This proposal describes a training program to advance my academic career in the study of the biology, genetics and therapy of lung cancer. Lung cancer is the leading cause of cancer-related deaths worldwide. While the increasing understanding of the genetic events underlying lung cancer have led to new therapies for a subset of patients, no effective therapeutic options exist for the treatment of lung cancer patient harboring mutations in KRAS. This research proposal aims to define the genetic requirements for the maintenance of KRAS-driven lung tumors, with the goal of identifying tumor-specific vulnerabilities that could be exploited for cancer therapy. My expertise in cancer genetics and the new genetic technologies that I have developed during my postdoctoral work put me in a unique position to significantly contribute to the understanding of lung cancer and the identification of new avenues for therapeutic intervention. The research outlined in this proposal extends directly from my long-standing interest in understanding cancer genetics and critical oncogenic programs to identify new therapeutic strategies, and my experience developing RNAi technology and genetically engineered mouse models.
In Aim1, I will address the biological basis for tumor dependency on KRAS during lung cancer initiation and progression, using the unique transgenic mouse model I developed, which allows temporal, spatial and reversible control of KRAS expression. The approach described combines existing and novel mouse strains to enable doxycycline-inducible shRNA-mediated KRAS silencing specifically in the lung of adult mice. In addition, I will use CRISPR/Cas9 genome editing technology to investigate the consequences of common genetic alterations on the dependence of RAS signaling in lung cancer.
In Aim 2, based on the hypothesis that the presence of signal transduction inhibitors creates new dependencies that attenuate their activity, I will use a multiplexed RNAi approach to identify effectors required for lung cancer maintenance in combination with RAS signaling inhibitors that are currently under clinical development. The work proposed will provide key insights into the role of commonly mutated genes in lung cancer and will define factors that are essential for the growth and survival of lung cancer cells, representing potential targets for rational drug development and combinatorial therapeutic strategies. To achieve the goals of this award, I will be mentored by Dr. Scott Lowe and guided by an advisory committee that I have established at MSKCC. Dr. Scott Lowe is an internationally recognized expert in cancer biology, in particular, the development of cancer mouse models and tumor suppressor genes, and has longstanding interest in RNAi and genome-editing technologies to understand how genetic alterations in cancer cells can be therapeutically targeted. The advisory committee consists of four successful scientists (Prof. Lowe, Prof. Sawyers, Dr. Rudin, and Dr. Ventura), who will specifically monitor and support my transition to independence providing valuable guidance for the process of applying and interviewing for faculty positions. Memorial Sloan Kettering Cancer Center (MSKCC) will provide institutional support to me, including the resources to conduct laboratory research, opportunities to foster career development and continuing education, and an open scientific environment to foster the interaction required for me to achieve my goals. My career goal is becoming an independent investigator in an academic institution to develop my own research program described in this research proposal. To this end, the K99/R00 award will be ideal as a stepping stone in my transition into a tenure-track faculty position.
Current treatment of lung cancer patients harboring mutations in KRAS is based on cytotoxic chemotherapies, which lead to minimal therapeutic responses accompanied by significant side effects. Thus, there is an urgent need to identify therapeutic regimens for the treatment of KRAS-driven lung cancers. This proposal is dedicated to the development of novel mouse and human models to investigate the functions of RAS signaling in lung cancer, and ultimately, the identification of new avenues for therapeutic intervention.
