New Therapy With Potential Benefit for Underserved Patients With Lung and Ovarian Cancers Identified

A novel drug called IPN60090 is under investigation in a phase 1 trial, according to researchers from The University of Texas MD Anderson Cancer Center's Therapeutics Discovery division and Ipsen Biopharmaceuticals. The researchers reported preclinical discovery and early-stage clinical development of the drug, which is a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1) that could have benefit for certain underserved patients with lung and ovarian cancers.

The results of the ongoing trial were presented April 27, 2020 by Jeffrey Kovacs, PhD, group leader with Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) and coleader of the GLS1 program, at the 2020 American Association for Cancer Research Virtual Annual Meeting I.

“This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine,” said Kovacs in a press release. “Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials.”

The GLS1 enzyme plays a key role in many metabolic processes. Since the dysregulation of cellular metabolism is a mainstay of cancer development, the GLS1 enzyme is a strong target for cancer therapy, according to Kovacs.

Researchers at the Institute for Applied Cancer Science (IACS) identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, while translational researchers at TRACTION went on to demonstrate IPN60090’s activity in fighting subsets of lung and ovarian cancer preclinical models.

Further research was then able to observe biomarkers of response that will help to identify patients who would benefit from the treatment. Generally, in lung cancers, mutations in the KEAP1 and NFE2L2 genes, which are able to regulate responses to oxidative stress, sensitize the cells to IPN60090 treatment. Additionally, a low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers can be a predictor for an effective response to IPN60090 treatment.

“Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we're able to offer patients the most relevant therapies,” said Timothy Yap, MBBS, PhD, FRCP, leader of the IPN60090 clinical trial at MD Anderson, associate professor of Investigational Cancer Therapeutics, and medical director of IACS, in a press release. “These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options.”

Those patients with lung cancers that present KEAP1/NRF2 mutations may not be able to benefit from treatment with immune checkpoint inhibitors, which can result in poorer treatment outcomes for these therapies, explained Yap.

IPN60090 is now being investigated by researchers in a Phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that have KEAP1/NFE2L2 mutations or low ASNS levels.

The researchers have also developed CLIA-certified assays to identify patients who are likely to benefit from IPN60090, as well as monitor the drug’s efficacy. The initial results demonstrate that the drug has been effectively inhibiting GLS1 activity in patients’ peripheral blood mononuclear cells.

Further investigation of IPN60090 in combination with checkpoint inhibitors, chemotherapy and targeted therapies is underway in trial cohorts by researchers, as these therapies have been identified as having potential synergistic benefits with IPN60090’s GLS1 inhibition.

REFERENCE

MD Anderson and Ipsen advance new therapy with potential benefit for underserved patients with lung and ovarian cancers [news release]. Houston, TX: University of Texas M. D. Anderson Cancer Center. April 27, 2020. eurekalert.org/pub_releases/2020-04/uotm-maa042420.php. Accessed April 30, 2020.