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Elucidating roles of the CD24 ligand in early lung cancer development, immune evasion and response to KRAS-targeted therapy

Award Number: R01CA301423
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Elucidating roles of the CD24 ligand in early lung cancer development, immune evasion and response to KRAS-targeted therapy - PROJECT SUMMARY A significant fraction (~30%) of lung adenocarcinomas (LUADs) in lifetime smokers harbor somatic mutations in the KRAS oncogene (KM-LUADs). KM-LUAD is increasingly being detected at earlier pathological stages, thus posing a growing public health burden that warrants improved early treatment strategies. The development of clinically active inhibitors of KRAS represents one of the most exciting recent advances in the field of targeted cancer therapy. Still, the clinical efficacy of KRAS inhibition in KM-LUAD is curtailed by emergence of acquired resistance. Thus, means to augment the therapeutic efficacy of KRAS inhibitors for treatment of patients with KM-LUAD are highly warranted. Limiting these advances is a poor understanding of targets that promote oncogenesis of KM-LUAD and thus would likely influence its response to early KRAS-targeted inhibition. In our preliminary efforts, we surveyed the ecosystems of matched early-stage LUADs, premalignant lesions and normal lung tissues and found that the CD24 ligand was at the hub of tumor-to-immune cell interactions. CD24 was not only elevated in premalignant and malignant cells relative to normal lung subsets but was also prominently increased in “normal” KRT8+ alveolar transitional cells (KACs) that we found to be cells-of-origin for KM-LUAD. We also found that targeting CD24 decreased growth of KM-LUAD tumors and enhanced anti-tumor immunity. Intriguingly, CD24 levels were strikingly increased in KM-LUAD following KRAS-targeted inhibition. Targeting both CD24 and KRAS in tobacco carcinogen-exposed mice resulted in improved interception of KMLUAD, reduced abundance of tumor progenitors, and enhanced anti-tumor immunity relative to monotherapies. Our findings motivate the hypothesis that CD24 signaling promotes early development and immune escape of KM-LUAD and that targeting this ligand in combination with KRAS inhibition will remodel tumorimmune co-evolution to result in enhanced treatment of KM-LUAD. Aim 1 will use tobacco carcinogen and mutant Kras-driven mouse models with lineage-reporter systems to discern roles of CD24 in KAC transition, cellular genesis, early development, and immune escape of KM-LUAD. Aim 2 will probe effects of CD24 blockade on tumor-immune co-evolution and response of KM-LUAD to RAS inhibitors, determine transcriptional mechanisms underlying CD24 induction by RAS-targeted therapy, and characterize the association of CD24 activation with response in patients with KM-LUAD treated with neoadjuvant KRAS inhibition or standard-of-care KRAS-targeted therapy. Our project uses vertebrate mouse models because they are necessary to model the evolution of KM-LUAD and its complex immune microenvironment over the pathological lifetime of the tumor and to study new drug combinations for generating preclinical assessment of efficacy all of which cannot be sufficiently replicated by in vitro systems, organoids, or computational modeling. At the completion of our studies, we will have unraveled the roles of CD24 signaling in development of KM-LUAD and determined how this highpotential target can be therapeutically leveraged to enhance response of the disease to KRAS-targeted therapy.


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 = $669,540 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	6/16/2026	NEW	$669,540
														Subtotal = $669,540

Grand Total All Awards = $669,540

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Elucidating roles of the CD24 ligand in early lung cancer development, immune evasion and response to KRAS-targeted therapy

Award Number: R01CA301423

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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