TP-0903 (AXL Kinase Inhibitor)

TP-0903 is an investigational small molecule that, in preclinical models, has been shown to inhibit AXL signaling and reverse the mesenchymal phenotype, both of which play a role in metastasis, tumor progression, and resistance to cancer therapy.1,2

AXL as a Potential Target in Cancer Treatment

AXL and other TAM family receptor tyrosine kinases (RTKs) are known to be involved in maintaining a mesenchymal phenotype in cancer cells.2 Mesenchymal cells have increased invasion and migratory properties, enhanced cell survival in stressed environments, and increased resistance to targeted therapies compared to epithelial cells. AXL overexpression has been observed in multiple tumor types that have acquired resistance to various agents.1

Preclinical Activity

In vitro, treatment of cancer cells with TP-0903 reverses the mesenchymal phenotype and sensitizes them to treatment with other targeted agents,3 e.g., erlotinib in EGFR-mutant lung cancer and cetuximab in head and neck cancer models. In preclinical tumor models, TP-0903 restored sensitivity to erlotinib by reversing the mesenchymal phenotype driving resistance.3

Clinical Development

Tolero is exploring parallel clinical development paths for TP-0903 in both solid and hematologic malignancies.

A phase 1, first-in-human, study of oral TP-0903 is currently being conducted in patients with advanced solid tumors.

TP-0903 is an investigational agent and is not approved by the US FDA or any other regulatory authorities.

References: 1. Park IK, Mundy-Bosse B, Whitman SP, et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29(12):2382-2389. 2. Soh KK, Bahr BL, Bearss JJ, et al. Inhibition of Axl kinase reverses the mesenchymal phenotype in leukemic cells through the disruption of retinoic signaling [Abstract]. Blood. 2015;126:3253. 3. Soh KK, Kim W, Lee YS, et al. Abstract 235: AXL inhibition leads to a reversal of a mesenchymal phenotype sensitizing cancer cells to targeted agents and immuno-oncology therapies. Exp Mol Ther. 2016;76(14 suppl).

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