A link between ovarian cancer driver and metabolism opens up new therapeutic strategies

PHILADELPHIA – (Jan. 11, 2020) – Variables that activate the ARID1A gene in ovarian cancer increase use of the amino acid glutamine making cancer cells dependent on glutamine metabolism, according to a study by the Wistar Institute that was published online in Cancer of nature. Researchers also showed that pharmacologic inhibition of glutamine metabolism may represent an effective therapeutic strategy for ARID1A-mutant ovarian cancer.

Up to 60% of ovarian clear cell carcinomas (OCCCs) are inactivated mutations in the ARID1A tumor suppressor gene. These mutations are known to be genetic drivers of this type of cancer, which do not usually respond to chemotherapy and carry the worst prognosis among all subtypes of ovarian cancer.

Laboratory Rugang Zhang, Ph.D., deputy director of the Wistar Institute Cancer Center, professor and director of the Immunology, Microenvironment & Metastasis Program, will examine the effects of ARID1A inactivity to new therapeutic strategies equipment-led and combination design methods develop immunotherapy for ovarian cancer.

“Metabolic regression is a hallmark of many cancers, including OCCC, so in this study we evaluated whether ARID1A plays a role in the regulation of metabolism,” said Zhang, corresponding author on paper. “We found that its inactivity in cancer cells creates a specific metabolic requirement for glutamine and this has emerged as a vulnerability that could be used for therapeutic purposes.”

The authors activated ARID1A in ovarian-type ovarian cancer cells and observed increased glutamine consumption. Glutamine is usually required for cancer cell growth, but Zhang and colleagues showed a stronger dependence of ARID1A-mutant cells on this amino acid, which contributed significantly to the growth caused by glutamine deficiency.

ARID1A is part of a protein complex called SWI / SNF that alters gene expression. The authors studied the transcription effect of ARID1A inactivation and found that GLS1, which encodes the glutaminase enzyme, was the main gene under control among those who controlling glutamine metabolism. Accordingly, GLS1 was expressed at significantly higher levels in tumor samples from patients with other cancers that also carry mutations in the SWI / SNF complex.

The team evaluated the therapeutic potential of inhibiting glutamine metabolism by inhibiting the enzyme glutaminase with the inhibitor CB-839. This molecule has been reported to be under study in clinical trials and is recovering well as a single agent and in combination with other anticancer medications.

When tested in vivo on OCCC mouse models, CB-839 significantly reduced tumor burden and longevity. These studies were extended to mice carrying tumor transplants derived from patients, confirming that CB-839 inhibited the growth of ARID1A-mutant but not ARID1A-wildtype tumors.

Researchers also combined CB-839 with anti-PDL1 treatment and revealed an interaction between glutaminase inhibitors and immune inhibitors in inhibiting the growth of ORIDC ARID1A-mutant tumors.

“Our findings suggest that glutaminase inhibitors warrant further studies as a standalone or combinatorial therapeutic intervention for OCCC, for which effective options are very limited,” said Shuai Wu, Ph.D. , the study’s first author and staff scientist at the Zhang Lab.

Glutaminase inhibitors could become a new strategy to precisely target specific vulnerabilities of OCCC cells associated with loss of ARID1A function.

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Co-authors: Takeshi Fukumoto, Jianhuang Lin, Timothy Nacarelli, Heng Liu, Nail Fatkhutdinov, Joseph A. Zundell, Sergey Karakashev, Wei Zhou, Hsin-Yao Tang, Qin Liu, Andrew V. Kossenkov, David W. Speicher, Zachary T . Schug, and Chi Van Dang of the Wistar Institute; Yemin Wang, Dionzie Ong and David G. Huntsman of the University of British Columbia, Vancouver, British Columbia, Canada; and Lauren E. Schwartz and Ronny Drapkin of the University of Pennsylvania.

Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, R01CA239128, P01AG031862, P50CA228991, K99CA241395, R50CA221838, S10OD023658, S10OD023586; R01CA195670, F31CA247336, and T32CA009191; US Department of Defense grants OC180109 and OC190181. Additional support was provided by the Rev. Tina Brozman Foundation for Ovarian Cancer Research and the Tina Brozman 2.0 Ovarian Cancer Research Consortium; and Ovarian Cancer Research Alliance (Collaborative Research Development Award # 596552 and Mentored Ann and Sol Schreiber Researcher Award # 598026). Key support for the Wistar Institute was provided by the P30CA010815 Cancer Center Support Grant.

Disclosure information: Targeting glutamine dependence through GLS1 inhibition eliminates ARID1A-inactivated clear cell ovarian carcinoma, Cancer of nature, 2020. Online publication.

The Wistar Institute is an international leader in biochemical research with specialized experience in cancer research and vaccine development. Founded in 1892 as the first nonprofit biomedical research institute in the United States, Wistar has been named the prestigious Cancer Center of the National Cancer Institute since 1972. The Institute actively works to ensure that research advances are moving from laboratory to clinic so quickly. where possible. wistar.org.