# Therapeutic vulnerabilities associated with PTEN missense mutations

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $204,531

## Abstract

Project Summary/Abstract
Genetic loss or acquisition of missense mutations within the phosphatase and tensin homolog (PTEN) gene is
a frequent event in glioblastoma multiforme (GBM). Loss of PTEN activity leads to a robust activation of PI3K
signaling due to its established role as a lipid phosphatase but also to an activation of the MAPK pathway.
Missense mutations within PTEN that retain phosphatase catalytic activity are common in GBM and we
demonstrate their capacity to drive gliomagenesis in vitro. The molecular mechanisms by which these
mutations abrogate PTEN's tumor suppressive function are unknown and represent a crucial area of research
in cancer. We hypothesize that phosphatase activity-retaining missense mutations are not synonymous
to complete loss of PTEN or phosphatase activity dead missense mutants in their mechanisms of
tumor suppression and represent distinct categories of PTEN driven cancers that will respond
differently to PI3K- and MEK-centric treatment regimens. On this basis, we propose to 1) develop new
PTEN genetically engineered mouse models of missense mutants and utilize these models to optimize
targeted therapies against PI3K and MEK, and 2) create isogenic PTEN missense mutant human GBM PDX
lines to uncover new PI3K and MEK inhibition strategies. The overall goal of the proposed research is to
deliver on an effective translational use of genetically cutting edge models of GBM that accurately recapitulate
human disease to direct research toward the development of new treatments.

## Key facts

- **NIH application ID:** 10056208
- **Project number:** 5R21CA245337-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Alain Charest
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,531
- **Award type:** 5
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056208

## Citation

> US National Institutes of Health, RePORTER application 10056208, Therapeutic vulnerabilities associated with PTEN missense mutations (5R21CA245337-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10056208. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*