Researchers at The University of Texas MD Anderson Cancer Center have developed a novel targeted therapy, called POMHEX, which blocks critical metabolic pathways in cancer cells with specific genetic defects. Preclinical studies found the small-molecule enolase inhibitor to be effective in killing brain cancer cells that were missing ENO1, one of two genes encoding the enolase enzyme.
The study results, published today in Nature Metabolism, provide proof of principle for a treatment strategy known as collateral lethality, in which an important protein is lost through genetic deletion as a bystander near a tumor suppressor gene, and a redundant protein is blocked therapeutically.
"Collateral lethality could expand the scope of precision oncology beyond activated oncogenes, and allow targeting of genomic deletions, largely considered un-actionable," said corresponding author Florian Muller, Ph.D., assistant professor of Cancer Systems Imaging and Neuro-Oncology. "Our work provides proof of principle that this approach can actually work with a drug in animal models."
Enolase is an essential enzyme involved in glycolysis, a metabolic pathway that is elevated in many cancers to fuel their increased cell growth. Two genes, ENO1 and ENO2, encode slightly different but redundant versions of enolase, and several cancers, such as glioblastoma, are missing the ENO1 gene because of chromosomal loss. This leaves the cancer cells with only ENO2 to continue glycolysis, making them highly sensitive to enolase inhibitors, Muller explained.
Therapies that target both forms of enolase have previously been developed, but blocking ENO1 can have unwanted side effects in normal cells. Targeting ENO2 specifically is attractive because it allows for the selective treatment of cancer cells missing ENO1.
The research team therefore worked to generate an enolase inhibitor, called HEX, that preferentially targets ENO2 over ENO1. To improve the drug's ability to enter cells, the team created the prodrug POMHEX, which is biologically inactive until it is metabolized into HEX within cells.
In cancer cell lines lacking ENO1, treatment with POMHEX blocked glycolysis, inhibited cell growth and stimulated cell death. Conversely, treatment of cells with normal ENO1 showed minimal effects.
Further, in animal models of ENO1-deficient tumors, both HEX and POMHEX treatment was well- tolerated and effectively blocked tumor growth relative to controls, with some instances of complete tumor eradication. Taking the work one step further, the team demonstrated that the therapeutically effective dose could be safely given in multiple models, suggesting favorable future translation to the clinical studies.
"We were encouraged by the promising preclinical activity of these novel enolase inhibitors and that the safety profile extends to higher models. While there could be further refinements, I am optimistic that even HEX would show significant clinical activity against ENO1-deleted cancers," Muller said.
ENO1 deletions also occur in liver cancer, bile duct cancer and large-cell neuroendocrine lung cancers, all of which share poor prognosis and limited treatment options, Muller explained. Thus, once an optimal therapy candidate has been developed, there is potential to evaluate the ENO2 inhibitor in treating patients with multiple cancer types.
This research was supported by the National Institutes of Health/National Cancer Institute (CA16672, P30CA016672, P50CA127001-07, 2P50CA127001-11A1, CA225955), the American Cancer Society, the National Comprehensive Cancer Network, the Andrew Sabin Family Foundation, the Dr. Marnie Rose Foundation, the Uncle Kory Foundation, the MD Anderson Institutional Research Grant, and the Cancer Prevention & Research Institute of Texas (RP140612).
In addition to Muller, MD Anderson co-authors on the study include: Yu-Hsi Lin, Naima Hammoudi, Ph.D., Victoria C. Yan, Yasaman Barekatain, Sunada Khadka, Jeffrey J. Ackroyd, Dimitra Georgiou, Ph.D., Cong-Dat Pham, Ph.D., Kenisha Arthur, Federica Pisaneschi, Ph.D., Susana Castro Pando, Xiaobo Wang, and Theresa Tran, all of Cancer Systems Imaging; Nikunj Satani, of Cancer Systems Imaging and UTHealth Institute of Stroke and Cerebrovascular Disease; David Maxwell, Ph.D., of Institutional Analytics & Informatics; Paul G. Leonard Ph.D., Barbara Czako, Ph.D., Pijus Mandal, Ph.D., Quanyu Xu, Ph.D., Qi Wu, Yongying Jiang, Ph.D., and Zhijun Kang, all of the Institute for Applied Cancer Science; Yuting Sun, Ph.D., and Joseph R. Marszalek, Ph.D., of the TRACTION platform; Rafal Zielinski, Ph.D., and Waldemar Priebe, Ph.D., both of Experimental Therapeutics; and Ronald A. DePinho, of Cancer Biology. Additional authors include Zhenghong Peng, Cardtronics, Houston, TX; John M. Asara, Ph.D., Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and William Bornmann, Ph.D., Advanced Organic Synthesis LLC, Houston, TX. A full list of author disclosures can be found with the full paper here.
