Shooting for three strikes not to be out

MENLO PARK, Calif.—Triple-negative breast cancer is a particular problem, as it represents some 20 percent of such cancer cases, and its tumors are unresponsive to hormone therapy or drugs targeting the three most common receptors that tend to drive breast cancer progression. A new collaborative project between scientists at SRI International and physician-researchers from the Stanford Cancer Institute aims to solve—or at least reduce—that problem through efforts that will support development of novel drugs for treatment of triple-negative breast cancer.

The research collaboration will explore the use of a preclinical drug known as sudemycin D6 that targets, as the collaborators put it, a “molecular machine” called the spliceosome. The spliceosome is critical to the basic biological transformation of DNA to RNA to proteins, they say, as it “edits” raw RNA transcribed from DNA, cutting and piecing together stretches of code to form the instructions for creating various functional proteins.

SRI and Stanford liken the process to that of a film editor producing a finished movie from raw footage.

If this biological editor complex is defective, proteins that ultimately result from its actions can be dysfunctional and lead to various forms of cancer, including triple-negative breast cancer. And that’s where the research team—led by Dr. Thomas R. Webb, director of medicinal chemistry at SRI Biosciences, a division of SRI International, and Dr. George Sledge, professor and chief of the Division of Oncology at Stanford University Medical Center—is directing its attention.

“As both a medicinal chemist and cancer survivor, I know that new treatments are desperately needed for cancer,” said Webb. “It is my greatest hope that we can combine the unique strengths of SRI Biosciences and the Stanford Cancer Institute to make long-lasting impact in the treatment of triple-negative breast cancer, where unfortunately there are currently few effective therapeutic options. The strategy may also work for a range of other cancers, including lymphoma, melanoma, and certain brain and colon cancers.”

“Stanford and SRI both have unique strengths, and together we can create something wonderful for patients with cancer: new treatments that are more effective and less toxic,” said Dr. Sledge.

Webb’s research group designed sudemycin D6 to neutralize the SF3B1 protein of the spliceosome with enhanced activity and duration of action as well as less toxicity than previous spliceosome targeting agents. The team has also developed a marker tumor cell line that fluorescently glows when treated with sudemycin D6. This advance enables real-time monitoring of the drug’s activity, which will support translation to the clinical setting.

The SRI Biosciences and Stanford Cancer Institute collaboration is the first step in determining whether sudemycin D6 may be effective against triple-negative breast cancer. As part of the research, tumor samples from anonymous patients will be analyzed at the molecular level and examined in mouse models.

This work is an expansion of efforts already ongoing between the two organizations. It was just a few months ago, in early January, that SRI and Stanford announced they would team up to enhance drug development efforts in response to a lack of innovative new treatments for cancer and other diseases.

And even that partnership built on previous collaborations between the two institutions. For example, the development of Tirapazamine, an experimental cancer therapy, was made possible by the teamwork of SRI and SCI researchers.

The Drug Discovery and Development Program formed in January is coordinated by Sanjay V. Malhotra, associate professor of radiation oncology at Stanford, and Nathan Collins, executive director of the Pharmaceutical and Chemical Technologies Section in SRI Biosciences.

“The SCI-SRI Biosciences collaboration provides a fully integrated engine for taking ideas to the investigational new drug stage and beyond,” Collins said. “Our focus is on developing ‘first-in-class’ drugs and delivering improved outcomes for patients.”

SRI Biosciences integrates basic biomedical research with drug and diagnostics discovery and preclinical and clinical development.

For its part, SCI is a National Cancer Institute-designated Cancer Center dedicated and resourced to catalyze the vast scientific, technological and human capabilities of Stanford University and Stanford Healthcare to advance understanding of cancer and rapidly translate research discoveries into improved prevention strategies, diagnostics and therapies.