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AACR Panel: Small Studies Can Yield Cancer Treatment Insights

WASHINGTON (GenomeWeb News) – Small studies, sometimes containing a single patient, can be applied to unravel the biological mechanisms behind cancer drug response as well as identify possible drug treatments for a specific cancer type, according to researchers.

While such small studies may be dismissed by some as anecdotes, panelists at an afternoon session yesterday at the American Association for Cancer Research annual meeting here argued that such studies can be used to resurrect abandoned drugs and to reveal known drugs to which a tumor may be susceptible.

Drugs from clinical trials that failed often fall by the wayside, but some of those trials contain gems of information that researchers can use to work out the biology of the disease and, potentially, establish a use for that drug. Even if the drug failed the trial overall, it may have worked for a subset of the clinical trial participants.

David Solit, a physician and researcher at Memorial Sloan-Kettering Cancer Center, has been studying such extraordinary responders to determine whether those drugs, specifically cancer therapeutics, work on tumors with a certain genetic background.

For example, a 73-year-old woman with metastatic bladder cancer had been enrolled in a clinical trial looking at everolimus, an mTOR inhibitor. mTOR regulates growth and proliferation.

Solit noted that there was no rationale for putting this patient in this study; it happened to be enrolling.

Overall the study of everolimus was a negative, but this patient showed a complete response to the drug. Now, three and half years later, the patient still shows a complete response, he said.

To figure out why this particular patient responded so well to the drug, Solit and his colleagues sequenced the patient's whole genome. Two mutations jumped out at them, Solit said. The genome harbored mutations in TSC1 and NF2 — gene products of both of those play a role in the mTOR signaling pathway. In addition, he noted that a New England Journal of Medicine article appeared around the time they were studying this patient that showed that everolimus could treat tuberous sclerosis in patients with TSC1 or TSC2 mutations.

"Perhaps [it was] not surprising our patient responded as well," Solit said.

After further investigation, Solit and his group found that many bladder cancers contain TSC1 mutations.

In a similar extraordinary responder study, that of a patient with small cell ureteral cancer who responded to treatment with irinotecan, whole-genome analysis uncovered three interesting mutations, including one in RAD50. In an in vitro study, Solit and his colleagues found that RAD50 mutations made cells more sensitive to irinotecan.

In addition, the National Cancer Institute is putting together a clinical trial that, James Doroshow, a senior investigator at NCI, said aims to "systematize what Solit has done."

For that trial, Doroshow said NCI is currently trying to identify such extraordinary responders by combing back through 10 years of data from studies that may never have been published.

Data can also flow the other way, with sequencing driving discoveries. Elaine Mardis, the co-director of the Genome Institute at Washington University in St. Louis, is combining whole-genome sequencing, whole-exome sequencing, and transcriptome sequencing to study cancer patient genomes. Her group has developed a database called the Drug-Gene Interaction database, or DGIdb, that can identify possible druggable genes from a list.

As an example, Mardis recounted the case of a male patient in his 30s with B-cell acute lymphoblastic leukemia. She and her team performed whole-genome sequencing, whole-exome sequencing, and transcriptome sequencing on bone marrow isolates from the patient. It took about a month to get results. "That's about as fast as it can be done today," she said.

From this, the researchers found 91 somatic mutations in exons, 42 of which were expressed, but no druggable mutations according to DGIdb. The patient also had two apparent tumor subclones.

However, they did notice that the FLT3 gene was very highly expressed. The literature, Mardis said, indicated that it could be pathogenic in B-ALL. This was predicted to be sensitive to sunitinib, a tyrosine kinase inhibitor. The patient received the drug, underwent a bone marrow transplant, and now is in remission, Mardis said.

Upon further investigation, Mardis and her team found that in children with ALL FLT3 is overexpressed, and they identified two somatic mutations, a composition insertion and deletion event in the patient. Her team is now following up on that with regulatory and functional assays.

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