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Gopal N. Gupta, MD, provides additional insight on this topic. Click here for more.
In a step forward for targeted therapy, genomic profiling of one patient with bladder cancer who had an exceptional response to everolimus found two mutations that may help identify other patients who would have a similar favorable response.
Exceptional responders are patients who benefit from therapies that are largely ineffective in other patients.
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“Studying exceptional responses can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents,” said lead author Nikhil Wagle, MD, an instructor in medicine at Dana-Farber Cancer Institute and an associate member at the Broad Institute in Cambridge, MA. “We can use that information to identify patients whose tumors have genetic alterations similar to those found in exceptional responders, and treat them with those same agents.”
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The phase 1 trial included nine patients with advanced solid tumors, including five with bladder cancer, three with lung cancer, and one with adrenocortical cancer. Patients received one to 13 cycles of combination therapy with everolimus and pazopanib.
The patient with bladder cancer who had an exceptional response lasting 14 months was aged 70 years. Three other patients with bladder cancer had stable disease for less than 6 months and the patient with adrenocortical cancer had stable disease for 13 months. Patients with lung cancer did not benefit from the drug combination.
Seeking reasons for the exceptional response, the researchers focused on the genomics of the patient’s cancer. “We performed whole-exome sequencing of the patient’s tumor, and to our surprise, we identified two mutations in the gene mTOR [mammalian target of rapamycin], which is the target of everolimus,” said Dr. Wagle.
The two mutations, mTOR E2419K and mTOR E2014K, had not been previously identified in humans, although mTOR E2419K has been studied in yeast and in human cell lines.
Further study demonstrated that these mutations activated the mTOR-mediated cell signaling pathway. The presence of two activating mutations in the same tumor suggests that the tumor was highly dependent on mTOR signaling for survival, and thus highly susceptible to mTOR inhibition by everolimus.
Pazopanib, the agent that was combined with everolimus in this study, is a tyrosine kinase inhibitor. Although an effect from pazopanib treatment to the patient’s response could not be ruled out, in vitro studies showed that extremely high doses of the drug were required to overcome the effects of the mutations, making a significant contribution unlikely. Moreover, the researchers were unable to identify any additional genomic alterations that would increase tumor susceptibility to pazopanib.
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“Results of our study suggest that we should make a catalog of activating genomic alterations in the genes in the mTOR pathway,” said Dr. Wagle. “Patients with tumors that harbor these alterations might be particularly suitable for treatment with drugs like everolimus and other mTOR inhibitors.”
Dr. Wagle sees implications in this research for the future direction of personalized treatment. “This study is yet another example of how therapies targeted toward the genetic features of a tumor can be highly effective, and our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients,” he said.
| Expert Opinion | ||
 Gopal N. Gupta, MD What makes this study so interesting is the validation of the concept of personalized medicine; by working backwards, the investigators have identified a genetic susceptibility to targeted therapy in a tumor. mTOR activation alone is not novel in urothelial carcinoma; however, demonstrating causality of an activating mutation of mTOR and therapy targeted towards mTOR activation is exciting… Read more Gopal N. Gupta, MD
Assistant Professor, Genitourinary Oncology Oncology Institute, Cardinal Bernardin Cancer Center Loyola University Medical Center, Departments of Urology and Surgery Maywood, IL |
Reference
- Wagle N, Grabiner BC, Van Allen EM, et al. Activating mTOR mutaions in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014 Mar 13. [Epub ahead of print]
