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7.30.2014

Top Urologic Researcher Wins NIH Grant to Study Potential Breakthrough Kidney Cancer Therapy

A long-time Miller School researcher, who has dedicated her career to studying the mechanisms that fuel cancers of the prostate and bladder, is now studying a promising drug combination to combat kidney cancer. More than one-third of patients with kidney cancer develop metastasis despite treatment, and less than 10 percent of them survive beyond five years.

Vinata B. Lokeshwar, Ph.D., professor of urology and cell biology and Director of Pilot Studies at the Miami Clinical and Translational Science Institute (CTSI) was awarded a five-year, $1.7 million grant from the National Institutes of Health to test a combination of sorafenib, a drug already approved for kidney cancer, with the dietary supplement hymecromone in pre-clinical models. The drug combination was shown to eliminate kidney tumors in mice without toxicity, and if successful in humans could be the first to prevent the cancer from metastasizing.

“Finding a drug that would work without causing significant side effects is a major discovery, because of the high morbidity and mortality associated with metastatic kidney cancer,” said Lokeshwar, who is also a member of the Sylvester Comprehensive Cancer Center. “It’s important to know why a drug fails and what you can do to improve its efficacy without increasing the side effects.”

Lokeshwar’s quest to unlock the mystery of the cancer’s aggressive nature and why existing drugs were ineffective started more than three years ago, and it took a significant clinical problem, a novel idea, a lot of team effort and even leniency from a federal judge to get the grant funded.

Initially, Lokeshwar’s team discovered that higher levels of hyaluronic acid (HA) family molecules in tumor tissues predict whether patients’ kidney cancer will metastasize. “If you know this, then you can treat the cancer more aggressively so that patients may never develop metastasis,” said Lokeshwar.

The work from Lokeshwar’s laboratory, which spans more than a decade, has shown that the HA family of molecules promotes cancer growth, metastasis and growth of new blood vessels that feed cancer. Her previous work on prostate cancer had shown that hymecromone, which is sold over-the-counter in Europe and parts of Asia as a dietary supplement to boost liver health, inhibits prostate cancer cell growth by inhibiting HA synthesis.

“If kidney cancer cells produce a lot of HA, and hymecromone inhibits HA synthesis, why not combine it with existing drugs on the market?” said Lokeshwar, who along with her former graduate student Travis Yates, Ph.D., and research associate Luis Lopez combined hymecromone with a variety of kidney cancer drugs. “And of all of the drugs, sorafenib was the only one that synergized with hymecromone,” said Lokeshwar.

Sorafenib has long been a second line of kidney cancer treatment because it delays metastasis for only a couple of months at best. However, in cancer cell cultures, the combination of hymecromone with sorafenib effectively inhibited the growth of kidney cancer cells and their ability to metastasize. It also completely eliminated a sorafenib-resistant kidney tumor in mice, without toxicity. “The amazing thing is that the combination works at doses at which hymecromone and sorafenib individually have no effect. So the combination appears to be very promising,” said Lokeshwar.

With the NIH grant, and the help of several collaborators at the Miller School and outside institutions, the team is trying to identify how the combination works. Their hunch is that hymecromone attacks the mechanism by which the kidney tumors inactivate sorafenib, making it an ineffective drug.

As Lokeshwar’s team embarks on this study, her gratitude extends beyond the NIH support to a federal judge, the Honorable Alan S. Gold, and his judicial administrator, Lynn Surowiec, who in an unusual twist of events helped make the study possible.

Last year, Lokeshwar was in the final stages of submitting the grant application when Lopez was selected to serve as a juror in Judge Gold’s court. Lopez was needed to compile the grant against a tight deadline.

In desperation, Lokeshwar contacted Surowiec. Gold conducted a hearing over the phone in the presence of the prosecutor and defense attorney about Lokeshwar’s request to have Lopez released from jury duty. After careful consideration of the importance of the grant and Lopez’s role in it, the judge made a rare exception and dismissed Lopez from jury duty.

Lokeshwar and Lopez both recently thanked Judge Gold and Surowiec, because, as Lokeshwar said, “It’s not every day that a cancer researcher and a federal judge cross paths, and we wanted them to know the outcome.”

Lokeshwar also marvels at the dedication of Yates, now a postdoc at the University of Pennsylvania, who delayed graduating for six months to work on this project. “He truly sacrificed to move this research forward and I could never have done it without him,” she said.

Lopez, who has worked with Lokeshwar for 10 years and kept his juror badge as a memento, said, “We had to overcome a few bumps in the road, but this grant could allow us to reverse the course of kidney cancer mortality forever. It was too important to lose.”

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