Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting
NCI - National Cancer Institute
About This Grant
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.
Grant Summary
Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting is a NCI - National Cancer Institute grant providing up to $693K for university, nonprofit, healthcare org. Applications are due 2031-05-31 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $693K
2031-05-31
- 1Confirm your organization is eligible for Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting from NCI - National Cancer Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NCI - National Cancer Institute before the deadline.
Don't want to draft it yourself?
We'll draft the complete application against NCI - National Cancer Institute's requirements, run a quality review, and email you a submission-ready PDF plus an editable Word doc within 5 business days. Most orders deliver in 24-48 hours. Flat $399, any grant size.
AI Requirement Analysis
Detailed requirements not yet analyzed
Have the NOFO? Paste it below for AI-powered requirement analysis.
Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting: Frequently Asked Questions
Who is eligible for the Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting?
Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting is offered by NCI - National Cancer Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting provide?
Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting provides up to $693K per award from NCI - National Cancer Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting deadline?
Applications for Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting are due 2031-05-31 (open). Because deadlines can change, verify the date with the funder, NCI - National Cancer Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting?
To apply for Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NCI - National Cancer Institute.