Searching for New Drug Therapies

Fall 2013

When a doctor prescribes a medication — whether for a common sinus infection or a complex cancer — most people follow their doctor’s orders and trust that the medicine will fight their illness. They probably don’t think about how it works or the years-long process it took to get to the pharmacist’s shelf.

Luckily, there are people who focus their careers on the intricate task of discovering new drugs that can lead to longer, healthier lives.

One such person is Peter Crooks, Ph.D., D.Sc.

A self-proclaimed “drug hunter,” Crooks has spent the past 40-odd years in the field of drug discovery, searching for ways to convert scientific discoveries into potentially viable drug therapies.

“I come in after a basic scientist has discovered a new protein that is a potential target for a new drug therapy,” said Crooks, chairman of the Department of Pharmaceutical Sciences in the UAMS College of Pharmacy. He then begins a stringent, multi-step process that can take 10 or more years and may or may not result in a new drug hitting the shelves.

“The chances of finding a drug that will work well are pretty remote,” he said. That’s why “drug hunters” test thousands of compounds looking for the ones that are most likely either to shut down or activate the protein in question and alleviate the symptoms of the disease.

Through a process called optimization, his group painstakingly searches for a molecule that is potent and will selectively bind to the protein without affecting other proteins in the body. When they find that molecule and it passes toxicological scrutiny, drug development begins, eventually leading to clinical trials in humans and potentially FDA approval for widespread use in patients.

But before Crooks can start his discovery process, a basic scientist has to lay the groundwork. Thomas Kieber-Emmons, Ph.D., is one such scientist who has made his mark in the field of immunotherapy, a process that engages the immune system to accomplish a goal, such as inhibiting tumor growth.

“In immunotherapy, you are either targeting a specific tumor cell or trying to circumvent the shutdown of the immune system caused by tumor cells,” said Kieber-Emmons, professor of pathology. The problem, he added, is that no one is exactly sure how that process works.

A breast cancer vaccine developed by Kieber-Emmons to prevent recurrence of the disease is nearing the end of its phase 1 clinical trial, which is being conducted at the UAMS Winthrop P. Rockefeller Cancer Institute. The vaccine was computer engineered and rationally designed as a “shotgun approach,” Kieber-Emmons said, meaning that the vaccine was designed to elicit a response that hits multiple targets simultaneously.

Phase 1 trials are intended to » test safety and tolerability of new drugs and involve a small group of participants. All of the women in Kieber-Emmons’ trial are stage 4 breast cancer patients, and so far they are showing positive results.

“Our vaccine is inducing an immune response directly destroying tumor cells, similar to what you see with drugs in chemotherapy. It’s very hard to do that, and we’ve accomplished it,” he said. “We think we’re succeeding because we’re hitting multiple targets associated with cancer cell survival.”

Another immunotherapy vaccine developed at UAMS is designed to prevent cervical cancer in women who have already acquired the virus that causes the disease, human papillomavirus (HPV). Developed by Mayumi Nakagawa, M.D., Ph.D., associate professor of pathology, this vaccine also is in a phase 1 clinical trial at UAMS and uses candida, a naturally occurring yeast in the body, with the vaccine to enhance the immune response.

Both of these vaccines have passed many hurdles from drug discovery to human clinical trials, but they still have intense testing to complete before becoming available to the general public.

The multiple myeloma program at UAMS perhaps best epitomizes the path from immunotherapy research to direct patient care. The UAMS Myeloma Institute for Research and Therapy is highly regarded for its aggressive treatment of myeloma, which is characterized by malignant plasma cells that reproduce uncontrollably.

Mayumi Nakagawa, M.D.

Mayumi Nakagawa, M.D., Ph.D., is testing a vaccine she developed for HPV.

“Recent advancements in the treatment of myeloma have resulted in new drugs with promising results,” said Sarah Waheed, M.D., associate professor of medicine in the UAMS College of Medicine. UAMS myeloma patients are actively involved in clinical trials of new medications, and two new myeloma drugs approved by the FDA in the past year are showing strong results.

Another drug, elotuzumab, also has shown success in targeting an antigen on the myeloma cell surface called CS1. When used alongside immune cells known as natural killer cells, a mechanism called antibody-dependent cell-mediated cytotoxicity occurs and myeloma cells are killed.

“Elotuzumab, in combination with other drugs, has shown an 82 percent response for relapsed myeloma patients participating in phase 1 and 2 clinical trials,” Waheed said.