Treating HIF2 drug resistance with RNA-based therapy: newsroom

Dallas – October 3, 2022 – Expected to be diagnosed in 2% of men and 1% of women in the United States, kidney cancer has traditionally been one of the most difficult to treat cancers. Until 2005, only one drug had been approved by the Food and Drug Administration (FDA) to treat kidney cancer, which is resistant to both chemotherapy and conventional radiation. Since then, discoveries regarding its biology have led to a wave of targeted and immunological therapies. But despite these advances, most patients still succumb to the disease once the cancer has spread to this day.

Find out at UT Southwestern Medical Center (UTSW), HIF2α . protein It is the most important driver of kidney cancer, which has traditionally been viewed as untreatable. Select UTSW Scholars A asthenia In HIF2α protein structure and identification Chemicals HIF2α inhibition. Licensed to Peloton Therapeutics at the UTSW BioCenter, these chemicals laid the foundation for the development of PT2977 (also called belzutifan), which received FDA approval for the treatment of hereditary kidney cancer in 2021, and is currently being evaluated against non-familial kidney cancer in multiple phase 3 clinical trials by Merck, which acquired Peloton.

However, studies in mice and then in The patients showed that kidney tumors are gaining resistance. Resistance arises as a result of mutations, including mutations that prevent binding of the drug to HIF2α.

James Progarolas, MD, PhD.

Over the past seven years, scholars have been in Brugarolas Lab UTSW in partnership with Arrowhead Pharmaceuticals To develop a second generation inhibitor with activity not only against unmodified HIF2α but also against mutated HIF2α. using the same a program of tumors from patients transplanted into mice that provided the first evidence of anticancer activity By Peloton HIF2α-blocking drugs, the authors Now show This second-generation drug is also effective against kidney cancer. Evidence of principle activity is also provided in humans by The first stage of the trial led James Progarolas, MD, PhD.Professor of Internal Medicine and Director Kidney Cancer Program In the Harold C Simmons Comprehensive Cancer Center from UTSW.

Like the FDA-approved Pfizer-BioNTech and Moderna COVID-19 vaccines, the second generation HIF2α inhibitor (ARO-HIF2) is an RNA-based drug. ARO-HIF2 is a dsRNA drug that inhibits HIF2α production in cancer cells. A special feature of ARO-HIF2 is the presence of a ‘guiding device’ that specifically targets cancer cells by interacting with a protein on their surface.

Downregulation of HIF2α by ARO-HIF2 in patient tumor biopsies. Courtesy of Dr. Payal Kapoor

“RNA-based drugs hold promise for treating many different diseases, as evidenced by a recent series of new FDA approvals. However, the unresolved challenge in cancer is delivery. Developing delivery systems to target cancer cells, which is the thing which was accomplished with ARO-HIF2, is a domain Expand your search,” He said Daniel Siegwart, Ph.D.D., associate professor of biochemistry at UTSW and a member of the Simmons Cancer Center.

These studies were supported by Arrowhead Pharmaceuticals as well as National Cancer Institute through the Specialized Program in Research Excellence Award (SPORE). Dr. Brugarolas previously worked as a consultant for Arrowhead Pharmaceuticals and has several patent applications related to HIF2.

Dr. is running. Progarolas Sherry Wigley Crowe Chair for Cancer Research in honor of Robert Louis Kirby, MD. Dr. Siegwart holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s leading academic medical centers, combines groundbreaking biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 investigators of the Howard Hughes Medical Institute. Our 2,900-plus full-time faculty members are responsible for pioneering medical developments and are committed to quickly translating scientific research into new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties for more than 100,000 hospitalized patients, more than 360,000 emergencies, and oversee nearly 4 million outpatient visits annually.

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