In a groundbreaking phase one clinical trial led by UT Southwestern Medical Center, a short interfering RNA (siRNA) drug directed to tumor cells effectively disrupted HIF2α, a key driver of clear cell renal cell carcinoma (ccRCC). Published in Clinical Cancer Research, the findings illustrate the potential of siRNA for cancer therapy.
Developed by Arrowhead Pharmaceuticals, ARO-HIF2 is designed to selectively target HIF2α mRNA blocking the production of the HIF2α protein, showcasing a new avenue for targeted cancer therapy. The drug’s unique guidance system promotes delivery to tumor cells through an interaction with a protein (integrin αvβ3) on the surface of ccRCC cells, enhancing its uptake and therapeutic potential.
ccRCC is the most common type of kidney cancer in adults, characterized by the presence of clear cells in the tumor. It is a challenging disease to treat, especially in advanced stages, necessitating innovative therapeutic approaches.
The study, sponsored by Arrowhead Pharmaceuticals, enrolled 26 patients across several institutions, including at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, where the first patient enrolled, and The University of Texas MD Anderson Cancer Center. Patients with advanced ccRCC and progressive disease after typically having three or more prior therapies received ARO-HIF2 intravenously at progressively higher doses in three consecutive cohorts. ARO-HIF2 halted tumor growth in 40% of participants, and two patients achieved a partial response.
Detailed analyses in responding patients comparing pre- and post-treatment biopsies showed that HIF2α was depleted by ARO-HIF2 in the tumor. Furthermore, ARO-HIF2 suppressed tumor-produced erythropoietin, indicating effective blockade of HIF2α.
“ARO-HIF2’s ability to target cancer cells disrupting a key tumor-driving mechanism illustrates the potential of siRNA technology in oncology,” said lead author James Brugarolas, M.D., Ph.D., Professor of Internal Medicine in the Division of Hematology and Oncology and founding Director of the Kidney Cancer Program at the Simmons Cancer Center at UTSW.
Nizar M. Tannir, M.D., Professor of Genitourinary Medical Oncology at MD Anderson, who co-led the study, added, “These encouraging results pave the way for further research, highlighting a novel strategy in our fight against cancer.”
Parallel experiments in mice transplanted with a tumor sample from a biopsy of one of the responding patients in the phase one trial confirmed siRNA drug efficacy. These studies built upon preclinical studies of ARO-HIF2 through the UTSW Kidney Cancer Specialized Program of Research Excellence (SPORE), funded by the National Cancer Institute. ARO-HIF2 was first tested in mice transplanted with ccRCC patient tumors in the Brugarolas Lab. Tumors chosen for this study expressed αvβ3 on the surface and were dependent on HIF2α for their growth, as determined by sensitivity to a drug developed by the UTSW spinoff company, Peloton Therapeutics, which is now part of pharmaceutical giant Merck. These studies found that ARO-HIF2 was taken up by the transplanted tumors in mice where it depleted HIF2α, arresting ccRCC growth.
While ARO-HIF2 has shown efficacy, its development faces challenges due to neurotoxicity observed in some patients. This underscores the need for ongoing research to refine and enhance the safety profile of such innovative treatments.
Dr. Brugarolas holds The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D.
He received research funding from Arrowhead Pharmaceuticals and has a patent and other applications pertaining to HIF2.
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(Newswise/KV)