New approach to attacking cancer: Find out what's gone and exploit it
When missing segments of the genome matter in cancer, it's bad news because those deletions have wiped out a gene that blocks or hinders cancer formation and growth.
But now scientists have found genomic deletions that expose weaknesses to exploit in malignant cells. These deletions occur as collateral damage to neighboring genes when tumor-suppressors are destroyed.
This week in Nature, Florian Muller, Ph.D., instructor in MD Anderson's Department of Genomic Medicine, and colleagues demonstrate how to identify and attack these vulnerabilities.
Working in cell lines and mouse models of glioblastoma multiforme, the most lethal form of brain tumor, the team discovered that when collateral damage erases a "housekeeping" gene that is vital to cell survival, cancer cells can be killed by blocking another gene that does the same job.
"In this case, we looked at passenger deletions - genes co-deleted along with tumor-suppressor genes, but not directly involved in cancer promotion - as a starting point for identifying potential targets and therapies," Muller said.
Most cancer research focuses on understanding and attacking active cancer-driving genes that are amplified or dysfunctional due to genetic mutations. Efforts to counter driver deletions of tumor-suppressors have yet to show promising results.
Innovative way to develop targeted therapies
The team identified a gene called ENO1 that is deleted in about 5% of glioblastoma cases on part of chromosome one that harbors candidate tumor-suppressing genes. When the scientists inhibited activity of ENO2, a gene on chromosome seven that backs up ENO1, they killed glioblastoma cells.
ENO1 and ENO2 both encode for the enzyme enolase, which carries out a mandatory step in glycolysis, the processing of glucose into energy that is important to solid tumors in general and glioblastoma in particular. Cells can tolerate the loss of ENO1 or ENO2, but not both.
Healthy brain cells were unaffected by treatment with an enolase inhibitor,as were glioblastoma cells with ENO1 intact.
"The principle of collateral vulnerability caused by passenger deletions of redundant essential genes provides the basis for a new approach to identify potential targets and develop targeted therapies," said MD Anderson President Ronald DePinho, M.D., senior author of the paper.
"These deletions are found in hundreds of genes in many types of cancer, so our model for glioblastoma multiforme should apply to developing personalized treatments for other cancers as well," DePinho said.
"Passenger mutations may be Achilles heel of cancer genomes"
Two independent scientists who wrote a commentary in Nature agreed. Ben Lehner and Solip Park of the Universitat Pompeu Fabra in Barcelona, concluded:
"Muller and colleagues' results provide an impetus for two major conceptual advances: first, that the loss of protein redundancy pro®Îvides a therapeutic opportunity to kill specific cells, and second, that passenger mutations may be the Achilles heel of cancer genomes.
"In our opinion, this second idea is the more important, and the plethora of passenger mutations present in cancer genomes should create many opportunities for personalized therapies. This underlines how crucial it is that, rather than simply focusing on cancer-causing genes and pathways, researchers also consider the therapeutic opportunities created by common passenger mutations.
Research began when DePinho and Muller were at Dana-Farber Cancer Institute at Harvard Medical School and continued when they moved to MD Anderson last year.
The enolase inhibitor they used in the experiments, with the jaw-breaking name phosphonoacetohydroxamate (PHAH), is not approved for humans and its structure makes it unlikely PHAH will penetrate tissues and tumors effectively.
Muller said the research team is working with MD Anderson's Institute for Applied Cancer Science and other scientists to develop a drug based on their findings.
MD Anderson news release
Nature article (paywall alert)
Nature News and Views piece