In mapping the entire genome of a tumor from a patient with advanced bladder cancer, researchers at Memorial Sloan-Kettering have uncovered a genetic weakness that could potentially be targeted with an existing drug. Published in the journal Science on August 21, the findings could lead to new and potent therapies for a subset of patients with the disease.

In addition, the investigators hope that their study might encourage more research on cases in which a cancer drug is shown to work in a small number of patients but further investigation has not been pursued because the treatment was found to be ineffective in the majority of patients.

The findings were made after an early-stage clinical trial in which Memorial Sloan-Kettering physicians treated advanced bladder cancer patients with everolimus (Afinitor^®), a targeted therapy already used in the treatment of kidney cancer, among other cancer types. While the drug did not help the vast majority of patients enrolled in the trial, the doctors were encouraged by the outcome of one patient – a 73-year-old woman – whose condition radically improved.

“Her response is absolutely remarkable,” affirms physician-scientist David B. Solit, of Memorial Sloan-Kettering’s Human Oncology and Pathogenesis Program, who led the study. “Most impressively, more than two years after starting the treatment, she continues to do well on everolimus, and all signs of her disease are gone.”

By comparison, the health of the other patients on the trial typically worsened two to three months into the study.

Focusing on the Exceptional Case

It is not uncommon for a new cancer drug to have mixed results when tested in patients. One or several trial participants may have good outcomes while others receive no benefit from the treatment. “When favorable responses are seen in only a small fraction of patients, the therapy is often deemed ineffective, and further research studies are not pursued,” says Dr. Solit.

In particular, the investigators noted in their report, cases where only a single patient does remarkably well in a trial have traditionally been “dismissed as failing to provide meaningful clinical evidence” of benefit.

But according to the researchers the findings of the everolimus study suggest that trials in which a drug appears to be successful in only one or several exceptional cases might in fact warrant further scrutiny. In determining the underlying reason why one patient in the largely negative everolimus trial had responded favorably to the drug, the researchers gained new insights about how this therapy could be used to its full advantage to benefit a small subset of bladder cancer patients.

Combing through the Genome

Everolimus works by targeting a cellular process called the mTOR pathway, which often goes awry in cancer cells. Although the researchers did not know why the drug had worked so well for one patient in the study, they hypothesized that a genetic abnormality in the patient’s tumor might be altering this pathway, making her cancer cells vulnerable to the therapy.

Initially, they tested samples of the patient’s tumor for a number of known gene changes. “We didn’t find any of these ‘usual suspects,’” Dr. Solit says. “There are thousands of genes that may be disrupted in cancer. Identifying the mutation that caused her disease to respond so profoundly to everolimus was like looking for a needle in a haystack.”

However, more-powerful technologies for whole-genome sequencing have recently become available, allowing scientists to determine the entire DNA sequence of a tumor or blood sample within weeks or days. As Dr. Solit puts it, “we are now able to discover new mutations by taking the entire haystack apart.”

Using this method, the investigators found that the woman’s tumor carried a mutation in a gene called TSC1, which is known to be involved in the mTOR pathway. “All of a sudden, it made perfect sense that her disease would be so sensitive to everolimus,” says Dr. Solit.

Incremental Progress

Dr. Solit and his colleagues were then able to confirm that mutations in the TSC1 gene were linked to a tumor’s sensitivity to everolimus by analyzing additional tumor tissue from patients in the trial. They found that three other patients whose tumors had partly shrunk in response to the drug also had a mutation in TSC1, while the participants whose disease had not improved did not have this genetic change.

“This tells us that everolimus might be an option for the minority of bladder cancer patients whose tumors have TSC1 mutations, even though the drug was not effective in most patients with this disease,” explains Dr. Solit. The researchers are now planning a new clinical trial in which the drug will be offered only to patients whose cancer cells test positive for TSC1 mutations. He estimates that such mutations are likely to be present in approximately one out of ten people with bladder cancer.

“Over time,” he adds, “as other mutations are found that can be targeted therapeutically, we believe that doctors will be able to offer more-effective treatments to a growing number of patients.”

Source: Source: MCKCC