# Developmental and Hyperactive Ras Tumor (DHART) SPORE

> **NIH NIH U54** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $2,198,683

## Abstract

ABSTRACT – OVERALL
 Neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome of a
group of developmental disorders that are collectively termed “Rasopathies”. Germline NF1 mutations cause
neurofibromatosis type 1 (NF1), a multi-system developmental disorder that is also the most common inherited
cancer predisposition syndrome. NF1 is of exceptional importance in cancer biology because it encodes a
GTPase activating protein (GAP) called neurofibromin that binds to active Ras-GTP and terminates signaling
by accelerating guanine nucleotide hydrolysis. Thus, NF1 inactivation and somatic cancer-associated RAS
mutations result in constitutively elevated Ras-GTP levels and aberrant activation of Ras-regulated kinase
effector pathways in susceptible cell lineages. A markedly increased incidence of developing specific benign
and malignant tumors is a hallmark of NF1 that results in substantial morbidity and mortality that affect
children, adolescents, and young adults (AYAs) in a range of tissues. Investigating NF1-associated tumors
represents a unique opportunity to interrogate therapeutic responses and mechanisms of intrinsic and acquired
drug resistance in cancers that are initiated by a mutation that directly enhances Ras output. Given the central
importance of aberrant Ras/GAP function in human cancer, and the emerging role of somatic NF1 mutations in
common sporadic malignancies, achieving the goals of this SPORE will broadly advance translational cancer
research and treatment. The overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPORE
is to implement effective targeted therapies for neoplasms and cancers characterized by mutations in the NF1
tumor suppressor gene (TSG) by conducting integrated, mechanistically based translational research. The
DHART SPORE deploys novel organizing principles and approaches to address the key challenge of how to
accelerate new therapies for uncommon (“orphan”) benign and malignant tumors across an organ spectrum
with a common driver mutation. The DHART SPORE is comprised of a highly integrated group of translational
scientists that are addressing central issues for implementing mechanism-based treatments for rare tumors
driven by hyperactive Ras signaling in the pediatric, adolescent, and young adult (AYA) population. Across all
three projects, state-of-the-art core facilities will inform the patient-oriented therapeutic and prevention aspects
by delineating mutations that contribute to cancer pathogenesis, and by uncovering new biomarkers of drug
response and resistance that will inform the development of “next generation” treatments. Achieving the
objectives of the proposed Projects 1-3 will not only improve the outcomes of NF1 and non-NF1 patients with
specific cancers but has the potential to inform new therapeutic approaches for the substantial proportion of
human cancers characterized by somatic NF1 and RAS mutations that have implications for enhancing the
...

## Key facts

- **NIH application ID:** 10270577
- **Project number:** 2U54CA196519-06A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** David W Clapp
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,198,683
- **Award type:** 2
- **Project period:** 2015-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10270577

## Citation

> US National Institutes of Health, RePORTER application 10270577, Developmental and Hyperactive Ras Tumor (DHART) SPORE (2U54CA196519-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10270577. Licensed CC0.

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