MD Anderson Therapeutics Discovery team identifies and advances a drug that targets metabolic vulnerability and impairs cancer cell growth and survival

Pre-clinical results for IACS-10759 drug leads to Phase I clinical trials in AML and solid tumors; two papers published in Nature Medicine

A drug discovered and advanced by The University of Texas MD Anderson Cancer Center’s Institute for Applied Cancer Science (IACS) and TRACTION platform inhibits a vital metabolic process required for cancer cells’ growth and survival.

IACS-10759 is the first small molecule drug to be developed from concept to clinical trial by MD Anderson’s Therapeutics Discovery team, which includes IACS and TRACTION. Therapeutics Discovery is a unique group of clinicians, researchers and drug development experts working collaboratively to create new treatment options, including small molecules, biologics, and cell-based therapies.

New data related to IACS-10759 were published in two papers in the June 11 online issue of Nature Medicine. The first paper reports the preclinical work led by Joseph Marszalek, Ph.D., head of Translational Biology for TRACTION, and Emilia Di Francesco, Ph.D., associate director of Medicinal Chemistry at IACS, which resulted in the discovery of IACS-10759 and its advancement into Phase I clinical trials for acute myeloid leukemia (AML) and solid tumors. A second paper, authored by Andrew Futreal, Ph.D., chair, and Yonathan Lissanu Deribe, Ph.D., instructor, both of Genomic Medicine, describes the potential of IACS-10759 for treatment of lung cancers harboring a specific epigenetic alteration.

The pathway to discovery of IACS-10759

Metabolic reprogramming is an emerging hallmark of tumor biology where cancer cells evolve to rely on two key metabolic processes, glycolysis and oxidative phosphorylation (OXPHOS), to support their growth and survival. Extensive efforts have focused on therapeutic targeting of glycolysis, while OXPHOS has remained largely unexplored, partly due to an incomplete understanding of tumor contexts where OXPHOS is essential.

“Through a comprehensive translational effort enabled by collaboration across MD Anderson, we have identified multiple cancers that are highly dependent on OXPHOS,” said Marszalek.

This effort inspired the discovery and development of IACS-10759, a potent and selective inhibitor of OXPHOS. Its advancement to clinical trials was made possible by a multidisciplinary team of more than 25 scientists across Therapeutics Discovery.

“Through this collaborative, 18-month process, we identified and rapidly advanced IACS-10759 as the molecule for clinical development,” said Di Francesco. “We believe IACS-10759 will provide a promising new therapy for cancer patients.”

The pre-clinical research conducted by IACS and TRACTION led to an ongoing first-in-human Phase I clinical trial, launched in October 2016, evaluating IACS-10759 in AML, led by Marina Konopleva, M.D., Ph.D., professor, and Naval Daver, M.D., associate professor, both of Leukemia. A second Phase I trial in solid tumor indications, started in November 2017, is led by Timothy Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics.

IACS-10759’s potential for clinical study of mutant lung cancers

IACS-10759 was evaluated in pre-clinical studies for treating lung cancers harboring mutations in the SMARCA4 gene, which render tumors sensitive to the drug due to an increased dependence on OXPHOS for survival.

SMARCA4 is a component of a chromatin modeling complex called SWI/SNF, which plays a vital role in gene expression. The study team’s analyses showed SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity, making them susceptible to treatment with an OXPHOS inhibitor like IACS-10759.

“Our findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against cancers with SWI/SNF-mutant tumors,” said Lissanu Deribe. “Through multidisciplinary studies of new agents like IACS-10759, we aim to accelerate the availability of enhanced therapies for our patients.”

