The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics for solid tumors has been successful. Targeting two distinct emerging hallmarks, such as non-mutational epigenetic changes by panobinostat (Pan) and delayed cell cycle progression by abemaciclib (Abe), inhibits pancreatic cancer growth. HDAC and CDK4/6 inhibitors are effective but are prone to drug resistance and failure as single agents. Therefore, we hypothesized that combining Abe and Pan could synergistically and lethally affect PDAC survival and proliferation. Multiple cell-based assays, enzymatic activity experiments, and flow cytometry experiments were performed to determine the effects of Abe, Pan, and their combination on PDAC cells and human dermal fibroblasts. Western blotting was used to determine the expression of cell cycle, epigenetic, and apoptosis markers. The Abe-Pan combination exhibited excellent efficacy and produced synergistic effects, altering the expression of cell cycle proteins and epigenetic markers. Pan, alone and in combination with Abe, caused apoptosis in pancreatic cancer cells. Abe-Pan co-treatment showed relative safety in normal human dermal fibroblasts. Our novel combination treatment of Abe and Pan shows synergistic effects on PDAC cells. The combination induces apoptosis, shows relative safety, and merits further investigation due to its therapeutic potential in the treatment of PDAC.

Glioblastoma (GBM) is a fatal cancer with a dismal prognosis and a dire need for novel chemotherapeutics. Metabolic reprogramming is an established hallmark of cancer. In our previous study on GBM, we aimed at targeting the metabolic reprogramming of cancer by using stiripentol (STP), a putative lactate dehydrogenase (LDH) inhibitor and an FDA-approved anti-epileptic drug. However, the precise mechanism of STP’s anti-cancer activity remains unclear. We aimed to elucidate the mechanism of action of STP in GBM to further develop STP as a therapeutic. We employed a multiomic approach followed by metabolic and cellular assays. STP treatment induced genetic and metabolic alterations in GBM cells. Inhibition of LDH by STP was moderate but not potent. The cellular changes were accompanied by an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, and induction of senescence in GBM cells. Our research indicates that further research in senescence-inducing agents and novel LDH inhibitors can provide novel therapeutics for GBM.

Hepatocellular carcinoma (HCC) is one of the leading cancers in terms of incidence and mortality. There are fewer chemotherapies with HCC with a low survival rate. One of the prominent features of cancer is metabolic reprogramming and thus metabolic proteins are viable targets for cancer treatment. Glycogen is a polymer of glucose, which acts as a reservoir of energy in mammalian cells. The levels of glycogen have been found to correlate with biological processes in cancer cells, however, the role of glycogen metabolism in carcinogenesis, cancer cell growth, metastasis, and chemoresistance is not completely understood. Thus, we studied the cellular processes involved in the inhibition of glycogen metabolism in HCC. Pharmacological inhibition of glycogen phosphorylase (GP) by CP‐91149, a rate‐limiting enzyme in glycogen catabolism, led to a decrease in HepG2 viability. GP inhibition induced the intrinsic apoptosis pathway causing HepG2 cell death. This process was accompanied by mitochondrial dysfunction and autophagic adaptations, whereas endoplasmic reticulum stress, necrosis, and necroptosis were not involved. In addition, GP inhibition potentiated the effects of the multi‐kinase inhibitors sorafenib and regorafenib, which are key drugs in advanced‐stage HCC therapy. Our study provides mechanistic insights into cell death by perturbations of glycogen metabolism and identifies GP inhibition as a potential cancer pharmacotherapy target. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .