Interrogating SOS1-2 (Son of Sevenless 1 and 2) as Therapeutic Targets in Treatment-Resistant EGFR and K-ras-Driven Lung Cancer
Abstract
Scientific Objective and Rationale: Lung adenocarcinoma is the leading cause of cancer death. Traditional chemotherapeutic treatment of lung cancer has involved using nonspecific cytotoxic drugs that (hopefully) harm the rapidly growing tumor cells to a greater extent than their normal surroundings. However, new treatments now focus on identifying and then targeting those intracellular signals that specifically drive tumor growth and survival. The objective of this project is to identify novel therapeutic targets to treat lung adenocarcinoma. For 75% of lung adenocarcinomas, these intracellular driver signals involve components of one particular signaling pathway that originates at a cell-surface receptor known as epidermal growth factor receptor (EGFR) and signal to its downstream components, including the oncogene K-Ras. Therapeutics directly targeting the EGFR enhance survival in a subset of patients. However, resistance almost invariably occurs, leading to recurrence of the tumor. Therefore, identifying other therapeutic targets within this signaling pathway holds enormous therapeutic promise. The long-term goal of my research program is to identify novel therapeutic targets within the EGFR signaling pathway that can be targeted therapeutically. This proposal tests one such family of targets, the proteins Sos1 and Sos2, which are central to signaling from EGFR to the oncogene K-Ras. We hypothesize that Sos1 and Sos2 are viable therapeutic targets both in primary tumors and in tumors resistant to current targeted therapies. This proposed research will help us understand susceptibility or resistance to treatment and allow us to identify innovative strategies for treatment of early and/or localized lung cancer, areas of emphasis to the Lung Cancer Research Program (LCRP). Principal Investigator?s Career Goals in Lung Cancer Research: My goal is to become a leader in the field of lung cancer research, and an integrated member of the larger Uniformed University of the Health Sciences/Walter Reed National Military Medical Center (WRNMMC)/National Cancer Institute (NCI)community trying to effectively treat lung cancer using targeted therapeutics. To achieve this goal, I will use my expertise in EGFR/K-Ras signaling to perform translational studies with the goal of identifying new therapeutic targets to treat lung cancer. While I am well trained in signal transduction, this career transition to performing translational research in lung cancer requires me to obtain additional training to understand the pathophysiology and treatment of lung cancer, and to gain experience using clinically relevant mouse models. This award will afford me the protected time required to achieve these goals. My mentoring team and I have identified key training opportunities including interest group meetings, lectures, tumor board and clinical trial meetings, clinics, and national research meetings tailored to this goal. Both the research and career development plans include interactions with scientists at WRNMMC and NCI that will help foster my integration into the community of lung cancer researchers in these institutions. Ultimate Applicability of the Research: Driver mutations in RTK/K-Ras pathway members are found in three-quarters of lung adenocarcinomas. Successful targeting of this pathway would be a major advancement to the treatment of a majority of lung cancer patients and have the potential to significantly eradicate deaths from lung cancer. This proposal uses lung cancer cell lines to test whether two integral members of this signaling pathway, the proteins Sos1 and Sos2, are viable therapeutic targets to treat lung cancer. From the research outlined in this proposal, we expect to know which molecular subtypes of lung adenocarcinoma could be successfully targeted by blocking Sos1 and Sos2 (Sos1/2) function. Since a number of academic labs and drug companies are currently designing compounds that can target Sos1/2,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710178
Entities
People
- Robert L Kortum
Organizations
- Uniformed Services University of the Health Sciences
- United States Army