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ACETATE
METABOLISM
Cells under stressed conditions of hypoxia and glucose depletion turn to other biomolecules to fulfill their energy needs. One such biomolecule is acetate which can be sourced directly from the circulation or freed up within cells by the action of stress activated enzymes. Acetate is readily converted to acetyl CoA that enables numerous cellular functions.
Survival requires dynamic reprogramming and rebuilding of cellular machinery to deal with the challenges of the new environment. This is achieved by epigenetic gene expression programs that are activated by acetylating master genes in the nucleus that redirect cellular priorities to overcome the environmental stress.
Studies demonstrating that tumor cells take up significant amounts of acetate often in preference to glucose has led to the investigation of acetate metabolism in cancer and stress. The inner tumor mass is a poorly vascularized nutritionally barren region in which cells survive by rewiring their metabolism. The propensity of certain tumors to take up acetate has been exploited by using 11C-acetate guided positron emission tomography (PET) imaging for the detection of primary tumors and distant metastases. In fact, 11C-acetate guided PET has been reported to be more efficient than labeled 18Fluoro-Deoxy Glucose (18FDG) in detecting or grading gliomas, hepatocellular carcinomas, non-small cell lung cancer and metastases in prostate cancer patients.
ACSS2
Acetate is directly converted to acetyl CoA by a family of Acyl-coenzyme A synthetase short-chain enzymes (ACSS). Among these, ACSS2 has attracted special interest. There is an increasing body of clinical evidence that places acetate and ACSS2 at a critical metabolic node in tumor cells under nutritional and hypoxic stress. High ACSS2 expression in patients with grade-2/3 gliomas or triple negative breast cancer is associated with shorter overall survival. Infusions of 13C-acetate into the brains of GBM patients with brain tumors has established that almost half of the acetyl-CoA in the tumors originated from acetate and that these tumors expressed moderate to high levels of ACSS2.
Curadev’s ACSS2 program focuses on the ability of tumors to survive in hostile microenvironments by altering their metabolic requirements. We have developed potent small molecule inhibitors of Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2) to target tumor survival in these conditions. Combinations of these inhibitors with other forms of cancer therapy are being investigated to identify synergistic modes of tumor elimination.
Other applications of ACSS2 inhibitors: ACSS2 which plays a role in lipid metabolism could also be targeted in hepatic steatosis to reduce lipid accretion without altering lean body mass.