# Mitigation of Radiation Induced Gastrointestinal Syndrome.

> **NIH NIH R44** · BCN BIOSCIENCES, LLC · 2023 · $1,034,934

## Abstract

Abstract:
Currently RAS has been considered a high value target in cancer drug development considering
that over 30 percent of all human cancers – including 95% of pancreatic cancers and 45% of
colorectal cancers — are driven by mutations of the RAS family of genes. The first clinical
launch of a G12C KRAS inhibitor is Lumakras™ (sotorasib) from Amgen for non-small cell lung
carcinoma and Mirati Adagrasib™ is on the way to approval with its G12C inhibitor however, the
development of G12D and V inhibitors of KRAS are stalled in the preclinical realm with similar
strategies used for G12C inhibitors which is likely more difficult or impossible to apply to other
mutations. In addition, then there is also the challenge of overactive wildtype RAS mutations
where targeting mutations in the protein become difficult with an overactive RAS pathway which
can result from RAS upregulation or dysregulation of its partnering proteins. This is not
addressed by the current approaches which seeks to inhibit the mutant forms only but in fact
has led to a mechanism of resistance within the mutant forms of RAS with a complex network of
pathways where isotypes of RAS are involved. Here we present what is unfolding as another
possible target for oncogenic RAS. A hallmark of all oncogenic RAS is suppression of
Phosphatase and tensin homolog is a phosphatase (PTEN) expression. PTEN is a multi-
functional tumor suppressor that is very commonly lost in human cancer but is a requirement in
cancerous RAS signaling to prevent the cells from being able to die (causing immortalization).
Thus, this is widely regarded as a driver mutation. The other hallmark of oncogenic RAS
signaling is a protein known as GSK3 is overexpressed. We have recently reported BCN057
restores PTEN expression to abrogate the immortalized phenotype in oncogenic KRAS. Why
this is important is because the signal transduction “wiring” appears to differ in KRAS mutant vs
normal tissue. Thus, normal tissue responds by increasing its resistance to chemotherapy and
radiation while inducing cell death in the KRAS mutant tumor cells resulting in an increase in the
therapeutic index. This is a breakthrough for oncogenic KRAS epithelial cancers and colorectal
cancer treatment and may eventually have significant implications for a variety of cancers. In
the US alone there are over 150,000 new cases of colorectal cancers and studies like
Foundation Medicine (FM) estimate a KRAS mutation frequency of approximately 50%. In
summary, the proposed work will provide a clear path to subsequent studies related to product
development in a phase II application.

## Key facts

- **NIH application ID:** 10706240
- **Project number:** 1R44AI177220-01
- **Recipient organization:** BCN BIOSCIENCES, LLC
- **Principal Investigator:** Andrew John Norris
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,034,934
- **Award type:** 1
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706240

## Citation

> US National Institutes of Health, RePORTER application 10706240, Mitigation of Radiation Induced Gastrointestinal Syndrome. (1R44AI177220-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10706240. Licensed CC0.

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