# Exploiting Cancer Metabolism and Drug Efflux with Bystander-Assisted Immunotherapy

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $343,885

## Abstract

ABSTRACT. Two hallmarks of drug resistance in cancers are irregular metabolism and drug efflux. In multidrug-
resistant cancers, both of these processes disarm the efficacy of chemotherapeutics, ultimately resulting in de-
creased chemotherapeutic efficacy and increased mortality. Several strategies in development attempt to miti-
gate the effects of drug resistance by modulating specific metabolic pathways or disrupting drug efflux. Specifi-
cally, these strategies include inhibitors, interference RNAs, and nanomedicine approaches. However, a funda-
mental challenge to these strategies is the off-target toxicity that arises from disrupting metabolism or drug efflux
mediated by P-glycoprotein (P-gp), as these mechanisms are also critical to a number of healthy processes
throughout the body. To address this, our long-term objective is to develop a therapeutic strategy that exploits
both of these mechanisms of drug resistance in tandem to generate a therapeutic anti-cancer immune repsonse.
Our central hypothesis is that rationally designed prodrugs can co-opt cancer cell metabolism and drug efflux to
cause an anti-cancer immune response via a mechanism of action we have termed Bystander Assisted Immu-
noTherapy (BAIT). In BAIT, an enzyme-directed prodrug is first metabolized to an immunotherapeutic metabolite
by the irregular metabolism of multidrug-resistant cancer cells. Next, the immunotherapeutic is transported, via
P-gp-mediated drug efflux, to the extracellular space. This results in the activation of bystander immune cells in
local proximity, which initiate an anti-cancer immune response. Because BAIT requires tandem metabolism and
drug efflux, we anticipate a uniquely enhanced specificity for multidrug-resistant phenotypes that exhibit both of
these processes. To develop rationally designed BAIT prodrugs, we first identify small-molecule immunothera-
peutics that are susceptible to drug efflux. In concurrent studies, we also develop synthetic enzyme-directing
groups that modulate the activity of immunotherapeutics and are specifically removed by enzymes expressed in
the irregular metabolism of multidrug-resistant cancer cells. Combining these two research areas, we generate
enzyme-directed BAIT prodrugs that confer immunogenicity to multidrug-resistant cancers. In-vitro, this is con-
firmed in co-cultures of immune cells and cancer cell lines that express these metabolic enzymes and P-gp. In-
vivo, we use a murine model system for prostate cancer (TRAMP-C2 allograft) to demonstrate that BAIT pro-
drugs result in lowered toxicity, decreased tumor volume, and increased progression-free survival, relative to
conventional immunotherapeutics in immunocompetent mice. Taken together, we envision that this research will
establish BAIT as a therapeutic strategy that is enhanced, rather than disarmed, by drug resistance. It is our
long-term vision that this strategy could be widely applicable to multidrug-resistant cancers that evade the action
of co...

## Key facts

- **NIH application ID:** 9986695
- **Project number:** 5R01CA234115-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Rock Mancini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,885
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986695

## Citation

> US National Institutes of Health, RePORTER application 9986695, Exploiting Cancer Metabolism and Drug Efflux with Bystander-Assisted Immunotherapy (5R01CA234115-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9986695. Licensed CC0.

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