Nuzhat Ahmed, PhD
- Women’s Cancer Research Center (Australia)
Determining the MicroRNA Signature of Isolated Chemoresistant Ascites Tumor Cells
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.
Matjaz Barboric, PhD
- University of Helsinki
Examining the Tumor Suppressor Function of Cdk12/CycK Kinase in Ovarian Cancer
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.
Dalibor Blazek, PhD
- Masaryk University (Czech Republic)
The Roles of Cdk12 in Ovarian Tumorigenesis
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.
Hiu Wing Cheung, PhD
- Medical University of South Carolina
Development of Oncogene-Targeted Therapy 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.
Hani Gabra, PhD, FRCP
- Imperial College London
Therapeutic Delivery of OPCML Tumor Suppressor Protein Using Virus-Like Particles
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.
Karen Lounsbury, PhD
- University of Vermont
Protein Translation Regulators and the Ovarian Cancer Microenvironment
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.
Anirban Mitra, PhD
- University of Chicago
Microenvironment Induced Epigenetic Regulation in 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.
Neveen Said, MD, PhD
- University of Virginia
Regulation and Function of SPARC in 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.
Yunfei Wen, PhD
- University of Texas MD Anderson Cancer Center
Suicidal Autophagy: Targeting Tumoral PRL/PRLR Axis in Ovarian Cancer
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.
Lin Zhang, MD
- University of Pennsylvania
Reconstruction of the Heterochronic Pathway for Ovarian Cancer Treatment
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.