Marszalek and Di Francesco Team Members and Funding Sources:

MD Anderson study team members included: Jennifer Molina, Ph.D.; Yuting Sun, Ph.D.; Marina Protopopova, Ph.D.; Sonal Gera; Madhavi Bandi, Ph.D.; Christopher Bristow, Ph.D.; Edward Chang, Ph.D.;  Angela Deem, Ph.D.; Ningping Feng, Ph.D.; Guang Gao; Jason Gay; Virginia Giuliani, Ph.D.; Jing Han, Ph.D.; Tin Khor, Ph.D.; Timothy Lofton; Mikhila Mahendra;  Robert Mullinax; Michael Peoples; Thomas Shi; Melinda Smith;; Carlo Toniatti, M.D., Ph.D.; Giulio Draetta, M.D., Ph.D.;  and Timothy Heffernan, Ph.D., all of TRACTION; Timothy McAfoos, Ph.D.; Jennifer Bardenhagen; Christopher Carroll, Ph.D.; Jason Cross, Ph.D.; Barbara Czako, Ph.D.; Mary Geck Do, Ph.D.; Jennifer Greer; Sha Huang; Yongying Jiang, Ph.D.; Zhijun Kang;  Gang Liu, Ph.D.; Pietro Morlacchi, Ph.D.;  Alessia Petrocchi; Jay Theroff; Quanyun Xu, Ph.D.; and Philip Jones, Ph.D., all of IACS; Naval Daver, M.D.; Lina Han, M.D., Ph.D.; Helen Ma; Polina Matre, Ph.D.; Yoko Tabe, M.D., Ph.D.; Qi Zhang, Ph.D.; and Marina Konopleva, M.D., Ph.D., all of Leukemia; Gheath Al-Atrash, D.O., Ph.D.; and Stefan Ciurea, M.D.; of Stem Cell Transplantation and Cellular Therapy; Caroline Carrillo; Verlene Henry; John Frederick de Groot, M.D.; and Jian-Wen Dong, all of Neuro-Oncology; Sergej Konoplev, M.D., Ph.D., of Hematopathology; Jeffrey Ackroyd; Yu-Hsi Lin; and Florian Muller, Ph.D.of Cancer Imaging Systems; Jaime Rodriguez-Canale, M.D., of Translational Molecular Pathology; and Ronald DePinho, M.D. of Cancer Biology. Other participating institutions included The University of Texas at Austin; Cambridge University, U.K.; Agilent Technologies, Inc., Lexington, Mass.; Beth Israel Medical Center and Harvard Medical School, Boston; and the Juntendo University School of Medicine, Tokyo.

The studies were funded by TRACTION, IACS, the Glioblastoma Moon Shot™, and the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot™, all part of the MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

The studies were also supported by the Cancer Prevention and Research Institute of Texas (RP140218, RP140612); the American Cancer Society (RSG1514501CDD); the American Association for Cancer Research (13-90-25); the National Institutes of Health (P50CA12700107); the Sheikh Ahmed Bin Zayad Al Nahyan Center for Pancreatic Cancer; the Leukemia and Lymphoma Societies Therapeutic Accelerator Program; the Medical Research Council (U105663141).

Futreal and Lissanu Deribe Team Members and Funding Sources

MD Anderson study team members included Christopher Terranova, Ph.D.; Fatima Khan; Juan Martinez-Ledesma, Ph.D.; Chia-Chin Wu,Ph.D.; Claudia Reyes; Qian Peng; Akira Inoue, M.D., Ph.D.; and Kunal Rai, Ph.D., all of Genomic Medicine; Yuting Sun, Ph.D.; Jason Gay; Guang Gao, Ph.D.; Robert Mullinax; Tin Khor, Ph.D.; Ningping Feng, Ph.D.; Frederick Robinson; and Joseph Marszalek, Ph.D., all of IACS; Yu-Hsi Lin; and Florian Muller, Ph.D., of Cancer Systems Imaging; Veena Kochat, Ph.D., of Surgical Oncology; Chang-Gong Liu, Ph.D., of Experimental Therapeutics; Cesar Moran, M.D., of Pathology; Jing Wang, of Bioinformatics and Computational Biology; Bingliang Fang, Ph.D.; and Vali Papadimitrakopoulou, M.D., of Thoracic, Head and Neck Medical Oncology; and Ignacio Wistuba, M.D., of Translational Molecular Pathology.