Patient’s Dramatic Response and Resistance to Cancer Drug Traced to Unsuspected Mutations

Researchers from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard said that the DNA of the woman whose lethal thyroid cancer unexpectedly “melted away” for 18 months has brought to light new mechanisms of cancer response and resistance to the drug everolimus.

The study was published in the October 9 issue of the New England Journal of Medicine. As per the study, it is said that the researchers two mutations in the cancer's DNA that were previous not known. One of the mutations made the woman's cancer quite sensitive to everolimus which explains the remarkably long-lasting response. The second mutation was found in the DNA of her tumor after it had evolved resistance to the drug 18 months after treatment started

This single case study demonstrates how repeatedly sequencing a patient’s cancer DNA can help in finding out unsuspected “response” and “resistance” mutations that may help guide treatment of other patients. The first sequencing is done prior to the treatment and again when the tumor shows signs of resistance. Jochen Lorch, MD, a thyroid cancer specialist at the Head and Neck Treatment Center at Dana-Farber and senior author of the report said that it is like a precise, personalized medicine at its best.

The mutation was identified in the gene called TSC2 “ it is what was responsible for the patient's dramatic response to everolimus. In order to research on the same further, Dana-Farber has opened a clinical trial to test the drug’s effectiveness in other patients with TSC2 mutations. Such a type of trial is common because the patients who are “exceptional responders” are revealing previously unknown response mutations to a variety of drugs. Such a trial helps in pooling patients with a particular response mutation, whatever be the type of cancer they suffer from.

First author of the report Nikhil Wagle, MD, oncologist at Dana-Farber and affiliated with Brigham and Women’s Hospital and the Broad Institute of MIT and Harvard said that the study of such patients is important as it gives crucial insights. It can also help in developing methods to make personalized drugs, highlight effective uses for otherwise ‘failed’ therapies, and design new therapeutic strategies that will aid in the fight against cancer.

The study was prompted due to the surprising response to the drug in a 56-year-old woman who was diagnosed with anaplastic thyroid cancer in 2010.  This type of thyroid cancer has always been fatal within a few months. Despite conducting surgery, radiation and chemotherapy, the tumor spread to her lungs. Lorch was at that time leading a clinical trial of everolimus for a more treatable type of thyroid cancer. He decided to include the woman and a handful of other anaplastic patients in the trail.

His trail yielded some unexpected results – he found that after a few months the tumor shrank to a very small size. In fact, it remained that way for a period 18 months which was unheard of before after which until it began to grow again. The investigators used whole-exome DNA sequencing to produce scans of the protein-coding regions of the genome and they discovered a mutation in the TSC2 gene. It is known that the TSC2 protein normally suppresses mTOR activity. In case of its mutation, the mTOR is over activated “ making it a prime target for everolimus. Other anaplastic patients didn't show such a condition that is why they didn't benefit from the drug.

When specimens taken from the tumor after it grew again was examined, it showed that there was a mutation in the mTOR protein which was not present in the original biopsy sample. Such type of mutation was not seen in humans earlier and that explained how the cancer acquired resistance to the drug. Further laboratory experiments revealed that even the mutated, resistant cancer cells remained sensitive to a different type of mTOR inhibitor. Now, to take the study further, a new kind of drug is supposed to enter clinical trials. It is going to be tested on the said patient diagnosed with the rare form of cancer and who is still alive four years after her diagnosis. Lorch added that if the study is successful, it can contribute significantly to the fight against cancer.

References

https://www.broadinstitute.org/news/6127

https://www.sciencedaily.com/releases/2014/10/141008203738.htm