California researchers are now suggesting that analyzing copies of genes may point to new treatments for ovarian cancer as well as for other tumor types. The researchers contend that targetable genetic changes in tumors should not be limited to mutations. Instead, they are focusing on an alteration that result in the loss or gain in a copy of a gene.
In a paper published February 15 in Nature Communications, Delaney et al. describe the Haploinsufficient/Triplosensitive Gene (HAPTRIG) computational tool to identify pathways significantly disrupted by the loss and gain of genes. Ovarian cancer in particular is fraught with these alterations, with more than 60% of genes affected. When the team analyzed ovarian cancer using HAPTRIG, the pathway that stood out was autophagy, which is a natural process of cell death that helps maintain normal cellular health. Looking at 187 pathways, autophagy was found to be the most significantly disrupted by coincident gene deletions.
“When most people think about cancer genetics, they think about single key mutations that foster tumor formation, very specific things like the BRCA genes,” said lead study author Joe Delaney, PhD, a fellow in the Clinical Translation program at UC San Diego Moores Cancer Center in San Diego. “These changes are often referred to as tumor drivers but these are not the only deviations that impact cancer growth. We explored other possibilities.”
The researchers used a combination of existing US Food and Drug Administration approved drugs to target autophagy and found ovarian cancer cells to be highly sensitive to these drugs in several different mouse cancer models, even among cells resistant to standard chemotherapy.
Human ovarian cancer cells were found to be highly sensitive to challenge with autophagy-targeting agents, suggesting a new approach to treating this tumor type. The combination of drugs appeared to be less toxic than standard chemotherapy and the combination was relatively inexpensive. The researchers contend these agents warrant further investigation.
They note that more than 90% of genetic changes in cancer cells involve the loss or gain of a single copy of a gene, rather than a mutation. Currently, the researchers are providing a free web tool to allow clinicians to perform a HAPTRIG analysis on 21 cancer types. The researchers theorized that evaluating the copy-number landscape of a tumor may help lead to improved outcomes. With further work, these findings could lead to new approaches to treat chemotherapy-resistant disease, and could enhance treatment of other cancers as well, according to the authors.