Mechanisms of Carcinogenesis and Therapeutic Vulnerabilities Associated with RBM10 Loss in KRAS Mutant NSCLC
Abstract
The identification of subgroups of lung cancer that are driven by defects in specific genes has helped establish the field of personalized cancer medicine, whereby cancer treatment is not prescribed in a blind, "one size fits all" manner but is rather tailored to the specific DNA abnormalities identified in each patient s tumor. This approach has been particularly successful for lung cancer patients whose tumors are found to harbor abnormalities in the EGFR and ALK genes; for these patients, drugs that specifically target the abnormal gene result in improved patient outcomes compared to conventional chemotherapy. However, despite these major breakthroughs, no targeted therapies have yet been approved for the largest group of patients with non-small cell lung cancer that are driven by alterations in the KRAS gene. We have recently discovered that one of the major obstacles hindering the development of targeted therapies for KRAS-altered lung tumors lies in their considerable heterogeneity. Our work has further revealed that the primary reason that explains why KRAS tumors differ significantly from each other is the presence of defects in additional genes that co-occur with alterations in KRAS itself. Thus, systematic examination of the impact of genes that are simultaneously altered with KRAS represents a novel strategy that may lead to more individualized, and ultimately successful, therapies for this challenging group of lung cancer patients. Our preliminary results have identified RBM10 as one of the most frequently co-altered genes with KRAS in lung cancer. Defects in RBM10 are identified in approximately 1 in 10 lung cancer patients and occur more frequently in males than in females. However, little is currently known about how RBM10 cooperates with KRAS to promote the development of lung cancer. In addition, it is unclear whether lung tumors with altered RBM10 have unique characteristics that may impact patient prognosis or response to therapy. This research proposal aims to: (a) Study the effect of defects in RBM10 in the development and behavior of lung cancer driven by alterations in KRAS. This will be achieved by faithfully modeling alterations in KRAS and RBM10 in laboratory mice. (b) Assess the impact of defects in RBM10 on the prognosis and behavior of lung cancer using large collections of tumor samples collected and stored at MD Anderson Cancer Center. (c) Develop targeted therapies for tumors with co-occurring KRAS and RBM10 alterations. Accordingly, this application addresses several Lung Cancer Research Program Areas of Emphasis including understanding molecular mechanisms that lead to lung cancer subtypes and mechanisms of progression to clinically significant lung cancer. This work represents a natural and logical next step in my career as a Medical Oncologist and Physician-Scientist with a major focus on the development of targeted therapies for the large group of patients with KRAS-altered lung cancer. I have a track record of impactful, clinically relevant research in this field during both my PhD and subsequent post-doctoral studies. Having recently commenced an appointment as Tenure-Track Assistant Professor in the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, this award will provide me with a unique and invaluable opportunity to establish a competitive independent research program in the field of lung cancer research while taking advantage of the existing clinical infrastructure at MD Anderson to rapidly translate key research findings for the benefit of lung cancer patients. Overall, this research is expected to shed light on mechanisms of lung cancer development and progression in the context of aberrant KRAS and RBM10, identify the major features of RBM10-altered tumors, and explore their unique therapeutic vulnerabilities. It is therefore well poised to have a direct and significant impact on the treatment of lung cancer patients, and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610094
Entities
People
- Ferdinandos Skoulidis
Organizations
- United States Army
- University of Texas at Austin