Lung Cancer

Project Summary

The goal of Project 1 is to develop a therapeutic ALK vaccine for advanced ALK-rearranged (ALK+) NSCLC. Acquired resistance to all available FDA-approved ALK TKIs is inevitable, at which time patients are typically treated with cytotoxic chemotherapy, which has only modest efficacy. Similarly, ICIs have little activity in ALK+ NSCLC, leaving no effective approaches for treating TKI-resistant disease. Since ALK is uniquely expressed in lung cancer cells, it is an ideal tumor associated antigen vulnerable to immunotherapeutic strategies that strive to achieve our overall goal of improving survival for patients with ALK+ lung cancers. This Project builds on an unparalleled foundation of excellence in the field of ALK+ lung cancer at HCC. Given our unique expertise we have become major referral centers for ALK+ patients.

Project Summary

The purpose of Project 2 is to develop novel treatment approaches for an emerging and clinically relevant subtype of NSCLC that currently lacks effective therapeutic options. SMARCA4 is one of the most frequently mutated genes in NSCLC, present in 9- 11% of patients, inactivating its gene product BRG1, a key subunit of the SWI/SNF chromatin remodeling complex. SMARCA4 mutations often overlap with molecular alterations (KEAP1, STK11) that decrease sensitivity to immunotherapy and chemotherapy; indeed, in retrospective series from MGH and MSKCC, NSCLC SMARCA4 mutations in advanced NSCLC were associated with poor prognosis and unfavorable disease characteristics. Thus, effective targeting of SMARCA4 NSCLC is a key unmet need.

Project Summary

The overall goal of Project 3 is to enhance the durable activity of targeted therapies for lung cancer. The best and most deeply characterized subset for this is advanced EGFR mutant lung cancer, which, despite all prior success, remains an incurable disease. Work from our investigators and others has solidified the fact that after an initial treatment response, tumors enter a quiescent phase (drug tolerant persister (DTP) state) lasting months or even years before tumor regrowth and acquired drug resistance occurs. Most strategies to enhance genotype directed therapy have focused on targeting molecular changes at the time of resistance or intensifying initial treatment approaches. But they fail to address the specific mechanisms of the DTP state, which could be targeted earlier to eradicate these and prevent resistance.