Study finds new drug combinations of mutation genes that can kill cancer cells -
In an effort to increase the number of genetic mutations of cancer that can be specifically targeted with personalized therapies, researchers at the University of California at San Diego School of medicine and Moores Cancer Center looked for combinations of mutated genes and drugs that kill all the cancer cells. Such combinations are expected to kill cancer cells that have mutations, but not on healthy cells, which do not. The study, published July 21 in Molecular Cell discovered 172 new combinations that could form the basis for future therapies against cancer.
"oncologists here at Moores Cancer Center at UC San Diego Health and elsewhere can often personalize cancer treatment based on unique cancerous mutations in each patient," said lead author Trey Ideker, PhD , professor of genetics at UC San Diego School of Medicine "But the vast majority of mutations are not an action. -. That is, knowing that a patient has a particular mutation does not mean that there is a treatment available that targets it The aim of this study was to increase the number of mutations that we can match with an accuracy of therapy "
most cancers have genetic mutations that do one of two things. - promote cell growth or prevent cell death the first type is the subject of many therapies that inhibit the growth of cells. . But it is much harder to develop therapies that restore malfunctioning genes that should trigger cell death in abnormal cells, called tumor suppressor genes.
Rather than targeting a tumor suppressor gene directly, Ideker and the team took the approach to identify genetic interactions between a tumor suppressor gene and another gene, such that the simultaneous disruption of both genes selectively kill cancer cells.
Researchers first used to screen a yeast cheaply and quickly 169.000 interactions between the different yeast versions of a human tumor suppressor genes and genes that can be inhibited by drugs, sometimes called " druggable targets. " To do this, they suppressed each gene one at a time, in combination with another mutation. These whittled the best combinations experiences - those lethal to the yeast cells -. A few thousand
Next the team prioritized 21 drugs for which the yeast druggable targets were involved in the largest number of lethal cellular interactions. They have tested these medicines one at a time to the fatal interaction with 112 different mutations in the tumor suppressor gene in human cancer cells growing in the laboratory.
The researchers were left with 172 combinations of gene mutation that killed drug successfully in both yeast and human cancer cells. Among these combinations, 158 was not discovered earlier
This is an example of how this information could be useful for doctors and patients. Irinotecan is a medicament indicated only by the FDA for use in colon cancer. But this study suggests that this class of drugs should be evaluated for efficacy in all tumor with a mutation that inhibits RAD17 , a tumor suppressor gene that normally helps cells fix damaged DNA.
The next steps are to test these combinations in most types of human cancer cells and possibly in mouse models. 172 combinations but is much more than a single laboratory test can, say the researchers. They hope other research teams will also take their list and also test each combination in a variety of conditions. To help disseminate this information to scientists around the world, all the data of this study was made available on Ndex, a new network data sharing resource developed by Ideker and UC San Diego School of Medicine Dexter Pratt science.
"We created a major translational research resource for other scientists and oncologists," said co-first author John Paul Shen, MD, clinical instructor and postdoctoral fellow at UC San Diego School of medicine and Moores cancer Center. "and since most cancer killing of interactions we found involve drugs already approved by the FDA, it may mean they could quickly reach the clinical translation. If these results are validated in subsequent tests, an oncologist in the future will have many more options for precise treatment of cancer. "
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