ANN ARBOR, MI - Researchers at the University of Michigan Comprehensive Cancer Center have been awarded a $6-million grant from the National Cancer Institute to discover and develop new drugs that target cancer cells that do not respond to current treatments. The goal is to find drugs that can be used to treat many different types of cancer.

The five-year grant is part of the National Cooperative Drug Discovery Group, an NCI initiative that supports broad, innovative and multi-disciplinary approaches to the discovery of new drugs for cancer treatment.

All cells have a built-in mechanism providing for cell death. A major characteristic of the cancer cell, which distinguishes it from the normal cell, is its resistance to such programmed cell death, known as apoptosis. This plays a major role in the cell's resistance to chemotherapy or radiation and in the failure of drugs currently used to treat cancer.

Chemotherapy and radiation for the treatment of cancer work by directly or indirectly inducing cancer cells to die. It is now known that the ability to evade cell death is a hallmark of all cancers. The central goal of this grant is to design new small-molecule drugs that specifically thwart such evasion and challenge the resistance of cancer cells to apoptosis. Such drugs will form the basis of novel strategies aimed at improving the survival and quality of life of cancer patients.

The research team proposes to design and synthesize small molecules that specifically target two critical proteins that play a role in apoptosis, Bcl-2 and Bcl-xL. Small molecules can be designed to zero in on a specific site in the protein that researchers know is important to the protein's function.

“The Bcl-2 and Bcl-xL proteins are overexpressed in many types of cancer cells, making the cancer cells resistant to conventional anticancer drugs. That makes these two proteins very attractive molecular targets for the design of an entirely new type of anticancer drug,” says Shaomeng Wang, Ph.D., associate professor of internal medicine at the U-M Medical School, who also has a joint-appointment in the U-M College of Pharmacy. Wang, co-director of the Molecular Therapeutics Program at the U-M Comprehensive Cancer Center, is principal investigator for the grant.

Traditional chemotherapy is lethal to any cell that is dividing and copying itself, which is why patients experience so many side effects, like hair loss, nausea and vomiting. New targeted molecular therapies, like the one sought here, do not harm these normal cells. The currently available drugs Gleevec and Avastin are both targeted therapies.

“These new targeted molecular therapeutics are directed against the cancer cells themselves by attacking changes that are present only in the cancer cells. This decreases toxicity to the patient,” says Kenneth Pienta, M.D., director of Urologic Oncology at the U-M Comprehensive Cancer Center and professor of internal medicine at the U-M Medical School.

Pienta will lead one of the three programs involved with the grant, focusing on testing the therapy in animal models. Wang's lab will design and synthesize the compounds and study how they work. A third arm of the research, led by Jeanne Stuckey, Ph.D., a research assistant professor with the U-M Life Sciences Institute and Medical School, will use X-ray crystallography to determine how these newly designed small-molecule inhibitors interact with the Bcl-2/Bcl-xL proteins. This aspect of the project will also be aided by studies with nuclear magnetic resonance methods, conducted by York Tomita, Ph.D., assistant professor at Georgetown University.

In addition to Wang, Pienta, Stuckey and Tomita, other co-investigators on this grant include Gabriel Nunez, M.D.; Liang Xu, M.D. Ph.D.; James Rae, Ph.D.; Zaneta Nikolovska-Coleska, Ph.D.; Haiying Sun, Ph.D.; Renxiao Wang, Ph.D.; and Kent A Griffith, M.S.; all from the University of Michigan. In addition, scientists from the U-M and other institutions will serve as consultants. These include Paul Hollenberg, Ph.D., professor and chair of Pharmacology at U-M; Janet Smith, Ph.D., professor of biological chemistry at U-M; Alex Bridges, Ph.D., Quatrx Pharmaceuticals; David Kwok, Ph.D., Biopharmaceutical Research; Dennis Torchia, Ph.D., National Institutes of Health; Frederick Valeriote, Ph.D., Josephine Ford Cancer Center; and Dajun Yang, M.D., Ph.D., and Jon Holmlund, M.D., both from Ascenta Therapeutics.

The University of Michigan has partnered with Ascenta Therapeutics, a biopharmaceutical company focusing on oncology drug development, to pursue clinical development of the most promising small-molecule inhibitors of Bcl-2/Bcl-xL obtained from this research. Wang is a co-founder of Ascenta Therapeutics, serves on the board of directors and has significant financial interest in the company.

Written by Nicole Fawcett

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