# Exploiting vulnerabilities in GIST using novel combination therapies

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2021 · $427,763

## Abstract

Gastrointestinal stromal tumor (GIST) treated with targeted therapies such as imatinib mesylate (IM), sunitinib,
and regorafenib, generally escape disease control and progress over time. The current standard of care for
advanced inoperable GIST involves the sequential application of these inhibitors that target the activated forms
of the KIT or PDGFRA receptors found in GIST. We hypothesized that inhibiting additional molecular targets in
combination with IM may provide more substantial disease control. Recent studies have implicated the PI3-
kinase/AKT pathway in survival of IM-resistant GIST cell lines and tumors. We therefore challenged IM-
sensitive GIST xenografts with a novel combination of IM and an AKT inhibitor to test if the combination
enhanced disease stabilization afforded by front-line IM therapy. In these preliminary studies, the combination
therapy provided significantly improved efficacy as compared to treatment with monotherapy alone, as
measured by tumor response and animal survival. These results provide justification for additional pre-clinical
studies challenging various GIST xenografts modeling both intrinsic and acquired IM resistance, as described
in this proposal. To explore the molecular aspects of tumor response to this novel combination, we carried out
RNAseq studies on these xenografts, in the hope of identifying additional therapeutic targets for GIST. This
analysis was fruitful, identifying two genes, brain expressed, X-linked 1 (BEX1) and neuronal pentraxin I
(NPTX1), whose expression was significantly up-regulated only in combination-treated tumors. BEX1 and
NPTX1 have been implicated as tumor-suppressor genes in various cancers, and with the induction of
apoptotic pathways in diverse cell types. Specifically, BEX1 acts as a BCL-2 antagonist, inducing apoptosis by
binding BCL-2 and suppressing the formation of anti-apoptotic BCL-2/BAX heterodimers, while NPTX1
expression has been linked to enhanced mitochondrial translocation of pro-apoptotic BAD and BAX proteins
and enhanced neuronal cell death. We hypothesize that this combination results in induction of these two
genes that influence tumor cell fate by shifting the pro/anti-apoptotic balance towards cell death via the BCL-2,
BAD/BAX pathways, and may provide additional avenues to approach GIST treatment. This proposal seeks to
functionally test this central hypothesis, as well as to evaluate targeting members of these pathways in both
IM- sensitive and –resistant GIST xenograft models. The proposed studies are designed to provide support for
potential application of these novel therapeutic modalities in the clinical setting.

## Key facts

- **NIH application ID:** 10165655
- **Project number:** 5R01CA212662-05
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Lori Rink
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,763
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165655

## Citation

> US National Institutes of Health, RePORTER application 10165655, Exploiting vulnerabilities in GIST using novel combination therapies (5R01CA212662-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165655. Licensed CC0.

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