Targeting Tumor-Intrinsic Immunosuppressive Mechanisms to Enhance Efficacy of Immune Checkpoint Blockade in Lung Cancer
Abstract
Relevance. This project addresses LCRP overarching challenges of understanding the molecular mechanisms of initiation and progression to clinically significant lung cancer, and identification of innovative strategies for prevention and treatment of lung cancer. Lung cancer is highly prevalent in both veterans and active-duty personnel due to exposures to mutagens in industrial substances, cigarette smoke, asbestos bearing materials, and battlefield air pollution. The cost of lung cancer to the VA has been suggested to be greater than $1 billion a year. This study will mechanistically dissect the IRE1alphaXBP1 axis that constitutes a major immunosuppressive barrier that limits the efficacy of checkpoint blockade in NSCLC. Targeting the IRE1alpha has the immense potential to enhance the efficacy of PD-1 inhibition so that a larger cohort of NSCLC patients benefit. Background. Mutant KRAS represents greater than 30 percent NSCLC, and currently possess no effective therapeutic options. KRAS mutations typically predict a lack of response to conventional therapies and therefore, treatment of KRAS adenocarcinomas is an urgent unmet clinical need. We posit that targeting the ER stress IRE1alpha-XBP1 pathway has potential in the treatment of high-risk NSCLC patients. Overarching challenges. Of the 1.8 million individuals diagnosed per year worldwide, approximately 1.6 million succumb to death. Non-small cell lung cancer (NSCLC) constitutes 85-90 percent of all lung cancer. KRAS is the most frequently occurring oncogenic mutation in NSCLC, representing approx. 20-30 percent of NSCLC. Moreover, KRAS mutations are associated with a poor prognosis, and reduced benefit from adjuvant chemotherapy, compared with the general NSCLC population. Despite this clinical significance, there is not a single effective FDA approved targeted therapy against KRAS.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2021
- Accession Number
- AD1164086
Entities
People
- Vivek Mittal
Organizations
- Cornell University