Team Tackles Provocative Cancer Question

Sivanesan Dakshanamurthy, PhD, (right) and research assistant, Oakland Peters, BSSerendipity — the sweet thing that plays a big role in scientific discovery — happened between labs at Georgetown University Medical Center and Harvard University, just before the National Cancer Institute posited provocative question number 5.

The NCI’s Provocative Questions Project is offering grants to delve into 24 questions that, if answered, could lead to significant advances in understanding or treating cancer. The questions — such as why obesity contributes to cancer risk — have been around, but unanswerable, for a long time. But now the NCI feels the time is right to address them.

NCI solicited the questions from scientists in various fields and at various stages in their research, and then released a special solicitation just for research related to these 24 questions.

One of the questions — number 5 — seemed perfect for Stephen Byers, PhD, a professor and molecular oncologist at Georgetown Lombardi Comprehensive Cancer Center.

Given the evidence that some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?

The NCI says the implications of successfully answering this question “would be a major breakthrough in cancer prevention. This work could also provide molecular pathways that harbor other targets for prevention and encourage the development of second-generation drugs that might diminish toxicities associated with current agents while maintaining efficacy. Success in these studies would provide models for the types of responses that mark good chemoprevention trials.” 

Byers' proposal to answer this question was one of a small number of applications to be accepted out of almost 800 that were submitted. Work began September 1. The four-year, $2.5-million grant will be directed by Byers and includes several of his Georgetown colleagues, as well as scientists from Harvard and Columbia universities.

Serendipity reared its wonderful head twice in a series of discoveries that led up to Byers successful bid to answer his “PQ.” 

“Twofer” the price of one

Byers has long studied cadherin-11, an adhesion molecule that basically sticks cells together. The gene, and its protein, regulates the way that cancer cells can invade other tissues. 

The Byers group and other laboratories have found that cadherin-11 is over-expressed in some aggressive breast cancers, and in the brain tumor glioblastoma. “What these cancers have in common is cadherin-11, and a poor prognosis, with no effective therapies,” he says.

Up north, Harvard University’s Michael Brenner, MD, a member of the National Academy of Sciences and the Theodore Bayles Professor of Medicine, was simultaneously working on rheumatoid arthritis, and he found that cadherin-11 is one of the major targets of this immune disease. In other words, animals in which the molecule is “knocked out” do not develop rheumatoid arthritis. Brenner and his colleagues then produced antibodies to cadherin-11 to test treatment of the disorder.

That suggested that cadherin-11 antibodies designed to treat rheumatoid arthritis might also work against cancer, says Byers who was in close contact with Brenner. Shahin Assefnia in the Byers group is now testing the Brenner antibody in animal models of tumors that over-express the molecule.

At the same time, Byers and his team, which included Georgetown Lombardi drug designers Milton Brown, PhD, and Sivanesan Dakshanamurthy, PhD, had simultaneously made a small molecule, dubbed sd133, to block cadherin-11. 

Three drugs that may all do the same wonderful thing

Not long after, on one sunny serendipitous day, Dakshanamurthy walked into Byers lab. Dakshanamurthy had developed a novel computerized method to uncover new uses for existing drugs, of which there are about 27,000. His idea is to see what drugs fit into proteins known to be involved in disease.

Taking his “repurposing” system out for a run, Dakshanamurthy and his team screened almost 4,000 FDA approved drugs across more than 2,000 protein structures. He came across five big, promising “hits,” one of which he brought to Byers.

Dakshanamurthy had found that the arthritis drug Celebrex fits neatly into the cadherin-11 protein structure. 

“This was amazing,” Byers says. 

So Byers, Brenner, and Dakshanamurthy had each, independently, contributed to the new understanding that Celebrex — and sd133 and Brenner’s antibody — might effectively stop growth of untreatable tumors as well as rheumatoid arthritis.

That put Byers in the right position to be able to answer PQ no. 5 — can any of their candidate agents stop both cancer and arthritis, and how does it work?

Folded into Byers’ PQ collaboration is Columbia University structural biologist Lawrence Shapiro, PhD, who was first to determine the crystal structure of cadherin-11. Shapiro plans to build the structure of cadherin-11 bound to Celebrex.

“We need to figure out how cadherin-11 actually transmits a signal — and what that signal is — that allows cancer cells to grow and causes the symptoms of rheumatoid arthritis,” Byers says.

He can’t help but be optimistic about the potential answer that his PQ team will turn in to the NCI — findings that may translate quickly into advancements in the treatment of some very difficult diseases. Says Byers, “The prospect of using a drug developed for arthritis in cancer is very powerful.”

By Renee Twombly, GUMC Communications

Byers, Dakshanamurthy and Brown are inventors on patent applications that have been filed by Georgetown University on technologies that are related to this project.

The research described is supported by grant number W81XWH-10-1-0437 from the Department of Defense and 1R01CA170653-01 from the National Cancer Institute of the National Institutes of Health.
 
(Published September 05, 2012)