Abstract 2636: Targeting Autotaxin to suppress stromal signaling in the tumor microenvironment to improve outcome to therapy in fibrotic tumor types
Authors: Johnson Zoe , Deken Marcel , Medhi Ragini , Maggs Lauren , Carruthers Alan , Cheasty Anne , Tagliavini Alessia , Nizzardo Andrea , Pergher Marco , Niewola Karolina , Fraser Amy , van der Veen Lars , Shah Pritom , ZIviani Luigi , Milleri Stefano , Lahn Michael 
Published: June 2022

Recent findings indicate that in cancer, host immune suppression and resistance to therapy is orchestrated by the presence and activity of stromal cells in the tumor microenvironment. Therefore novel approaches to overcome stromal mediated resistance to therapy represent a potential strategy to improve the outcome to chemotherapy and immune checkpoint blockade, particularly in tumors that have a fibrotic microenviroment. Autotaxin is an enzyme that converts Lysophosphatidylcholine (LPC) to Lysophosphatidic Acid (LPA), a key pathway that is aberrantly activated in fibrosis. LPA has also been described to act directly on tumor cells, promoting their growth and proliferation via G protein-coupled LPA Receptors (LPARs). IOA-289 is a novel, potent, selective and orally bioavailable inhibitor of Autotaxin, a target with known clinical application in fibrotic diseases and with a strong rationale for exploration in cancer.

In preclinical models, IOA-289 modulated levels of circulating LPA in a dose dependent manner. At doses achieving at least 50% reduction of circulating LPA, IOA-289 showed monotherapeutic efficacy in in vivo mouse models of cancer. Notably the effects were most prominent in orthotopic models that recapitulate the stromal components of the microenvironment. In vitro studies investigated the mechanism of action of IOA-289, and it was shown to be driven by:

(i)Direct anti-tumor activity on cancer cell lines in vitro (ii)Modulation of the secretory profile of fibroblasts(iii)Increased T cell infiltration in vitro and in vivo

In a healthy volunteer study following a single oral ascending dose, IOA-289 showed a dose dependent increase in plasma and a corresponding decrease in circulating LPA. We also demonstrated that ATX was elevated in plasma from pancreatic cancer patients compared to samples from healthy volunteers and are correlated with soluble CA19-9.

Based on our preclinical data we postulate that inhibition of the ATX/LPA pathway with IOA-289 may be a beneficial therapeutic strategy for cancer patients with fibrotic tumor microenvironments. The predicted biologically effective dose of IOA-289 has been calculated using PK/PD modelling combining data from preclinical studies and from the phase Ia healthy volunteer study. IOA-289 is scheduled to enter a phase Ib clinical trial in pancreatic cancer.

Citation Format: Zoe Johnson, Marcel Deken, Ragini Medhi, Lauren Maggs, Alan Carruthers, Anne Cheasty, Alessia Tagliavini, Andrea Nizzardo, Marco Pergher, Karolina Niewola, Amy Fraser, Lars van der Veen, Pritom Shah, Luigi ZIviani, Stefano Milleri, Michael Lahn. Targeting Autotaxin to suppress stromal signaling in the tumor microenvironment to improve outcome to therapy in fibrotic tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2636.