Genome sequencing will help in cancer treatment
The mystery of frequent failures of clinical trials of anticancer drugs has been revealed
Copper News based on ScienceNOW: Genome Sequencing Clears Up a Cancer Medical Mystery Genome-wide sequencing of a malignant neoplasm of one of the participants in clinical trials of an anti-cancer drug allowed us to understand the reasons that drugs that showed good results in laboratory conditions often turn out to be ineffective when tested on humans.
It turned out that it's all about genetic mutations in tumors, on which the sensitivity of neoplasms to specific drugs depends. On August 23, the results of the study were published online in the journal Science (Iyer et al., Genome Sequencing Identifies a Basis for Everolimus Sensitivity – VM).
Most experimental anti-cancer drugs never enter the market due to the failure of clinical trials, without having the expected effect on malignant neoplasms in the absolute majority of patients. Nevertheless, there is always, as a rule, one or more patients among the participants in the trials, on whom the drug being tested has the expected effect.
Trying to solve this mystery, specialists from the New York Memorial Sloan-Kettering Cancer Center, where unsuccessful clinical trials of the drug everolimus (everolimus), designed to fight bladder cancer, took a closer look at the tumor of the only patient whom this medicine helped - the woman had a 2.5–year remission, which, according to According to David Solit, who led the research team, this is an unprecedented success for this extremely resistant to chemotherapy type of cancer.
The figure from the article in Science shows the patient's tomograms before taking the experimental drug and 3, 6 and 15 months after. The red arrows indicate tumor metastases – VM.
At first, the Solita group tried to find mutations in the genes encoding the mTORC1 protein involved in the growth of the neoplasm and being the target of everolimus, which could explain the sensitivity of the tumor to the drug, but without success. Then a sample of the tumor tissue was sent for genome-wide sequencing to the Bioinformatics Technology Laboratory at the University of California.
As a result, mutations were found in two genes, NF2 and TSC1. The last of the genes attracted special attention of the authors of the study – it was not previously associated with mTORC1, however, it was known that people with a congenital mutation in TSC1 (tuberous sclerosis complex 1) are prone to the development of benign tumors. Mutations in TSC1 were then found in the genomes of neoplasms of four participants in the same failed clinical trials of everolimus, whose tumors shrank in size under the influence of the drug. At the same time, a similar mutation was found in the tumor of only one of the group of patients whom everolimus did not help.
Now, Solit and his team plan to select bladder cancer patients with a TSC1 mutation in the tumor genome in order to continue testing everolimus and other drugs that target mTORC1 on these patients.
According to Solit, this approach should now be applied during all clinical trials of anti-cancer drugs. A complete decoding of the tumor genome will reveal the genetic changes that cause sensitivity to the drug in each case. In addition, the achieved understanding of the reasons for the failure of clinical trials gives a new chance to promising drugs that were previously rejected due to their ineffectiveness when tested on humans.
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