Researchers from MD Anderson's Therapeutics Discovery division previously reported the discovery and development of IACS-6274, a novel small-molecule inhibitor targeting the metabolic enzyme glutaminase (GLS1).
Through a patient-driven translational biology effort, the researchers now have identified and validated asparagine synthetase (ASNS) as a candidate biomarker to predict those most likely to benefit from the therapy.
The new findings were shared in a minisymposium presentation at the virtual AACR Annual Meeting 2021 by Nakia D. Spencer, institute associate scientist IV with the Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform and one of the GLS1 project leads.
The development of IACS-6274, previously known as IPN60090, was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and TRACTION platforms, both engines within Therapeutics Discovery.
The drug is now under investigation in a Phase I trial for advanced solid tumours.
"Ovarian cancer remains an area of unmet medical need for our patients," Spencer said. "Utilising team science to drive patient-focused research, we discovered that ovarian tumours lacking ASNS respond to IACS-6274 treatment, pointing us toward a significant number of patients who may benefit from this therapy."
Disruptions in normal cellular metabolism are distinguishing characteristics of many cancers, and the GLS1 enzyme is critical to many metabolic processes.
In the preclinical development of IACS-6274, TRACTION researchers demonstrated promising activity in certain ovarian cancer preclinical models.
In ovarian cancer cell lines that respond to IACS-6274, treatment disrupts normal metabolism of specific amino acids and antioxidants, resulting in the accumulation of DNA damage that the cells cannot survive.
By comparing sensitive and resistant cell lines, the researchers discovered that high expression of the metabolic enzyme ASNS predicted response to IACS-6274.
These results were confirmed in animal models, where ovarian cancers with low ASNS expression were responsive to IACS-6274 treatment and those with high ASNS expression were not.
Using tissue samples from MD Anderson patient biopsies, the team created a CLIA-certified assay to quantify ASNS levels in tumour samples.
"Advancing treatments that provide the greatest benefits to patients requires a strong translational and drug discovery package that complements the clinical efforts," Spencer said. "Applying what we've learned from the clinical study, we continue to develop multiple biomarker-driven patient stratification strategies to identify those most likely to benefit from IACS-6274."
Therapeutics Discovery researchers will share additional updates on IACS-6274 development in poster sessions, including the identification of rational combination strategies for GLS1 inhibitors and the effects of IACS-6274 on the antitumour immune response.
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