhno1 leads to ovarian cancer. This study is important as levels of Rhno1 may affect how patients respond to new therapies (i.e.Wee1, ATR, Chk1 inhibitors) that target cell replication stress. Additionally, Rhno1 may itself be an effective target for which therapies can be developed in future studies.

Srinivas Sridhar, PhD
Northeastern University

Targeted PARP Inhibitor Nanotherapy for Ovarian Cancer

PARP inhibitor therapy has shown promising results in clinical trials for ovarian cancer, but oral administration of these drugs requires high doses leading to toxic side effects, and very little drug actually reaches the tumors. Dr. Sridhar and colleagues have synthesized nano-scale formulations of Olaparib and Talazoparic, two promising PARP inhibitors, which can be injected intravenously. In mice, these nanoformulations are more effective than the oral version of the drug at treating ovarian cancer, but there are still off-target effects and toxicities in other organs. In this study, Dr. Sridhar will engineer a targeted nanoformulation of Olaparib and Talazoparib, meaning the molecules will specifically target the tumor and bypass other organs. He predicts these targeted drugs will be 100X more effective than the oral version of the drug with greatly reduced toxicity.  More than half of ovarian cancer patients could benefit from treatment with these targeted PARP inhibitor therapies.

Bo Yu, MD
University of Washington
2017 Cookie Laughlin Bridge Funding Award

The role of fallopian tube microbiome in ovarian carcinogenesis

Ovarian cancer is the most lethal gynecological cancer in the United States. The high mortality rate is due to a lack of understanding of the origin and development of this disease, which makes both early detection and targeted treatment difficult. We critically need innovative research to understand how this deadly cancer initiates and progresses. Dr. Yu proposes to test a novel and highly plausible hypothesis for the origin of ovarian cancer: infection arising from genital tract bacteria that travel to the fallopian tubes causing inflammation and damage to DNA in cells leading to ovarian cancer. Several pieces of existing evidence have led Dr. Yu to this yet untested hypothesis. First, we know that the fallopian tube is the site of origin for a large proportion of ovarian cancer, and it was recently shown to carry genital tract bacteria. We also know that blocking the communication between the fallopian tubes and the environment, such as through tubal ligation or hysterectomy, decreases ovarian cancer incidences. Dr. Yu will directly investigate the connection between the fallopian tube bacteria and ovarian cancer development by using a well-established bacteria sequencing technology and an ovarian tissue bank at the University of Washington. If Dr. Yu can establish an association between the fallopian tube bacteria and ovarian cancer, it would provide a major new perspective that would influence early detection, prevention and treatment of ovarian cancer.

Manish Patankar, PhD
University of Wisconsin
2016 Lynda’s Fund Bridge Award

Identifying ovarian cancer biomarkers though lineage specific assessment of immune cell transcriptome

Several decades of work have focused on the liquid portion of blood samples in order to identify biomarkers for early detection of ovarian cancer. Unfortunately, no biomarkers yet identified have proved useful for revolutionizing early detection. Dr. Patankar’s study will instead focus on the white blood cells in circulating blood as they are the sentinels of the immune system that constantly survey the body for the presence of abnormal cells, including cancer cells. The molecules that white blood cells produce to signal and activate other components of the immune system will be exploited as early detection signals. The immune system is typically very robust and effective at eliminating cancerous cells. However, Dr. Patankar will hone in on breakdowns in the signaling process of the immune system which can lead to cancer cell growth instead of cancer cell eradication.

Jia Liu, PhD
University of Arkansas for Medical Science
2016 Cookie Laughlin Bridge Funding Award

Myxoma Virus in Combination with Chemotherapy for Treatment of Ovarian Cancer

Resistance to chemotherapy occurs in the vast majority of women diagnosed with ovarian cancer and is a major barrier for effective treatment of the disease. Additionally, cells called tumor-associated macrophages (TAMs) prevent the immune system from eliminating tumor cells. Dr. Liu proposes an innovative approach using a virus called myxoma virus (MYXV), which naturally infects rabbits but does not harm humans, to combat both chemotherapy resistance and the decreased immune response caused by TAMs in ovarian cancer. Dr. Liu’s early studies have shown that MYXV can infect ovarian tumor cells and allow low doses of cisplatin chemotherapy to kill chemotherapy-resistant cells. She has also found that MYXV can disable TAMs, which awakens the immune system to eliminate tumor cells. Dr. Liu’s work utilizing the Cookie Laughlin Bridge Funds will help develop a better understanding of how MYXV infection of ovarian tumor cells makes them more susceptible to cell death by chemotherapy and how MYXV infection of TAMs improves immune response. This work addresses an urgent need for treatments that help overcome chemotherapy resistance, as it affects most women who are diagnosed with this deadly disease.

