# Targeting Aldehyde Dehydrogenase for Cancer Prevention

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $641,281

## Abstract

ABSTRACT:
In cancer, aldehyde dehydrogenase (ALDH) enzyme activity is high in dendritic cells and regulatory T-cells,
hypothesized to modulate the immune response and also in cancer stem cells (CSCs) to aid the development of
recurrent resistant disease. It is therefore surprising that drugs targeting ALDH have not been developed to
modulate these processes in cancer. To investigate this issue, we tested the efficacy of existing isoform-specific
and broad-spectrum ALDH inhibitors on cultured cells and found that none were very effective at modulating cell
survival. Furthermore, we predicted that a broad-spectrum inhibitor would be needed due to the overlapping
functions of the ALDH family members. These observations provided the rationale to develop a non-toxic broad-
spectrum ALDH inhibitor, which would kill ALDH+ CSCs to prevent recurrent resistant disease, and improve
immunotherapy of melanoma. Thus, the central hypothesis is that a non-toxic ALDH inhibitor can be developed
to reduce recurrent resistant disease development mediated by ALDH+ CSCs and improve the efficacy of
existing immunotherapies by reducing immune suppression. Preliminary data show development of a potent
non-toxic ALDH inhibitor built on the backbone of the Isatin natural product. This agent eliminates CSCs with
high ALDH activity, preventing increases in ALDH+ cells typically seen with traditional drug treatments. Finally,
the inhibitor improves the preclinical efficacy of anti-PD1 immunotherapy in a syngeneic mouse melanoma model
where this approach alone is not effective. Based on these hypothesis-supporting preliminary data, the following
Specific Aims are proposed. First, determine how effectively a non-toxic broad-spectrum ALDH inhibitor
eliminates the melanoma ALDH+ CSC population that expands when treating with traditional chemotherapy.
Furthermore, determine its potency when combined with traditional chemotherapy to prevent recurrent resistant
disease development. This will be achieved by isolating ALDH+ and ALDH- cell populations from cell lines and
patient derived (PDX) tumors and determining inhibitor efficacy for preventing recurrent resistant disease
development when provided in combination with current clinically relevant chemotherapy. Finally, the
mechanistic basis for inhibition of resistance by the agent combination will be identified. Second, determine the
efficacy of a non-toxic broad-spectrum ALDH inhibitor on immune regulatory and effector cells in the tumor
microenvironment, alone and when combined with anti-PD1 antibody immunotherapy. Specific targeting of
ALDH in melanoma tumor cells and in host cells on therapeutic efficacy will be tested. Mechanisms leading to
enhanced immune response will be identified by defining the impact of the inhibitor and antibody combinations
on immune cell composition and function within the tumors, assessing the relative ALDH levels in the immune
cell populations, and using transient and genetic approaches to target the...

## Key facts

- **NIH application ID:** 9973328
- **Project number:** 1R01CA241148-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** SHANTU G AMIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $641,281
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973328

## Citation

> US National Institutes of Health, RePORTER application 9973328, Targeting Aldehyde Dehydrogenase for Cancer Prevention (1R01CA241148-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973328. Licensed CC0.

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