A Houston Methodist Hospital researcher is investigating whether adding all-trans retinoic acid (ATRA) to a proteasome inhibitor can squelch multiple myeloma's natural resistance to chemotherapy, a hurdle that's historically rendered the deadly bone cancer incurable.

Dr. Qing Yi, Ph.D., a medical immunologist, has been awarded a $2 million grant by Texas' cancer agency to conduct the first-in-human phase IB/II clinical trial determining the safety, efficacy and recommended dosing of the combination therapy of ATRA and carfilzomib, a newer proteasome inhibitor often used to treat multiple myeloma (MM) in patients who've already been treated with other drugs that didn't work.

"There is a great need to develop better methods or drugs to overcome drug resistance (in multiple myeloma)," Dr. Yi, a professor of cancer biology in medicine with the Houston Methodist Research Institute, wrote in the grant application. "We believe that ATRA may be used to treat MM patients to restore their response."

The trial is born of the Yi team's high-throughput screening of 1,855 FDA-approved drugs that found ATRA enhances human multiple myeloma cell sensitivity to carfilzomib and bortezomib, another proteasome inhibitor. ATRA, used to treat patients with acute promyelocytic leukemia, does not kill MM cells on its own.

The Cancer and Prevention and Research Institute of Texas (CPRIT) grant is providing Yi's team $1.92 million over three years for the project.

Improving cancer prevention in underserved communities

The grant is one of two recently awarded to Houston Methodist by the agency, a taxpayer-funded initiative launched in 2007 that invests $300 million a year in the fight against cancer. The agency is the nation's largest public funder of cancer research and prevention efforts outside the federal government.

CPRIT also awarded a $1.44 million grant to Dr. Nestor F. Esnaola, chair and deputy director of the Dr. Mary and Ron Neal Cancer Center at Houston Methodist, for an initiative to improve cancer screening and prevention education services in urban medically underserved areas. Such areas suffer from significantly higher cancer incidence and mortality rates.

The initiative makes cancer-related preventive services available in collaboration with Legacy Health Services, the state's largest federally qualified health center, and Texas A&M Health Science Center. It will target the Greater Fifth Ward, Santa Clara and San Jacinto/Baytown — three of Houston's most medically underserved communities.

Specific goals include:

• Providing screenings for breast, cervical, colorectal and liver cancer, as well as the hepatitis C virus that leads to liver cancer, at Legacy clinic sites in the three communities
• Navigating patients to treatment and follow-up diagnostic services to reduce barriers to cancer/hepatitis C screening
• Delivering comprehensive cancer prevention education and outreach activities tailored to the needs of medically underserved populations

"We fully expect this collaborative cancer screening and early detective program to provide a replicable community-partner model for addressing the significant need for more evidence-based cancer prevention and care focusing on medically underserved populations," Dr. Esnaola wrote in the grant application.

How ATRA enhances myeloma cell sensitivity to proteasome inhibitors

Dr. Yi, also director of Houston Methodist's Center for Translational Research in Hematological Malignancies, has conducted research on multiple myeloma for more than 25 years. He came to Houston Methodist in 2008, thanks to a $6 million CPRIT recruitment grant. Such grants allow Texas institutions to lure top investigators from out of state.

Multiple myeloma, an accumulation of tumor cells in the bone marrow that presents in such areas as the spine, skull, pelvis and ribs, can be medically managed for years, though patients eventually relapse. About 35,000 U.S. people are diagnosed with the disease annually, and about 12,500 a year die from it.

ATRA, a vitamin A derivative, was the first retinoid to be approved by the FDA as a cancer treatment in the U.S. Its use in acute promyelocytic leukemia was part of that cancer's journey from highly fatal to highly curable.

The therapy works by binding to retinoic acid receptors and retinoid X receptors, which disrupts pathways involved in drug resistance and allows proteasome inhibitors to exert their anti-cancer effects more effectively.

Although proteasome inhibitors have demonstrated therapeutic efficacy, only 48% of multiple myeloma patients never treated with any of them respond to carfilzomib, and significantly less, 27%, respond to bortezomib. In addition, most patients who respond well to the drugs initially become resistant when treated again after relapse.