Paul Campagnola, PhD
University of Wisconsin – Madison
2015 Joanie Warner Bridge Funding Award

Quantitative Assessment of the Role of Collagen Alterations in Ovarian Cancer

High grade serous ovarian cancer arises from fallopian tube cells that migrate and implant on the ovaries, then subsequently metastasize to other sites in the body. The 3-dimensional composition and architecture of the surroundings of cancer cells can determine whether the cancer cells migrate and metastasize or whether they stay put. The surroundings, called extracellular matrix (ECM), is made up of molecules secreted by cells to provide structural and biochemical support to nearby cells. Think of the ECM as scaffolding that provides the roads on which cells travel and the buildings in which cells do their work. Dr. Campagnola’s lab has developed a technique to build this scaffolding on a submicron scale to study how cancer cells move depending on their surroundings. In addition, this lab is pioneering the use of second harmonic generation (SHG) microscopy to look at ECM inside living tissues. Already SHG microcopy is able to distinguish multiple subtypes of ovarian cancer simply by identifying distinct ECM patterns. Not only will this research project investigate cancer cell metastasis, but it will also develop second harmonic generation microscopy as a diagnostic tool for ovarian cancer.

Cheng Wang, PhD
University of Nebraska Medical Center
2015 Barbara Learned Bridge Funding Award

The Hippo/YAP Signaling Pathway in Ovarian High Grade Serous Carcinoma

Knowing where and how ovarian cancer starts will lead to earlier detection and better therapies. Recent studies have identified the fallopian tube secretory epithelial cell as the origin for high-grade serous ovarian carcinoma, the most common and deadly form of ovarian cancer. Dr. Wang’s project will determine how high-grade serous ovarian cancer starts in the fallopian tube cells and how these cells move into the ovaries and lead to ovarian cancer. Past studies in Dr. Wang’s lab found that YAP, a key regulator of the Hippo pathway which orchestrates organ development, is able to transform fallopian tube secretory epithelial cells from normal cells into cells with cancerous properties. The proposed study will examine the ability of YAP to promote cell migration and invasion (properties of metastatic cancers), angiogenesis (formation of new blood vessels that sustain cancer growth), and ovarian tissue remodeling.

Yang Yang-Hartwich, PhD
Yale University
2015 Cookie Laughlin Bridge Funding Award

Targeting p53-regulated Twist1 Degradation to Inhibit Ovarian Cancer Metastasis

Metastasis is a hallmark of advanced high-grade serous ovarian carcinoma. Turning off the ability of ovarian cancer to spread or metastasize to other places in the body would provide better therapies and prevent recurrence. The objective of Dr. Yang-Hartwich’s study is to better understand and inhibit the progression of metastasis. The proposed study focuses on a protein called Twist1 that turns on a biological process called epithelial mesenchymal transition (EMT). Ovarian cancer cells that undergo the EMT process can gain the ability to leave the primary tumor, travel with the fluid in the abdomen, and invade other organs to form metastases. Dr. Yang-Hartwich’s research will attempt to target and degrade Twist1 using a nanoparticle drug delivery system in order to inhibit the EMT process and thereby preventing metastasis of cancer cells from the ovaries to other organs in the body.

Yunfei Wen, PhD
University of Texas MD Anderson Cancer Center
2014 Margaret Sherman Bridge Funding Award

Promoting Autophagic Catabolism in Chemoresistant Ovarian Cancer

Cells routinely remove unnecessary or damaged cellular components by a process called autophagy in which small pockets of enzymes inside cells degrade those components and recycle them for other uses. Dr. Wen has discovered a way to trigger autophagy in tumor cells that may become a useful therapy for ovarian cancer. She has targeted the protein prolactin (PRL) and its receptor (PRLR) as they are easily accessible on the surface of ovarian tumor cells and are responsible for promoting tumor growth. When she blocked the interaction of PRL and PRLR with a small peptide, multiple pockets of enzymes accumulated in tumor cells which caused whole cell degradation leading to autophagic cell death. In this project, Dr. Wen will look at whether autophagy can be used to kill chemoresistant ovarian cancer cells and, more importantly, cancer stem cells in order to prevent cancer recurrence and metastasis.

Dipanjan Chowdhury, PhD
Dana-Farber Cancer Institute

OC130658: Noncoding RNAs as Prognostic and Predictive Biomarkers in BRCA 1/2-Mutated and Wildtype Epithelial Ovarian Cancer

Patients with epithelial ovarian cancer that carry BRCA1 or BRCA2 mutations can successfully be treated with platinum chemotherapy and PARP inhibitors because the BRCA1/2 mutations cause a defect in DNA repair. This allows the platinum drugs and PARP inhibitors to damage the DNA of the tumor cells without proper repair mechanisms to restore the DNA. Accumulation of DNA damage in the tumors cells will eventually kill them. Dr. Chowdhury has recently discovered two sets of microRNAs, one of which seems to enhance DNA damage and the other which seems to suppress DNA damage. He proposes to validate these microRNAs as prognostic and predictive biomarkers that can distinguish which patients would benefit most from treatment with platinum chemotherapy and PARP inhibitors, even in women who do not have BRCA1 and BRCA2 mutations. These biomarkers would also predict which patients will be resistant to treatment so that new therapeutic avenues may be explored.