Overcoming Lung Cancer Immunotherapy Resistance by Targeting Bone Morphogenetic Proteins
Abstract
One reason why lung cancer is so deadly is that in most cases, the disease has already spread beyond the lung when it is diagnosed, and current treatments are not effective against disease that has already spread. However, new treatments that harness the immune system to fight lung cancer have shown exciting results. Two such drugs, nivolumab and pembrolizumab, block a signaling pathway (PD1) that helps cancer cells escape detection and destruction by the immune system. These drugs have produced spectacularly long-lasting results in some patients with difficult-to-treat tumors. However, most patients with lung cancer do not respond to this therapy, and even those who do often develop disease progression. Thus, we propose to identify the mechanisms of resistance to PD1 inhibitors and validate new targets that can be used for re-sensitize resistant tumors to immunotherapy. Our early comparisons of molecular signaling pathways in mouse and patients’ tumors that are resistant to anti-PD1 showed that specific inflammatory pathways is related to response to immunotherapy. In this grant, we will explore how these molecules influence the ability of tumor cells to evade the immune system and then use these molecules as the basis for treatments that can overcome anti-PD1 resistance or as biomarkers that can help identify, before treatment, which patients will (or will not) respond to these drugs. We believe that reactivating a patient’s immune system in ways that allow them to fight tumors from the inside will provide the best chance of curing lung cancer. This proposal addresses the following FY20 LCRP Areas of Emphasis “Identify innovative strategies for the treatment of lung cancer” and “Understand mechanisms of resistance to treatment (primary and secondary)” by identifying novel approaches to address PD1 resistance in lung cancer. The impact of successfully completing this proposal would be to (1) identify new mechanisms behind resistance to immunotherapies; (2) identify biomarkers and potentially treatment approaches likely to be successful for patients who do not respond to immunotherapy; and (3) extend the benefits of immunotherapy to larger numbers of patients including VA patients and their families with lung cancer and, ultimately, to those with other anti-PD1-resistant solid tumors as well
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110336
Entities
People
- Maria Cortez
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army