Low-grade serous carcinoma (LGSC) is often resistant to platinum based chemotherapy and new treatment strategies are needed. Dana-Farber/Havard Cancer Center (DF/HCC) has been awarded a grant from the National Cancer Institute (NCI) for a Phase 2 Clinical trial evaluating the MEK inhibitor trametinib and BCL-2/XL inhibitor navitoclax.
Trametinib is a MEK inhibitor which targets the MAP kinase pathway used in cell growth. It was originally developed for melanoma. A recent Phase 3 clinical trial (GOG 0281) found trametinib was more effective than existing therapies for treating recurrent LGSC with an average progression free survival of 13 months. Navitoclax is a Bcl-2/XL inhibitor. Bcl-2 proteins help regulate programmed cell death. It is an experimental drug that was developed for lung cancer.
Trametinib and Navitoclax have been studied in combination in high-grade serous carcinoma (HGSC) mouse models, and a Phase 1 clinical trial which showed safety and tolerability of the combined treatment.
The study will test the treatment in LGSC and HGSC women, with and without a RAS/RAF ovarian cancer mutation to measure its effectiveness in treating cancer. In addition the researchers will collect information to try and identify genetic and protein markers related to treatment efficacy. One potential marker is the BIM protein which has shown promise in HGSC mouse models. Pre-clinical (laboratory) studies will also be performed to look for potential ways to improve the effectiveness of the drug combination in women.
The project forms part of a larger Specialized Program of Research Excellence (SPORE) grant. The project leads are Dr Joan Brugge, Dr Gad Getz and Dr Ursula Matulonis.
“Our focus will be on new ovarian cancer therapies for which laboratory research provides evidence of their effectiveness. Physician-researchers across the DF/HCC institutions will work collaboratively to test and develop the next generation of agents that we can deliver to our patients and ultimately improve outcomes. This is a very important collaborative grant for us.” – Ursula Matulonis, MD.