# Synthetic Lethal Targeting of Growth Factor Receptors

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $356,850

## Abstract

One of the greatest challenges facing the development of improved cancer therapeutics is the need to
selectively kill all of the cancer cells in a patient without harming normal cells. To achieve this high level of
selectivity, the genetic concept of synthetic lethality offers a promising strategy. This concept is based on the
observation that mutations in two different genes that both contribute an essential biochemical pathway, such
as the genes BRCA1/2 and PARP, can be exploited to make certain cancers uniquely sensitive to anticancer
agents. In this mechanism, disruption of either gene alone does not affect cellular viability, but agents or
mutations that affect both genes are lethal. Based on our preliminary research results, we propose here to
extend the concept of synthetic lethality to the targeting of pairs of growth factor receptors that drive the
proliferation of highly aggressive cancers. To accomplish this objective, we will create novel antibody
conjugates, similar in structure to the FDA-approved anticancer antibodies Kadcyla and Adcetris, designed
with the unique ability to synergistically kill cancer cells that express two distinct cell surface receptors. To
enable this cytotoxic synergy, one targeting antibody will be linked via a disulfide to a cell-impermeable
cytotoxin that is incapable of unaided passage across cellular membranes. When this first antibody binds a
specific growth factor receptor on the cell surface, and is internalized by endocytosis, the stability of the
disulfide, in conjunction with the cell-impermeability of the cytotoxin, will cause entrapment in membrane-
sealed endosomes. This entrapment will prevent toxicity unless membranes of these endosomes are disrupted
by co-administration with a secondary agent. To synergistically kill cancer cells, this antibody conjugate will be
co-administered with a second anti-growth factor antibody linked to a non-toxic endosome disruptive peptide.
Release of this peptide from the second antibody will form pores in endosomal membranes. These pores will
enable cytosolic glutathione to enter endosomes, break the disulfide bond linking the toxin to the first antibody,
and activate toxicity by enabling escape of the cytotoxin into the cytoplasm. This unique design of antibody
conjugates will provide high selectivity for killing specific cancer cells that express two distinct cell surface
receptors without affecting normal cells that express one of these two target proteins. This novel approach,
termed here synthetic lethal targeting, will be pursued by the synthesis of masked cytotoxins and endosome
disruptive peptides, the elucidation of mechanisms of pore formation in endosomal membranes, conjugation of
these agents to antibodies that bind the growth factor receptors EGFR, HER2, and HER3, and evaluation of
efficacy in vitro and in mouse models of cancer. Given that co-expression of HER2/EGFR and HER2/HER3 in
breast cancer, and EGFR/HER3 in lung and pancreatic cancer, drives ...

## Key facts

- **NIH application ID:** 10065292
- **Project number:** 7R01CA211720-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Blake Peterson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,850
- **Award type:** 7
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065292

## Citation

> US National Institutes of Health, RePORTER application 10065292, Synthetic Lethal Targeting of Growth Factor Receptors (7R01CA211720-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065292. Licensed CC0.

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