# Use of BCL-xL Proteolysis targeting chimeras to treat pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $515,151

## Abstract

PROJECT SUMMARY / ABSTRACT
In response to NCI PQ9, we propose to generate platelet-sparing BCL-XL Proteolysis Targeting Chimeras
(PROTACs) or BCL-XL-Ps for the treatment of cancer, particularly pancreatic cancer (PC), because BCL-XL is
one of the most important and best validated cancer targets and has been identified as the most important drug
resistance gene in human PC cells. Potent BCL-XL selective inhibitors and BCL-XL and BCL-2 dual inhibitors
such as ABT263 (or navitoclax) have been developed. However, the on-target and dose-limiting
thrombocytopenia of these inhibitors has hampered their clinical translation because platelets solely depend on
BCL-XL for survival. We hypothesize that we can circumvent BCL-XL inhibition-induced platelet toxicity by
converting ABT-263 into BCL-XL-Ps that target BCL-XL to an E3 ligase poorly expressed in platelets for
ubiquitination and degradation, because BCL-XL-Ps depend on the E3 ligase to promote BCL-XL ubiquitination
and degradation by the ubiquitin proteasome system (UPS). This hypothesis is supported by our preliminary
data demonstrating that our newly generated BCL-XL-Ps, which target BCL-XL to the cereblon (CRBN) or von
Hippel-Lindau (VHL) E3 ligase, are capable of degrading BCL-XL in various cancer cells examined but have
minimal effects on the BCL-XL levels in human platelets, because platelets express significantly lower levels of
CRBN and VHL than these cancer cells. As such, these BCL-XL-Ps are more potent against BCL-XL dependent
human cancer cell lines but significantly less toxic to platelets than ABT263 in vitro. Compared with ABT-263,
one of our lead BCL-XL-Ps exhibited improved antitumor activities in a number of xenograft mouse models
without causing thrombocytopenia. In addition, we found that the BCL-XL-Ps converted from ABT263 can
specifically degrade BCL-XL but not BCL-2, indicating that the conversion increased the specificity of ABT263. It
is well established that inhibition of BCL-XL can sensitize tumor cells to chemotherapy, whereas BCL-2 inhibition
exacerbates chemotherapy-induced neutropenia by suppressing granulopoiesis. Thus, this increased specificity
of BCL-XL-Ps can potentially reduce another on-target toxicity of ABT263, i.e. neutropenia, which is dose-limiting
and prevents the combination of ABT263 with a standard-of-care cytotoxic chemotherapeutic agent to treat
cancer. Furthermore, our BCL-XL-Ps are also potent senolytic agents that can selectively kill senescent cells
(SnCs) induced by chemotherapy and radiation, because SnCs also rely on BCL-XL for survival. Clearance of
chemotherapy-induced SnCs has the potential to improve the therapeutic efficacy of standard-of-care
chemotherapy, because SnCs play an important role in mediating the induction of many adverse effects of
chemotherapeutic drugs as well as promoting cancer chemoresistance, relapse and metastasis, in part via
expression of the senescence-associated secretory phenotype (SASP). Collectively, these finding...

## Key facts

- **NIH application ID:** 10476325
- **Project number:** 5R01CA242003-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jose G. Trevino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $515,151
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476325

## Citation

> US National Institutes of Health, RePORTER application 10476325, Use of BCL-xL Proteolysis targeting chimeras to treat pancreatic cancer (5R01CA242003-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10476325. Licensed CC0.

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