# Tumor suppressor vulnerability conferred by aneuploid loss of haploinsufficient metallothionein genes

> **NIH NIH DP2** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $1,359,000

## Abstract

Abstract
Cancer will rarely be cured through pharmacologic targeting of single genes. Tumors evolve in response to
selection pressure. Precision oncology often targets a single gene product, and that gene simply becomes
mutated once the drug is administered. Although individual genes may mutate, tumor biology is nonetheless
constrained to dysregulating specific pathways for each cancer type. We have previously created cutting-edge
bioinformatic tools to better understand which constrained pathways are acting as tumor suppressors and
oncogenes, due to collaborative gene dysregulation at the molecular pathway level. Aneuploidy is a major cause
of molecular pathway changes in cancer and unfortunately each aneuploid event alters both predicted driver
genes and unknown passenger genes. Investigation of causal aneuploid changes in a tumor remains difficult, if
not impossible, to study with current cell biology and genetic tools. However, we have discovered a unique,
commonly suppressed (70% of high-grade serous ovarian cancers have a monoallelic loss, correlating with
average reduced expression), pathway which is amenable to well-controlled basic science experimentation: the
cadmium response pathway. It is composed of 11 highly homologous metallothionein genes arrayed on a single
chromosomal locus. Metallothioneins sequester the bulk of intracellular Zn2+ and environmental genotoxic Cd2+
ions. The loss of the metallothionein locus is associated with chromosome instability and occurs early in tumor
formation. Our in vitro assays show controlled metallothionein suppression results in elevated DNA damage.
However, the role of metallothioneins as tumor suppressors and as regulators of cancer cellular and molecular
biology is largely unknown. This project will establish specific tumor suppressor phenotypes of metallothioneins
in ovarian cancer and determine if this aneuploid pathway will serve as a representative example of how multi-
genic vulnerabilities can better enable next-generation cancer therapies. We will (1) characterize in vivo the
effects of metallothionein gene loss in spontaneous tumor formation in ovarian cancer, (2) develop controlled
models of gene suppression enabling suppression of all 11 genes, including by a synthetic dead-Cas9-based
transcription factor, (3) determine which cadmium-dependent and cadmium-independent metallothionein-
regulated molecular pathways convey tumor suppressor functions, and (4) discover drug classes which best
selectively kill low-metallothionein cells. Genetic tools created by this project will enable causal investigation of
entire molecular pathways for future projects. Taken together, this innovative research program will directly test
how an uncharacterized aneuploid-suppressed pathway contributes to oncogenesis and remains a
pharmacologically targetable vulnerability throughout tumor development.

## Key facts

- **NIH application ID:** 10469891
- **Project number:** 1DP2CA280626-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Joe R Delaney
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,359,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469891

## Citation

> US National Institutes of Health, RePORTER application 10469891, Tumor suppressor vulnerability conferred by aneuploid loss of haploinsufficient metallothionein genes (1DP2CA280626-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10469891. Licensed CC0.

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