Scot Wolfe Awarded ACS Grant for CRISPR Cancer Research

Scot Wolfe, PhD, has received a two-year American Cancer Society Discovery Boost Grant — a program that supports high-risk, high-reward exploratory cancer research — to develop an innovative strategy for selectively killing cancer cells that harbor focal gene amplifications.

The approach leverages a CRISPR-Cas9 nickase to introduce site-specific single-strand DNA nicks. During DNA replication, these nicks can be converted into single-ended double-strand breaks when encountered by a replication fork. Although cells can typically repair an isolated break, a large number of replication-associated breaks can overwhelm repair pathways and trigger cell death.

Wolfe aims to harness this mechanism as a cancer cell-selective genotoxic strategy. By directing multiple nicks to genomic regions that are highly amplified in cancer cells, the approach is designed to generate a toxic burden of DNA damage in tumor cells while sparing normal cells that carry only one or two copies of the same sequence.

As proof of concept, the project will focus on neuroblastoma, a childhood cancer in which MYCN amplification occurs in about 20% of cases and defines a high-risk, aggressive form with poor prognosis. Wolfe’s group will optimize CRISPR-Cas9 nickases to induce targeted toxicity in MYCN-amplified neuroblastoma cells and evaluate therapeutic efficacy in vivo using a xenograft mouse model.

This work seeks to establish a new framework for targeting cancers driven by gene amplification. Because CRISPR-Cas9 targeting is programmable, the platform could be adapted to treat a broad range of cancer types that harbor focal gene amplification.

Read more about Dr. Wolfe's research program here.