Inhibitors of ENPP1 for the treatment of hepatocellular carcinoma

This research aims to improve treatment outcomes for liver cancer patients (hepatocellular carcinoma, HCC) by identifying the most effective inhibitors of ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1) in HCC models. HCC is the most prevalent form of liver cancer, with a low survival rate and poor treatment outcome. Unfortunately, current therapies for HCC are effective in only a small minority of patients, and many who initially respond eventually progress. This presents the ongoing critical need for novel, improved therapeutic strategies against HCC. Recently, there has been a growing interest in ENPP1 as an anti-cancer agent. ENPP1 hydrolyzes cyclic GMP-AMP (cGAMP), a messenger molecule that upon release by cancer cells activates the innate immune system. By degrading cGAMP, ENPP1 prevents this immune activation. Compared to other cancer types, HCC expresses particularly higher levels of ENPP1, contributing to a cold tumor phenotype characterized by reduced immune cell infiltration and limited responses to immunotherapy. ENPP1 inhibition protects against cGAMP hydrolysis, leading to cGAMP accumulation and consequently activation of antigen-presenting cells, which in turn results in an effective anti-tumor immune response and tumor regression. Thus, we hypothesize that treating HCC with an ENPP1 inhibitor will reprogram the tumor microenvironment to yield greater responses to immunotherapy. Riboscience’s clinical compound RBS2418, the first-in-class ENPP1 inhibitor, has already demonstrated exceptional safety and clinical benefit, i.e., improved progression-free survival, in patients with advanced metastatic cancers in a Phase 1a/1b clinical trial at a wide range of tested doses. Riboscience has recently generated a series of second-generation ENPP1 inhibitors that demonstrate improved potency in vitro compared to RBS2418. Due to the differences in their physical properties, which affect their in vivo distribution, these inhibitors exhibited varying levels of efficacy across different cancer models. Thus, to mitigate the risks associated with developing ENPP1 inhibitors for HCC care, it is first crucial to test and compare the ENPP1 inhibitors rigorously to identify the most effective one for further combination and mechanistic studies. The Ho laboratory at John Hopkins has recently developed mouse models of HCC with varying responses to anti-PD1 immunotherapy. These models are characterized by different levels of T cell and myeloid subtype infiltration within the tumor immune microenvironment and also exhibit wide-ranging expression of cGAMP synthase (cGAS) and ENPP1. Thus, we will leverage these unique models to accomplish the following aims: 1) Identify the best ENPP1 inhibitor for treating HCC; 2) Determine the best treatment combinations of current Standard-of-Care (SOC) for HCC with ENPP1 inhibition; 3) Determine the immune responses to ENPP1 inhibitor alone or in combination with SOC therapies to gain mechanistic insights and predict patient response. Identification of the optimal ENPP1 inhibitor and the most effective combination strategy with SOC therapies in HCC will greatly benefit patients with HCC who exhibit limited response to current therapies. Project Number: 1R41CA302163-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Deepa Sengupta (+1 co-PI) | Institution: RIBOSCIENCE, LLC, PALO ALTO, CA | Award Amount: $306,739 | Activity Code: R41 | Study Section: Special Emphasis Panel[ZRG1 CDPT-R (12)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11183063