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Project Title: Targeting trametinib-resistant low-grade serous ovarian cancer by drug repurposing
Research Institute: MD Anderson Cancer Center Principal Investigator: Dr. Kwong K. Wong Ph.D., Professor Estimated Cost for Project: $76,000 Funded by: STAAR Ovarian Cancer Foundation STAAR Ovarian Cancer Foundation has awarded $76,000 to Kwong K. Wong, Ph.D., professor of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center, to learn more about trametinib adaptive resistant low-grade serous carcinoma (LGSOC) cell lines, and identify therapeutic agents to overcome resistance. With STAAR’s support, Wong and his team are investigating whether targeted drug therapy can suppress trametinib resistance in patients with LGSOC. “We are excited to be able to screen thousands of existing drugs for repurposing their current uses to overcome trametinib resistance in LGSOC,” Wong said. “These drugs include approved, discontinued and investigational therapeutics for other diseases. This approach could be faster and more cost effective than developing a new drug for treating patients who currently fail trametinib treatment but with very few other options.” LGSOC has fewer effective treatment options than high-grade serous ovarian cancer. The MEK inhibitor trametinib has shown promising results when LGSOC does not respond to chemotherapy or aromatase inhibitors. Research found initial tumor shrinkage in approximately 26% of patients. Unfortunately, patients can develop a resistance to the drug over time, allowing the disease to progress. Sara Vellve was diagnosed with LGSOC in 2015 at age 50, and participated in a trametinib trial in 2017. “At first I had adverse reactions, but after a dose reduction, I was stable for six months before my disease progressed,” she said. Since then, Vellve has continued to participate in trials to find the most effective treatment for her cancer. “There are too few treatment options for low-grade serous ovarian cancer. If this study could find a workaround to trametinib resistance, it would be a tremendous step forward in disease management.” Wong is testing the efficacies of 10-15 drugs that might suppress the growth of trametinib adaptive resistant LGSOC cells. He will investigate how these drugs overcome the adaptive resistance using both LGSOC cell culture and LGSOC mouse models. Once the trametinib adaptive response is deciphered, clinical trials can combine targeted therapy and repurposing drugs to improve LGSOC patient survival. More importantly, this study will generate critical data to support novel clinical trials with repurposing drugs for LGSC patients who develop trametinib resistance. Drug repurposing could also reveal new biomarkers and pathways that can be targeted for LGSOC. LGSC is a rare subtype of ovarian cancer, making up fewer than 10% of ovarian cancer cases. The average age at diagnosis is 45, and the average length of survival is about 9 years. STAAR Ovarian Cancer Foundation is the only U.S.-based nonprofit dedicated to low-grade serous ovarian cancer. It was co-founded by three women with LGSOC in early 2020. The foundation works with the global charity Cure Our Ovarian Cancer to advance research opportunities in the United States to find better treatment options for LGSOC.
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Project Title: Identifying Predictors for Chemosensitivity in Patients with Advanced and Recurrent Low-Grade Serous Ovarian Cancer
Research Institute: Memorial Sloan Kettering Cancer Center, Gynecologic Medical Oncology and Pathology services. Co-Principal Investigators: Rachel Grisham, MD; M. Herman Chui, MD, FRCPC Estimated Cost for Project: $150,000 for 1 year of funding or $250,000 for 2 years of funding Funded by: STAAR Ovarian Cancer Foundation Research at Memorial Sloan Kettering Cancer Center (MSK) seeks to predict whether low-grade serous ovarian cancer (LGSOC) patients will respond to chemotherapy. Studies have shown that cytotoxic chemotherapy is less effective for LGSOC patients than it is for people with high-grade serous carcinoma, but some LGSOC patients do respond to chemotherapy. Without a reliable predictor, the standard of care for both types of cancer typically has been the same: primary debulking surgery followed by adjuvant platinum/taxane based chemotherapy. STAAR Ovarian Cancer Foundation has awarded $250,000 to MSK’s Rachel N. Grisham, MD, and M. Herman Chui, MD, FRCPC, to develop a panel of biomarker tools to predict which patients are most likely to respond to chemotherapy. The research will help patients and doctors make treatment decisions and avoid unnecessary toxicity for those unlikely to benefit from chemotherapy. “I was devastated when I learned that my cancer had no response to three rounds of chemotherapy,” said STAAR board member Kari Neumeyer, a LGSOC survivor who was diagnosed at 44 years old. “This research could prevent women like me from having to go through unnecessary chemotherapy. I was fortunate that my surgeon removed all of the cancer. If I knew then what I know now, I would have chosen not to undergo chemo.” MSK’s Grisham and Chui will analyze the differences in tissue from patients who responded to chemotherapy and those who did not. Targeted panel sequencing will assess cancer driver mutations and measures of genomic instability such as mutation counts, fraction of genome altered by copy number changes, and frequency of intrachromosomal breakpoints. “I am incredibly grateful to STAAR Ovarian Cancer Foundation for their dedication and fundraising efforts,” Grisham said. “Low-grade serous ovarian cancer is a clinically and molecularly unique disease that requires dedicated research and studies to develop an individualized treatment approach.” "Because of its rarity, low-grade serous ovarian cancer is historically an underfunded area of research,” Chui said. “This generous grant is integral for us to further study the biology of this disease and to develop novel molecular tools to help guide treatment.” The research will set the foundation on the molecular basis for chemotherapy resistance in LGSOC, which could form the basis of future work to develop novel therapeutic strategies. LGSOC is a rare ovarian cancer, making up fewer than 10% of ovarian cancer cases. The average age at diagnosis is 45, and the average length of survival is about 9 years. About the Investigators: Herman Chui is a gynecologic pathologist in the Department of Pathology and Laboratory Medicine at MSK. He has a particular interest in the molecular pathogenesis of ovarian serous borderline tumor and low-grade serous ovarian cancer, engendered since his fellowship training at the Johns Hopkins Hospital, where he developed expertise and appreciation for the diagnostic subtleties and unique biology of this complex and unusual disease. Rachel Grisham is the section head of Ovarian Cancer Research and Treatment at MSK . She is committed to the development of novel treatment strategies for women with rare tumors. Her research has focused on the accelerated development of more effective and better tolerated treatment strategies for people with low-grade serous ovarian cancer. She serves as the Precision Therapeutics Chair for the International Consortium for Low-Grade Serous Ovarian Cancer (ICLC), serves on the Rare Tumor Committee for NRG, and has been the principal investigator for multiple clinical trials focused on novel therapeutics for low grade serous ovarian cancer and other rare tumors. STAAR Ovarian Cancer Foundation is the only U.S.-based nonprofit dedicated to low-grade serous ovarian cancer. It was co-founded by three women with LGSOC in early 2020. The foundation works with the global charity Cure Our Ovarian Cancer to advance research opportunities in the United States to find better treatment options for LGSOC. |
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