Identification and Validation of Kinase Targets in SCLC
Abstract
Lung cancer is the leading cause of cancer death in the United States, accounting for ~30% of all cancer deaths. Two major subtypes of lung cancer exist that can be distinguished by the size of the tumor cells and the markers they express: non-small cell lung cancer (NSCLC) represents ~85% of lung cancers and these cells express markers of lung alveolar cells -- the cells involved in gas exchange. In contrast, small cell lung cancer (SCLC) represents ~15% of all lung cancers; SCLC cells are peculiar in that they express markers of both neuronal cells and cells that secrete hormones ("neuroendocrine" markers). SCLC has several main features, including its strong association with tobacco smoking. The smoking rate in the military is still higher than in the rest of the population (~24% versus ~19% -- these numbers are even higher in Veteran populations), and SCLC development strongly correlates with cigarette smoking; thus, while the general population may benefit from our work, military personnel will likely benefit even more from our studies. More than 25,000 new cases of SCLC are diagnosed every year in the United States. SCLC typically grows quickly and tends to metastasize early in the course of the disease, and survival rates are extremely low: 5% patients survive 5 years post-diagnosis. Once SCLC has been detected in a patient, restoring lung health requires finding an appropriate treatment regimen. SCLC is often initially responsive to chemotherapy and radiation therapy, but tumor cells become rapidly resistant to treatment. Furthermore, a large number of clinical trials testing new molecules against SCLC have failed in recent years. Therefore, it is important to identify novel molecules that can be used as therapeutic targets against this deadly disease. Our work seeks to identify kinases that are active in SCLC cells, including early-stage tumors as well as chemoresistant, advanced cancer. Kinases are a class of enzymes that are often implicated in propagating signals within normal and cancer cells. In particular, subsets of kinases are often hyperactivated in human cancers. Importantly, kinases are usually very good drug targets, and many kinase inhibitors are currently in the clinic. Unfortunately, however, the identity of active kinases in SCLC has remained largely unknown. The ultimate applicability of our research would be the identification of active kinases in SCLC for which small molecule inhibitors already exist, or even better, are already Food and Drug Administration-approved. This would allow for a rapid transition from the laboratory to SCLC patients in the clinic. Hence, several of the Areas of Emphasis for this funding mechanism are addressed by our research, including helping better understand resistance to chemotherapy, a very common feature of SCLC. In addition, the identification of kinases involved in SCLC development may uncover drug targets to treat early tumors. Furthermore, our work may help identify responders and non-responders to inhibitors of these kinases. Beyond the clinical importance of identifying active kinase in SCLC, this work will further advance the field of lung cancer research by uncovering signaling pathways that were not evident from previous studies. These signaling pathways may include additional therapeutic targets. A unique aspect of our proposal is that it combines faithful preclinical models of SCLC (such as tumor cells directly obtained from patients as well as genetically engineered mice) with advanced proteomics studies (proteomics is the unbiased and comprehensive studies of proteins, including kinases). Because our groups have expertise in these two seemingly unconnected research fields, we believe that, together, we will make breakthroughs in this challenging field and identify important kinases and therapeutic targets within 2 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510250
Entities
People
- Julien Sage
Organizations
- Stanford University
- United States Army