ROS Exploitation to Increase Efficacy of RAF Pathway Inhibition in Melanoma
Abstract
Scientific Objective/Rationale: BRAF activating mutations are expressed in about 50% of all melanoma tumors. This had led to treatment of these tumors with Food and Drug Administration-approved BRAF and MEK inhibitors. However, tumors become resistant to these inhibitors and recur in almost all patients who initially respond to such treatment. We propose to examine if acquisition of resistance to BRAF and MEK inhibitors by melanoma cells is due to a specific mechanism involving reactive oxygen species (ROS). Furthermore, we propose to perform pre-clinical studies of the combination of a novel compound that targets reactive oxygen species developed by our collaborator at the University of Cincinnati and a BRAF inhibitor and a MEK inhibitor for studies in mice bearing human melanoma tumors. Principal Investigator’s Career Goals in Cancer Research: I have been engaged in cancer research since 2003 and am highly committed to a career in this field. I wish to establish an independent cancer research program that can utilize my knowledge of signaling in cancer for translational studies aimed at new treatments in melanoma. For the duration of the grant, I will be part of a pathway to independence program where I will learn new techniques including transcriptome profiling, applications of bioluminescent imaging of mice, and utilizing patient derived tumors in mice. I will meet several times a week with my mentor who has extensive experience training junior faculty. Additionally, my mentoring committee and I will meet every 3 months to ensure my professional and scientific development. During the mid-phase of this award, I will submit an application for an NCI R01 grant. Applicability of Research: Melanoma s 5-year survival rates are at only 10% to 18% for patients with advanced disease, underscoring a clear need for more optimal therapies to reduce the numbers of our military, Veterans, and the general public dying from melanoma. Still, there has been significant progress in understanding different subtypes of melanoma in recent years. The discovery that more than half of melanomas contain BRAF mutations led to the clinical development of inhibitors targeting the mutant BRAF protein and downstream, the MEK protein. Although there has been clinical success with these inhibitors, their long-term efficacy is limited by acquired resistance in mutant BRAF cells that typically occurs within one year. We hypothesize that a ROS-activatable prodrug will extend the efficacy of BRAF and MEK inhibitors. This hypothesis was formulated based, in large part, upon our own preliminary data demonstrating that ROS-activatable prodrug sensitizes BRAF inhibitors to BRAF-mutant melanoma cells. The rationale for the proposed research is that a determination of the effectiveness of a combination of ROS scavenger and BRAF pathway inhibitors is likely to provide new opportunities for the subsequent development of treatment strategies to combat BRAF-mutant melanoma. Clinical trials utilizing ROS targeting compounds could commence within 5 years of completion of this study. Benefit to active duty Service members, Veterans, and other military beneficiaries: This work has relevance to military personnel, because intense sun exposure during Service puts current and former military service members at increased risk of developing melanoma. The true cost of solar ultraviolet radiation exposure is best demonstrated by the increasing rates of melanoma among young adults, as well as its high incidence in individuals older than 60 years of age. Ultimately, this research aims to identify biomarkers associated with resistance and relapse in mutant BRAF melanoma patients treated with BRAF and MEK inhibitors. At the completion of the proposed work, the identification of novel resistance-promoting mechanisms in mutant BRAF melanomas will have a great impact on future BRAF and MEK inhibitor clinical trial strategies, likely within 5 years for both our troops and the ge
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910441
Entities
People
- Joan Garrett
Organizations
- United States Army
- University of Cincinnati