Overcoming Jumonji KDM4A Oncogenic Function in SCLC
Abstract
Small cell lung cancer (SCLC) is a recalcitrant disease that rapidly acquires drug resistance and for which no mechanistically novel drug therapies have been developed over the last several decades. SCLC responds poorly to second-line therapy or immunotherapy. There is therefore a challenging yet impactful opportunity to discover new therapeutic strategies against this recalcitrant tumor type. A major obstacle to accomplishing this goal is that over 500 drugs under clinical development have shown no benefit over current first-line etoposide treatment. We have highly promising preliminary data in cell culture and in vivo mouse models that strongly support that epigenetic enzymes of the Jumonji lysine demethylase family constitute viable druggable targets in SCLC and even in disease that has acquired chemotherapy resistance. We therefore propose a new concept: that Jumonji demethylases, and KDM4A in particular, are key contributors to SCLC tumorigenesis and to its fast-acquired resistance to therapy. We have novel biological tools to probe this concept molecularly and genetically. If Jumonji enzymes do indeed play a role, then this would mean that this cancer can be targeted and tumors killed using existing Jumonji enzyme inhibitors. Indeed, the first clinical trials for Jumonji inhibitors have just been posted in gastrointestinal tumors, so translation of our work to the lung cancer clinic is feasible in the near future. This will contribute to keeping the American public healthy and will provide potential cures for Service Members who develop lung cancer from environmental and other exposures during the course of duty.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310012
Entities
People
- Elisabeth D. MartÃnez
Organizations
- United States Army
- University of Texas Southwestern Medical Center