# Systematic Characterization and Targeting of Neomorphic Drivers in Cancer

> **NIH NIH U01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $813,823

## Abstract

PROJECT SUMMARY/ABSTRACT
More than 3 million somatic mutations and fusion genes have been identified in cancer. However, our ability to
predict functional consequences and the therapeutic relevance of these somatic aberrations remains a major
challenge. More critically, we have not solved the challenge of how to effectively target neomorphic aberrations
where functional consequences on tumor cell-intrinsic or tumor microenvironment processes are
altered through critical changes in regulatory processes, binding partners, or cellular locations, leading
to novel and unpredictable functions. To address this challenge, in response to PAR-21-274, we propose a
CTD2 Center that will employ
identify,
biomarkers.
state-of-the-art, high-throughput computational and experimental approaches to
characterize, validate, and target novel neomorphic drivers as well as nominate related predictive
We have selected glioma, sarcoma, and endometrial cancers for proof of concept as they represent
high unmet need cancer types that are driven by point mutations and fusion genes and encompass divergent
tissues of origin. Of the driver genes we identified, ~15% of the point mutations and ~30% of the fusions are
estimated to have neomorphic effects.
understanding
metastasis
possibly
determine
strategies
Our application wil address three key areas listed in the PAR: (i) improve
of gene functions in pathways and cellular wiring important in cancer initiation, progression, and
within the context of a few human tumors; (ii) identify and confirm candidate biological targets, and
associated predictive markers, involved in cancer etiology which are amenable to modulation; and (iii)
how these context-specific neomorphic pathways can be harnessed in combination with established
that target the immune system, and identify mechanisms of resistance. Based on the success of our
l
current CTD2 project, we have assembled a collaborative, productive, interdisciplinary team comprising Drs. Mills
(tumor biology/clinical trials), Deneen (molecular genetics/electroporation tumor models), Liang (computational
biology), and Chen (innovative algorithms) and will pursue three Specific Aims; Aim 1: To develop
computational algorithms for predicting neomorphic driver aberrations. Aim 2: To identify and elucidate
mechanisms underlying potential neomorphic driver aberrations. Aim 3: To elucidate therapeutic
liabilities engendered by neomorphic driver aberrations. We have chosen to evaluate neomorphic drivers
because they, as a class, have new and unpredictable functions that confound molecularly informed decisions,
potentially contributing to the failure of targeted therapy in many patients. By understanding how neomorphic
aberrations affect downstream function within the protein and cellular pathways in tumor cells and the tumor
microenvironment, we will identify therapeutic opportunities that can be directly tested in human clinical trials, as
demonstrated in the current CTD2 project (>10 trials laun...

## Key facts

- **NIH application ID:** 10931653
- **Project number:** 5U01CA281902-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Benjamin Deneen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $813,823
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931653

## Citation

> US National Institutes of Health, RePORTER application 10931653, Systematic Characterization and Targeting of Neomorphic Drivers in Cancer (5U01CA281902-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10931653. Licensed CC0.

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