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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 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. 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. Project title: Biomarkers of Sensitivity to Aromatase Inhibitors in Women with Recurrent Low-Grade Serous Ovarian/Peritoneal Cancer
Research Institute: MD Anderson Cancer Center Lead Researcher: Dr. David Gershenson Project cost: $150,000 Funded by: STAAR Ovarian Cancer Foundation STAAR Ovarian Cancer Foundation to Fund Biomarkers of Sensitivity to Aromatase Inhibitors Research A new research study at University of Texas MD Anderson Cancer Center funded by STAAR Ovarian Cancer Foundation will determine if biomarkers can identify how aromatase inhibitors influence clinical outcomes of patients with low-grade serous ovarian cancer. Aromatase inhibitors such as letrozole, anastrozole and exemestane reduce the level of estrogen in the body. They have been found to be effective against low-grade serous ovarian carcinoma (LGSOC), which can be resistant to chemotherapy. There is currently no known biomarker to predict if the patient will benefit from this type of treatment. If this biomarker exists, physicians would be able to use it to assess which patients are likely to benefit from the use of an aromatase inhibitor and which patients will not. “As a patient that has been on each of the three types of aromatase inhibitors (letrozole, exemestane, and anastrozole) in under a year, a study like this is very exciting,” said Morgan Gaynor, ovarian cancer survivor and Secretary of STAAR Ovarian Cancer Foundation. “These medications can come with debilitating side effects so it can be hard to find one to stick with. Being able to know which treatments will or won’t work for someone is a major incentive towards medication compliance, which leads to better outcomes.” The study will examine the molecular biology in LGSOC of dozens of women that have recurrent disease and were treated with aromatase inhibitors. Researchers will study tissue from LGSOC patients for gene abnormalities and the proteins expressed. “We are extremely grateful to STAAR for their generous support of this important research initiative. Low-grade serous ovarian carcinoma is a rare subtype of ovarian cancers that is relatively insensitive to chemotherapy,” said Dr. David Gershenson of University of Texas MD Anderson Cancer Center. “And because we know endocrine therapy can be successful, we need to better understand for whom.” LGSOC is a rare and extremely underfunded subtype of ovarian cancer, making up fewer than 10% of ovarian cancer cases. MD Anderson Cancer Center is a world leader in LGSOC research. Doctors there were instrumental in helping identify it as a unique cancer in 2004 and their research has formed the basis for many of the current treatment recommendations. In 2018, they added LGSOC to their Cancer Moon Shots Program. STAAR Ovarian Cancer Foundation is the only US-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. Project title: Estrogen Signaling in Low-Grade Serous Carcinoma (LGSOC)
Research Institute: MD Anderson Cancer Center Lead Researcher: Dr. KK Wong PhD, Professor Start date: June 2021 Project cost: $70,000 Funded by: STAAR Ovarian Cancer Foundation and Cure Our Ovarian Cancer STAAR Ovarian Cancer and international partner Cure Our Ovarian Cancer are proud to announce the funding of their first US based research grant at MD Anderson Cancer Center. STAAR Ovarian Cancer and Cure Our Ovarian Cancer have jointly contributed $70,000 to the project entitled: Estrogen Signaling in Low-Grade Serous Carcinoma (LGSC). The project seeks to better understand how LGSC can use estrogen to grow and spread – and identify potential targets to improve treatment options. “This is a unique opportunity to study the complex and elusive estrogen receptor signaling pathway in low-grade serous ovarian cancer, which would hopefully result in a successful and improved anti-hormone therapy,” said Dr. KK Wong of MD Anderson Cancer Center. Estrogens are major regulators of growth and differentiation in normal ovaries and potentially play a role in the development and progression of ovarian cancer, but the mechanisms of action remain unclear. The actions of estrogens on ovarian tissue are mediated by estrogen receptors. There are two major types of estrogen receptors – ERα and ERβ. Furthermore, multiple variants of the ERα have been identified in LGSC. The types of estrogen receptors found in LGSC are different from those in normal ovary. Hormonal maintenance therapies (HMT) have improved the progression-free survival of patients with recurrent low-grade ovarian cancer, but unfortunately, these treatments have not achieved comparable results as in breast cancer. Preliminary data suggests that estrogen signaling is unique in low-grade serous cancer, and there is a need to further explore and understand the mechanisms underpinning it, which could provide new and clinically relevant insights regarding the role of estrogen in low-grade serous ovarian cancer. Researchers will use advanced genetic sequencing and laboratory techniques to identify the specific type of estrogen receptors involved in LGSC (which they think will differ from breast cancer) and investigate the molecular and genetic characteristics involved in its expression. The study has the potential to find biomarkers to predict response to HMT, in addition to insights which researchers hope will guide future research to help HMT work better. Funds from the 2020 September Step Up event along with and hundreds of generous members of the public, helped make this grant possible. Nicole Andrews, who hosted a Step Up Challenge in her hometown prior to joining STAAR's Board of Directors shared her experience: "Being diagnosed with Low Grade Serous Cancer (LGSC), a rare form of ovarian cancer, was shocking. I felt scared, shut down, and out of control. The Step-Up Campaign gave me the opportunity to transform my thoughts and fears into constructive energy and focus on creating a positive future. I’m honored that my friends and family “stepped up” alongside me and helped me exceed my fundraising goal. While it’s unusual to know how funds you raise are used, I was thrilled to learn our donations are already working to help researchers understand why and how LGSC uses estrogen so that enhanced treatment options can be developed. My deepest thanks to all working tirelessly to improve outcomes for LGSC survivors, bringing invaluable hope and healing to me and my fellow LGSC sisters." MD Anderson Cancer Center are world leaders in low-grade serous carcinoma (LGSC) research. They were instrumental in helping identify LGSC as a unique cancer in 2004. In addition, their research has formed the basis for many of the current LGSC treatment recommendations. In 2018, they added LGSC to their Cancer Moon Shots Program. Cure Our Ovarian Cancer (COOC) is a global charity dedicated to improving the survival of people with LGSC through research. It was founded in 2018 by New Zealand woman Jane Ludemann following her diagnosis. Today COOC supports researchers in five countries, including the United States of America. |
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