Despite new therapies, Multiple Myeloma (MM) remains incurable causing most patients to ultimately develop drug resistance and succumb to the disease. The pursuit of drugs that inhibit cell cycle regulators especially cyclin-dependent kinases (CDKs), has been an intense focus of research in cancer. A new study by researchers at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai has shown that targeting both CDK4 and ARK5, proteins responsible for maintaining energy balance within the cell, was extremely effective in causing cell death in myeloma. Their research, published in the March issue of the journal Cancer Research, identifies new targets for myeloma drug development.
Multiple myeloma (MM) is a fatal blood cancer accounting for over 10,000 deaths in the United States each year. Better understanding of the molecular basis of myeloma has led to a growing list of treatments for this challenging disease. Despite recent advances in new therapies, this disease remains incurable with a median survival of 7 to 8 years.
"Even in the era of great drug development, there is an urgent need an urgent need to develop drugs that are less toxic and achieve longer remissions for all patients," said Samir Parekh, MD, Associate Professor of Medicine, Hematology and Medical Oncology, and Oncological Sciences at Icahn School of Medicine at Mount Sinai and co-author of the study.
The team along with Onconova Therapeutics, Inc. USA developed a compound, ON123300 that included multi-targeted inhibitors ARK5 and CDK4. The researchers treated both primary myeloma cells and cells line with ARK5/CDK4 inhibitor ON123300 which resulted in tumor cell death, and halted cancer cell growth in vitro and in vivo mouse models.
"ARK5 is critical for myeloma survival and this study suggests a novel function for ARK5 in bridging the mTOR and MYC pathways," said Deepak Perumal, PhD, lead author of the study and post-doctoral scientist, Hematology and Medical Oncology at Icahn School of Medicine at Mount Sinai. "Given that MYC is critically over expressed in myeloma, we sought to determine whether selective inhibition of ARK5 and CDK4 could be an effective way to target MYC-driven proliferation in myeloma."
Researchers evaluated the effect of ARK5/CDK4 inhibitor ON123300 against myeloma cell lines and primary samples from patients with recurring myeloma. Myeloma cells were sensitive to ON123300 while normal peripheral blood cells were spared from the effects of the compound confirming a potent and specific anti-cancer effect of ON123300.
"Our study results show that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells," said Dr. Parekh. "This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in MM and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for MM patients."
This work was supported by grants from The Chemotherapy Foundation and the NIH.
About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community-based facilities to tertiary and quaternary care.
The System includes approximately 6,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is ranked as one of the nation's top 10 hospitals in Geriatrics, Cardiology/Heart Surgery, and Gastroenterology, and is in the top 25 in five other specialties in the 2015-2016 "Best Hospitals" issue of U.S. News & World Report. Mount Sinai's Kravis Children's Hospital also is ranked in seven out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology, while Mount Sinai Beth Israel is ranked regionally.
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