ACB2003.4 (formerly known as LX3305/LX2931) is a S1P lyase inhibitor. It is designed to modify the tumor microenvironment by activating a novel pathway that allows chemotherapy drugs to penetrate hypoxic tumors (such as pancreatic cancer) more effectively. This is of particular importance in pancreatic cancer with its high density of the stroma and the associated vascular anomalies and impairment of the immune response. ACB2003.4 reinstates a vascular network, resulting in the co-administered anti-cancer drugs more effectively reaching and penetrating the tumor.
ACB2003.4 achieved breakthrough therapeutic results in pancreatic cancer experiments : ACB2003.4 and Gemcitabine combination shows superior effectiveness than the current standard-of-care treatment with Abraxane and Gemcitabine in in vivo PDX pancreatic model study.
Pancreatic cancer is characterized by excessive dense extracellular matrix deposition associated to vascular collapse and hypoxia with low drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer (Longo et al. 2016, Katsuta et al., 2019).
Frequent failures of chemotherapy treatments in clinical applications are due to their inability to reach the tumor cells, particularly in instances of a vascular disruption of abnormal tumor vessels. Re-instating vascular normalization is therefore one of the key prerequisites for efficient therapy.
The proangiogenic S1P metabolism modulators act as a tumor vascular normalizer. They work by re-building a functional vascular network, thereby improving the blood flow to – and oxygenation of – tumor tissue. Along these lines, and based on clinical observations, the company has developed a new paradigm – in contrast to the prevailing antiangiogenic doctrine – in the form of a neo-adjuvant therapy using a proangiogenic molecule acting as a tumor vascular normalizer and in fine improving drug delivery and treatment efficacy for all type of chemotherapy (except those with antiangiogenic molecules) and radiotherapy. Experimental proof of concept has been demonstrated both in clinical observations and also in a mouse model bearing a pancreatic adenocarcinoma where the combination of gemcitabine and S1P lyase inhibitor displayed a strong antitumor superiority compared to gemcitabine alone.
A functional plasmatic biomarker has been identified, allowing the selection of a subpopulation of eligible patients for such therapy.
Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor.
In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer.
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1. Cancers, 3 March 2022
