GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Abstract

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

Keywords: 9-ING-41; glycogen synthase kinase-3 beta; immunotherapy; pancreatic ductal adenocarcinoma.

Figure 1

Trial design of the Actuate 1801 trial. The objectives of the ongoing Part 1 and Part 2 are to determine the recommended phase II dose (RP2D) of 9-ING-41 with and without chemotherapy, respectively. The choice of the chemotherapy agent will be chosen by the investigator and depend on the diagnosis and prior treatment. Part 3 will be a Simon 2-stage phase II design which is an expansion cohort that will open based on the results of Part 1 and 2. It will evaluate 9-ING-41 with gemcitabine with nab-paclitaxel in advanced pancreatic ductal cancer (PDAC) for first-line therapy.

Figure 2

Rationale for combining GSK-3β inhibitors with immunotherapy and chemotherapy. GSK-3β increases tumor expression of programmed death ligand-1 (PD-1) and lymphocyte activation gene-3 (LAG-3), both of which can be reversed with small molecule inhibition of GSK-3β. Furthermore, GSK-3β inhibition can prevent DNA damage response activation by chemotherapeutic agents such as gemcitabine by preventing the induction of the ATR/TopBP1 pathway. Such mechanisms support a rationale for combining GSK-3β small molecule inhibitors with chemotherapy and immunotherapy. Created with BioRender.com (accessed on 21 February 2021).