Breast Cancer Breakthrough Award funds search for new treatments

Pilot study funded by Santa Cruz Cancer Benefit Group gave UCSC researchers preliminary data needed to win a major $350,000 federal research grant

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Seth Rubin (Photo by C. Lagattuta)

UC Santa Cruz cancer researcher Seth Rubin has received a $350,000 grant to fund his work toward the development of a new class of drugs for treating breast cancer. The grant is a Breast Cancer Research Program Breakthrough Award from the congressionally directed medical research programs of the U.S. Department of Defense.

Rubin, an associate professor of chemistry and biochemistry, will use the grant to build on his recent discoveries regarding a key tumor suppressor protein that is inactivated in most breast cancer cells. The retinoblastoma tumor suppressor protein (Rb) helps regulate the cycle of cell growth and division, putting the brakes on cell proliferation when it is active. In normal cells, Rb coordinates cellular growth signals, turning on and off to ensure that cells divide at the right time. Genetic changes in cancer cells disrupt this regulatory pathway and allow cells to multiply out of control.

Rubin's research has revealed important details of the molecular mechanisms involved in turning Rb on and off. These findings suggested the possibility of a new class of therapeutic molecules that target the retinoblastoma protein directly. Most attempts to target the retinoblastoma pathway with drugs have focused on blocking the action of other proteins that inactivate Rb.

"A common analogy is to think of cancer cells as being like a car with a jammed accelerator and broken brakes, so the cells can't stop proliferating. Most drugs target the jammed accelerator and knock down proteins that are too active. We want to target the broken brakes and restore the tumor suppressor activity," Rubin said.

This novel approach promises to have fewer toxic side effects and be less vulnerable to acquired drug resistance than other therapies. Traditional drug discovery efforts focus on finding molecules that block the activity of a target protein. Little attention has been given to using small molecules to activate a tumor suppressor directly. Rubin's research could open up a whole new class of targets for drug discovery efforts.

Rubin's lab developed an assay for Rb activity to use in large-scale testing procedures for identifying small molecules that can stabilize the activated form of Rb. Identifying molecules with the desired activity is the first step in the drug development process and requires screening huge numbers of compounds.

Rubin used a small grant from the Santa Cruz Cancer Benefit Group (SCCBG), a local charity supporting cancer research and patient care, to test his group's Rb assay in a pilot study conducted at the UCSC Chemical Screening Center. Their pilot screen of about 20,000 compounds showed that the assay works well in a high-throughput screening procedure.

The new grant will fund a collaboration with the Conrad Prebys Center for Chemical Genomics at the Sanford-Burnham Medical Research Institute in La Jolla. The center will use Rubin's assay to screen a library of about 320,000 compounds. Follow-up studies to further evaluate compounds identified in the large-scale screening tests will be carried out by Rubin's lab in collaboration with Julien Sage, a cancer biologist at the Stanford School of Medicine.

Rubin's lab will also investigate the molecular details of how the lead compounds interact with the retinoblastoma protein. These studies will provide a foundation for future work needed to develop promising compounds into medically useful drugs for breast cancer therapy.