SAN ANTONIO (November 20, 2014) — Two Cancer Therapy & Research Center scientists are leaders on $3.99 million in grants from the Cancer Prevention Research Institute of Texas that will help them develop next-generation breast cancer treatment drugs.
Rong Li, Ph.D., professor of molecular medicine, is principal investigator on a proposal that will both harness an existing drug for hot flashes that has potential anti-tumor activity, and create other agents that will help it work with greater precision.
“It balances feasibility and innovation,” Dr. Li said.
Ratna Vadlamudi, Ph.D., professor of obstetrics and gynecology, is leading a proposal to develop an innovative breast cancer drug that potentially could prevent the development of drug resistance in breast cancers.
“This funding will help us develop these first-in-class cancer therapy drugs that address the critical need of targeting therapy resistance and metastasis of breast cancer,” Dr. Vadlamudi said.
“Huzzah!” said Ian M. Thompson Jr., M.D., CTRC director. “This is a tangible confirmation of the exceptional merit of the science and clinical care provided by our CTRC scientists and physicians.”
Also collaborating on the two grants are scientists from the University of Texas at San Antonio — through the two institutions’ shared Center for Innovation in Drug Discovery — and UT Southwestern Medical Center and The University of Texas at Dallas.
In Dr. Li’s work, two different receptors drive estrogen activity – Estrogen Receptor alpha and Estrogen Receptor beta. Much more is known about ER alpha, while Dr. Li calls ER beta the “Cinderella sister.”
“It has a lot of similar characteristics, but in many cases it behaves in the opposite manner,” he said. “And in many cases – unlike ER alpha – it inhibits tumor growth.”
Because ER beta is present in as many as half of all breast cancer cases, scientists want to tap its tumor-suppressing activity.
A drug being developed by pharmaceutical company Ausio to treat menopause-related symptoms has already been tested enough to be proven clinically safe. One of its characteristics happens to be that it turns on the ER beta switch. Through an agreement with Ausio, the CTRC will be able to test this drug in combination with agents being developed at the Health Science Center.
“The novel part of this work is that we’ve discovered how to turn on the ER beta function – and also how to inhibit the process that turns it off,” Dr. Li said. “This proposal seeks synergy among these three approaches that might maximize the anti-tumor activity of ER beta.”
Dr. Vadlamudi’s proposal focuses on the mechanisms in treatment-resistant cells. The majority of breast cancers grow in response to the hormone estrogen, and therapies involve treating them with antiestrogens or aromatase inhibitors. But many patients, after an initial response, develop resistance to these drugs. Their tumors will mutate or modify an estrogen receptor (ESR1) and continue to develop by ESR1-driven pathways.
Dr. Vadlamudi and his team have designed a small-molecule drug called ECBI (ESR1 coregulator binding inhibitor) that has the potential to block multiple oncogenic pathways that occur in resistant cells, in that way preventing the development of drug resistance. The ECBI also potentially has fewer side effects and could delay the need to begin chemotherapy treatments that are much harder on the patient.
The CPRIT grant will allow researchers to take the next steps in the laboratory necessary to get the drug ready for clinical trials in patients. Both grants are early translational research awards.
Dr. Vadlamudi’s team includes Rajeshwar Rao Tekmal, PhD, of the Health Science Center, Ganesh Raj, M.D., PhD, of UT Southwestern Medical Center, and Jung Mo Ahn, PhD, of The University of Texas at Dallas.
Co-principal investigator on Dr. Li’s grant is Stanton McHardy, Ph.D., co-principal investigator and medicinal chemistry core director at the Center for Innovation in Drug Discovery, a collaboration of the Health Science Center and the University of Texas at San Antonio, and associate professor of chemistry at the University of Texas at San Antonio. Also working on the proposal are Steven Weitman, M.D., Ph.D., director of the Institute for Drug Development at the CTRC; John Kuhn, PharmD, professor of translational oncology at the UT College of Pharmacy and the UT Health Science Center and senior research director for the CTRC’s Institute of Drug Development; Matthew Hart, Ph.D., the CIDD high-throughput screening director from the UT Health Science Center; and Richard Elledge, M.D., CTRC oncologist.
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