The researchers discovered that existing drugs targeting autophagy were effective in drug-resistant human tumors grafted onto mice, in some cases nearly eradicating the cancer. Genes regulating autophagy are often dysfunctional in ovarian cancer.
This raises the possibility that a five-drug cocktail could be effective on otherwise resistant ovarian cancers, according to a study led by Dwayne Stupack and Joe Delaney of UCSD Moores Cancer Center. Moreover, the strategy might work against other cancers.
Drugs in the cocktail are chloroquine, nelfinavir, rapamycin, dasatinib and metformin. The cocktail is called COAST, for Combination of Autophagy Selective Therapeutics.
“COAST therapy should be clinically tested in OV (ovarian cancer), given its strong effects, minimal toxicity, and genetic rationale,” the study stated.
The study was published Feb. 15 in the journal Nature. It can be found at j.mp/ovcancer.
Ovarian cancer is usually responsive to initial treatment, but tends to recur. Each recurrence becomes harder to treat, as the cancer cells develop drug resistance. Developing new drugs to beat resistant tumors has been impeded by a lack of good targets.
Cancers are considered genetic diseases, caused by mutations, chromosomal rearrangement and other changes caused by the instability of the malignancy’s genome. Cancer researchers have traditionally searched for telltale mutations in important genes that drive the cancer’s progression. One of the most famous is p53, which in its normal state suppresses cancer. Such mutated genes are known as oncogenes.
“Interestingly, 48 percent of studied tumors have no mutations in these oncogenes or tumor suppressors, other than p53,” the study stated.
Since mutant p53 can’t cause cancer alone, the researchers decided to look at another effect of genomic instability, the loss or gain of copies of genes. These are called SCNAs, or somatic copy-number alterations.
Genes mostly come in pairs, one inherited from each parent. Often, just one functioning gene is enough to ward off disease. For example, a person carrying one mutation that causes sickle-cell anemia and a normal partner gene is a healthy carrier, but two mutant copies cause the disease.
This might not be the pattern in some cancers, the researchers reasoned. If multiple related genes were lost or duplicated, resulting in just one copy or three copies, the cumulative disruption of molecular pathways might perturb the cell enough to cause cancer.
To investigate this possibility, Delaney and colleagues designed software called HAPTRIG, for Haploinsufficient/Triplosensitive Gene. HAPTRIG searched for molecular pathways significantly disrupted by such omissions or duplications.
Using HAPTRIG, the team homed in on the autophagy system as a promising target for intervention.
“Our study suggests that a roadmap of targetable genetic changes in tumors should not be limited to mutations,” said Stupack, said in a UCSD statement. “HAPTRIG may reveal additional targetable pathways across cancer types. We have provided a free web tool to allow the community to easily perform a HAPTRIG analysis on 21 cancer types.”
The tool can be found at j.mp/haptrig.
Research funders include the National Cancer Institute and the Nine Girls Ask Foundation.
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