New York, NY (Press Release) – Despite new ther­a­pies, multiple myeloma 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 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.

Source: Mount Sinai.