# Understanding Tumor Suppressive Functions of Protein Phosphatase 2A

> **NIH CA R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2026 · $651,038

## Abstract

Colorectal Cancer (CRC) is the third most common cancer in men and women. While the 5-year survival rate
for localized CRC is 91%, the survival rate is less than 14% for patients with disseminated disease. With few
exceptions, metastatic CRC is incurable, largely due to resistance to available therapies. As a result, CRC is the
second leading cause of cancer death in the U.S.A. These statistics highlight an urgent clinical need for develop-
ment of effective treatments for patients with advanced CRC. Aberrant cap-dependent mRNA translation initia-
tion (CDT) has emerged as an attractive target for the clinical management of CRC based on its key role in
supporting selective synthesis of crucial oncogenic drivers such as growth factors, cell cycle regulators, anti-
apoptotic proteins, and Myc. A key negative regulator of CDT is 4E-BP1 which blocks the formation of the
translation initiation complex, eIF4F, by stochiometric binding to eIF4E. 4E-BP1 acts as a nexus for aberrant
upregulation of CDT by oncogenic signaling pathways that drive CRC (e.g., Wnt/β-catenin, RAS/RAF/ERK,
PI3K/AKT/mTOR). These pathways inactivate 4E-BP1 by (a) inhibitory phosphorylation, and/or (b) reducing the
4E-BP1:eIF4E ratio through upregulation of eIF4E or downregulation of 4E-BP1. Inactivation of 4E-BP1 is not
only critical for the transformed phenotype but is also a major mechanism underlying failure of targeted
therapeutics, including inhibitors of mTOR and the ERK pathway, which rely on inhibition of CDT for their
antitumor effects. Thus, restoration of 4E-BP1 holds promise for sensitization of CRCs to a broad range of
targeted agents. This proposal builds on our finding that a subset of protein phosphatase 2A (PP2A) heterotri-
mers are potent regulators of 4E-BP1 and CDT. Our group has developed first-in-class Small Molecule Activators
of PP2A (SMAPs) that activate a subset of B56-PP2As for tumor suppression in CRC and other cancer types. A
lead SMAP (EV440/SW-3431) is in clinical devel

## Key facts

- **NIH application ID:** 11298549
- **Project number:** 1R01CA300564-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Jennifer D. Black; Goutham  Narla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $651,038
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2031-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11298549

## Citation

> US National Institutes of Health, RePORTER application 11298549, Understanding Tumor Suppressive Functions of Protein Phosphatase 2A (1R01CA300564-01A1). Retrieved via AI Analytics 2026-05-17 from https://api.ai-analytics.org/grant/nih/11298549. Licensed CC0.

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