# The role of PTEN feedback mechanism in cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

Project Summary/Abstract
There remains a fundamental gap in our understanding of how PTEN maintains a tumor-suppressive
physiological level, and how this level becomes deregulated in cancer which renders PTEN biology in human
cancer largely incomprehensible. Our long-term goal is to fill that gap, and thereby enable the development of
novel targeted therapeutics for treating cancer. The specific objective of this application is to identify novel
regulatory mechanisms of PTEN signaling for preventative and therapeutic purposes. Our central hypothesis is
that PTEN is auto-regulated by feedback mechanism, and that this novel PTEN “integrated circuit” plays an
important role in tumor suppression and could offer exciting new options for cancer therapy. This hypothesis
has been formulated on the basis of preliminary data produced in the applicant's laboratory. The rationale for
the proposed research is that once we know how PTEN dosage is regulated in cancer, the activity of PTEN
modulators can likely be manipulated pharmacologically to restore PTEN expression, resulting in new and
innovate approaches to prevention and therapy. Guided by strong preliminary data, we will test our hypothesis
by pursuing three specific aims: 1) To define, in knockout mice, the role of a novel physiological deubiquitinase
(DUB) for PTEN in tumorigenesis; 2) To determine the molecular basis of the crosstalk between the DUB and
PTEN-PI3K-AKT networks; and 3) To assess the benefit of PTEN restoration induced by pharmacological
activation of DUB as a promising therapeutic option. Under the first aim, a series of PTEN specific DUB
knockout mouse models, which have been already created and found feasible by the applicant, will be
characterized for tumorigenesis. Under the second aim, the applicant's identification of PTEN specific DUB as
a novel, essential downstream target of the PI3K-AKT pathway will be further verified to explore a possible link
between the DUB and PTEN-PI3K-AKT networks in tumorigenesis. Under the third aim, a preclinical evaluation
of an already proven agent activating PTEN DUB and combined therapy with inhibitors of PI3K or PARP will be
undertaken in genetic models of cancer. This approach is innovative in that it explores the regulation of PTEN
dosage and activity by a novel, critical PTEN feedback mechanism as a source of exciting new therapeutic
opportunities, and the applicant is confident the resulting findings will open new horizons for therapeutic
research. The proposed work is also significant in that it is expected to vertically advance and expand
understanding of how PTEN-integrated signaling networks are deregulated in many human cancers.
Ultimately, therapeutic interventions designed to advance the PTEN feedback mechanism could prove useful
in blocking cancer development, and so hold great preventative and therapeutic promise.

## Key facts

- **NIH application ID:** 9973085
- **Project number:** 5R01CA196740-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Min Sup Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973085

## Citation

> US National Institutes of Health, RePORTER application 9973085, The role of PTEN feedback mechanism in cancer (5R01CA196740-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973085. Licensed CC0.

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