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Advancing Pan-RAS Inhibitors for Colorectal Cancer Interception: A Dual Approach Integrating Natural Product Drug Discovery and Preclinical Development

Award Number: R01CA316420
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Advancing Pan-RAS Inhibitors for Colorectal Cancer Interception: A Dual Approach Integrating Natural Product Drug Discovery and Preclinical Development - Mutations in RAS genes are responsible for about 30% of all human cancers and up to 50% of colorectal cancer (CRC) cases by activating KRAS, HRAS, and NRAS isoforms, which induce complex signaling pathways essential for tumorigenesis. RAS is an ideal target for CRC interception because it is either activated by mitogens in the tumor microenvironment or by gain-of-function mutations to drive adenoma-adenocarcinoma progression. While FDA-approved mutant-specific KRAS inhibitors have shown therapeutic promise, their utility for prevention is limited due to the heterogeneity of KRAS mutations and compensatory signaling from non-mutant RAS isoforms. A pan-RAS inhibitor capable of selectively eliminating premalignant adenoma cells harboring mutant or activated KRAS to block progression to CRC represents a transformative approach for CRC interception. Here, we describe a novel pan-RAS inhibitor, ADT-1004, that has shown robust and durable antitumor activity in mouse models of pancreatic cancer. We propose studies to assess efficacy and safety for CRC interception using a mouse model of colon tumorigenesis and to compare with another pan-RAS inhibitor, RMC-6236 (daraxonrasib), recently reported to significantly increase the survival of pancreatic cancer patients in phase 3 clinical trial. Given that safety is paramount for prevention, we also propose an innovative drug discovery and development campaign to advance a potentially safer and more efficacious pan-RAS inhibitor toward clinical development. For this secondary goal, we will screen a chemically diverse library of natural products (NP) in a series of assays to identify novel pan-RAS inhibitors potentially safer and more efficacious than either ADT-1004 or RMC-6236. Our screening strategy integrates cutting-edge phenotypic screening with advanced analytical and computational tools. Lead compounds from botanicals or traditional medicines will be prioritized and assessed for oral bioavailability, tolerance, and RAS selectivity, followed by evaluation of efficacy in the same mouse colon tumorigenesis model used to evaluate and compare ADT-1004 and RMC-6236. Hence, Aim 1 will evaluate and compare the chemopreventive efficacy and safety profiles of ADT-1004 and RMC-6236 in an AOMinduced RAS-driven mouse model of colorectal tumorigenesis and validate biomarkers for Aim 4. Aim 2 will curate and screen a library of traditional herbal medicines to identify NP extracts with pan-RAS inhibitory activity using cellular assays relevant to CRC interception and prioritize active extracts for purification in Aim 3. Aim 3 will fractionate and purify compounds from active NP extracts using computational and biochemical methods, followed by predictive assays of safety and drug-like properties to prioritize leads for in vivo evaluation in Aim 4. Aim 4 will determine the chemopreventive efficacy of an NP-derived pan-RAS inhibitor and benchmark its target selectivity, efficacy, and safety against either ADT-1004 or RMC-6236 as determined in Aim 1. The proposed mouse studies will allow for the assessment of whole-body effects and predicting human safety that cannot be replicated in vitro and are critical for determining whether the approach is suitable for clinical translation.


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 = $493,227 )
2026	2026	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Cause and Prevention Research	000	1	9/10/2026	NEW	$493,227
														Subtotal = $493,227

Grand Total All Awards = $493,227

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Advancing Pan-RAS Inhibitors for Colorectal Cancer Interception: A Dual Approach Integrating Natural Product Drug Discovery and Preclinical Development

Award Number: R01CA316420

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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