Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting

Award Number: R01CA299084
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/09/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

Group Awards By:

View Award Description

Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting - Summary KRas is the most commonly mutated oncogene in human cancers. A deregulated KRas GTPase activity is the consequence of each of the mutations. Currently, there are limited FDA approved drugs to counter tumors having activating Ras mutations. An active anti-KRas remedy would be a major advancement for the treatment of many cancers. To that end, the AM510 is an improved version of the KRasG12C inhibitor that is the first to enter to clinical testing and exhibited beneficial efficacy in 4 non-small cell lung cancer (NSCLC) patients recently approved by FDA for advanced lung cancer treatment. However, unlike other KRas mutants such as KRasG12V accounting for the vast majority of KRas mutations, KRasG12C only occurs in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer and 2% of other solid cancers, thus greatly limiting the use of AM510 in targeting human cancers with other types of KRas mutations and/or KRas overexpression. To overcome this problem, it will be crucial to identify other strategies and targeted agents to combat KRas-driven cancers. Although KRas mutations are frequently found in human cancers, amplification of KRas, albeit less frequent, has also been reported in certain types of human cancers. In both cases, activation of downstream Raf/MEK/ERK (MAPK) and PI3K/Akt kinase cascades represent key mechanisms that drive malignant tumor phenotypes through Ras, establishing a molecular basis for targeting Ras-driven cancers by inhibiting downstream kinase cascades. However, combination of inhibitors simultaneously targeting MAPK and Akt cascades fail to exhibit clinical efficacy in KRas-driven cancers, suggesting that other effectors downstream of activated KRas contribute to treatment failure. By screening an amide compound library with >30,000 compound in the cell-based viability assay and in vivo tumor assays, we identify the compound #1a as a promising lead compound that selectively and potently targets mutant KRas driven cancer survival and in vivo tumor growth in xenografts, patients- derived xenografts (PDXs) and genetic models without affecting normal cell survival and causing mouse toxicity. Of note, the lead compound #1a binds to a novel downstream effector of mutant KRas, which is crucial for cancer cell survival in the context of mutant KRas activation, and disrupts its activity leading to cancer cell catastrophe. In this proposal, we proposed three specific Aims to explore the efficacy of the lead compound #1a and its derivatives and their underlying mechanisms in targeting mutant KRas driven cancers using diverse tumor models. Our proposal is highly original and innovative, as we have developed a lead compound for targeting mutant KRas cancer and utilized cutting technologies including medicinal chemistry, genetic mouse models, and PDX models to validate our provocative concept. We have assembled a unique research team with diverse expertise that is highly capable of conducting the study. Our study provides novel downstream effectors for mutant KRas signaling and develops an effective strategy/agent for targeting mutant KRas-driven cancer, thus revolutionizing our understanding of KRas signaling and therapies for targeting mutant KRas driven cancers.


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 = $693,403 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	1	6/10/2026	NEW	$693,403
														Subtotal = $693,403

Grand Total All Awards = $693,403

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting

Award Number: R01CA299084

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/09/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer