Rational Development of Immune Therapy for Low-Grade Ovarian Serous Carcinoma to Overcome MEK Inhibitor Resistance
Abstract
The rationale and objective for the proposed work: The recent reports of two very long-term surviving low-grade serous carcinoma patients (both are still alive after more than 9 years, one without any evidence of disease) being treated with MEK inhibitor (a targeted drug) are very encouraging. In the phase II clinical trial study involving 52 patients treated, 8 patients’ tumors shrank significantly, and another 34 patients had stable disease. However, most patients with initially stable disease eventually died of the disease because the tumor became resistant to the MEK inhibitor and progressed. Our preliminary data showed that the treatment of low-grade serous ovarian cancer cells with MEK inhibitor increased the production of a novel protein (B7-H4). The B7-H4 protein is known to suppress immunity; thus immune suppression through B7-H4 may be a key player in MEK inhibitor resistance for recurrent low-grade serous ovarian cancer. Our objective is to decipher the largely unknown tumor immunity in low-grade ovarian serous carcinomas and develop novel treatment strategies by rationally designing immunotherapy in combination with MEK inhibitor treatment. Central problem addressed in the proposed research: Chemotherapy and hormonal therapy are relatively ineffective and have generally failed to reduce severe sickness and death of patients with low-grade ovarian serous cancer. Recent targeted therapy with MEK inhibitor has shown promising results, but further investigation in immune pathways in this rare disease is needed to enhance the efficacy of MEK inhibitor or to overcome MEK inhibitor resistance. How the proposed study would advance the field of ovarian cancer research and/or patient/survivor care: The immune status of low-grade serous cancer is largely unknown, and how the immune system will be affected by targeted therapy using MEK inhibitors is also unclear. By deciphering how targeted therapy may affect the immune system in low-grade ovarian serous cancer, rational design of clinical trials by combining targeted therapy and immunotherapy will be possible to improve low-grade ovarian serous cancer patient survival. Which individuals will it help, and how will it help them? Women with low-grade ovarian serous cancer will benefit from this study. This study will identify immune biomarkers in low-grade serous ovarian carcinoma that can predict responses to MEK inhibitor and/or immunotherapy. The knowledge gained from this study will also facilitate the rational development of immune therapy for low-grade ovarian cancer patients to overcome with MEK inhibitor resistance, which will improve the survival of this group of patients. Potential clinical applications, benefits, and risks (potential long-term outcomes): A detailed description of the immune status of low-grade serous cancer could predict the clinical outcomes of patients who are currently receiving MEK inhibitor treatment in the international clinical trial study, GOG-0281, which involves 250 patients. More importantly, this study will generate critical data to support clinical trials to combine targeted therapy and novel immunotherapy for patients with low-grade ovarian serous cancer in the near future. Potential impact of the proposed research on the health and welfare of military Service members, their families, and other military beneficiaries: Low-grade ovarian serous carcinomas account for a large percentage of the epithelial ovarian cancers in young women, and military Servicewomen and their families are no exception.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910169
Entities
People
- Kwong Wong
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army