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Targeting Jumonji KDM4A during the development of small cell lung cancer in GEMMs

Award Number: R21CA313738
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Targeting Jumonji KDM4A during the development of small cell lung cancer in GEMMs - 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. We have highly promising preliminary data in cell culture and in vivo xenograft models that strongly support that epigenetic enzymes of the Jumonji lysine demethylase family (Jumonji KDMs), and KDM4s in particular, constitute viable druggable targets across SCLC subtypes, even in disease that has acquired chemotherapy resistance. Here we therefore propose a new idea: that Jumonji demethylases are key contributors to SCLC development and to its fast-acquired resistance to therapy. We have novel tools to probe this idea pharmacologically: namely, enzyme inhibitors developed by us with proven in vivo efficacy. Thus, we propose an innovative three-pronged therapeutic paradigm: treating GEMM models of SCLC representing both ASCL1-high (RPR2) and NeuroD1-high disease (RPM) with Jumonji inhibitors as first line therapy, treating as second line post etoposide/cisplatin or in combination with immune checkpoint inhibitors. We will evaluate JIB-04 (pan Jumonji inhibitor with established efficacy in xenografts) and TACH101 (Jumonji KDM4 inhibitor in clinical trials for other cancers). We will furthermore define their transcriptional action in vivo and determine when during SCLC onset and progression Jumonji KDMs become activated. For this impactful work to be meaningful for clinical translation to humans, it must be conducted in animal models that represent the full progression of SCLC development over time and the onset of therapeutic resistance in a setting of immune competency. No human specimens are adequate for this purpose. Thus, genetically engineered mouse models of SCLC are imperative for meaningfully establishing the role of the targetable KDM4s in SCLC onset and progression as well as in the development of drug resistance. The increased molecular knowledge of SCLC epigenetic drivers throughout the course of this disease and the new therapeutic opportunities it will provide through Jumonji inhibitor use, are in full alignment with the mission of the National Cancer Institute. This work will positively impact public health, opening a new paradigm for SCLC prevention, for recalcitrant SCLC treatment with Jumonji inhibitors and for overcoming therapeutic resistance in ASCL1-high and in NueroD1-high.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $426,828 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	000	1	8/6/2026	NEW	$426,828
														Subtotal = $426,828

Grand Total All Awards = $426,828

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Targeting Jumonji KDM4A during the development of small cell lung cancer in GEMMs

Award Number: R21CA313738

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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