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Deciphering the Role of Tumor Suppressor Gene Deficiencies in Modulating PDAC Response to Oncogenic KRAS Inhibition and Immunotherapy

Award Number: K99CA312836
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Deciphering the Role of Tumor Suppressor Gene Deficiencies in Modulating PDAC Response to Oncogenic KRAS Inhibition and Immunotherapy - Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a five-year survival rate under 12%. More than 80% of PDAC tumors harbor oncogenic KRAS mutations, most commonly KRASG12D. Although recent development of oncogenic KRAS inhibitors represents a significant therapeutic advance, early clinical and preclinical studies have revealed only modest and transient responses, underscoring an urgent need to better understand resistance mechanisms and identify combinatorial treatment strategies. Emerging evidence suggests that co-occurring tumor suppressor gene (TSG) alterations, particularly in CDKN2A and SMAD4, may profoundly influence tumor behavior and therapeutic response. These TSGs are frequently inactivated in KRASmutant PDAC and are associated with worse prognosis, increased metastatic potential, and poor response to therapy. However, how these genetic contexts modulate resistance to KRAS inhibition remains poorly defined. This proposal aims to elucidate the role of TSG deficiencies in modulating therapeutic response to oncogenic KRAS inhibition and to identify new vulnerabilities for precision therapy tailored to specific context of TSG deficiencies. In the K99 mentored phase (Aim 1), I will use isogenic patient-derived organoid (PDO) and xenograft (PDX) models to investigate how loss of CDKN2A or SMAD4 alters PDAC cell state transition and tumor-intrinsic responses to oncogenic KRAS inhibition. I will profile treatment-induced transcriptional rewiring and validate phenotypes in vivo using orthotopic xenograft models. In the R00 independent phase (Aim 2), I will employ single-cell RNA sequencing and spatial transcriptomics and proteomics to characterize how TSG deficiencies shape the cellular and spatial landscapes of PDAC tumors under KRAS inhibition. This will uncover resistant cell states and spatially organized regulatory networks. In my R00 phase (Aim 3), I will also assess the efficacy and durability of combined KRAS inhibition with triple immunotherapy (KRASi + Triple-IO) across a complete allelic series of genetically engineered mouse models (GEMMs) harboring individual or combined loss of TP53, INK4a/ARF, and SMAD4. I will also conduct comprehensive molecular and immune profiling of tumors from these survival cohorts to elucidate how tumor suppressor genotypes influence therapeutic response and drive mechanisms of relapse. Together, this integrated approach will provide mechanistic insight into KRAS inhibitor resistance and tumor immune microenvironment reprogramming driven by TSG deficiencies and uncover novel genotype-tailored therapeutic targets. The proposed training in organoid engineering, spatial transcriptomics, and functional genomics, combined with mentorship from experts in cancer biology and immunotherapy, will position me to launch an independent research program focused on precision oncology for PDAC. Justification for the use of animal models in this project- Cancer is a systemic disease involving complex interactions within the tumor microenvironment that cannot be fully recapitulated in vitro. Therefore, in vivo assessment is required to evaluate tumor suppressor gene function and therapeutic response, and mouse models provide a well-established and physiologically relevant platform for these studies.


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 = $141,195 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Research Manpower	000	1	5/7/2026	NEW	$141,195
														Subtotal = $141,195

Grand Total All Awards = $141,195

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Deciphering the Role of Tumor Suppressor Gene Deficiencies in Modulating PDAC Response to Oncogenic KRAS Inhibition and Immunotherapy

Award Number: K99CA312836

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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