Tolero Pharmaceuticals Presents Data Demonstrating Inhibition Of AXL Kinase In Cancer Cells Restores Drug Sensitivity Through A Mechanism Involving Retinoic Acid Signaling

Poster presented at the 57^th ASH Annual Meeting and Exposition

SALT LAKE CITY--(BUSINESS WIRE)--Tolero Pharmaceuticals, Inc., a clinical-stage company developing treatments for serious hematological diseases, today announced the presentation of positive preclinical data on TP-0903, an AXL kinase inhibitor, in a poster at the 57^th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida. AXL inhibition, through TP-0903, has previously been shown to reverse the mesenchymal phenotype commonly associated with various cancers and a known mechanism of drug resistance. While this effect has been seen repeatedly, the mechanism underlying how the receptor tyrosine kinase, AXL, induces a drug resistant phenotype and how AXL inhibition quickly reverses this has not been previously known. In this presentation, Tolero demonstrates that AXL signaling results in the suppression of retinoic acid (RA) signaling and that TP-0903 inhibits this suppression leading to a reversal of a mesenchymal phenotype.

“Drug resistance in hematological malignancies is an ongoing issue, even as novel targeted agents continue to be approved”

"Drug resistance in hematological malignancies is an ongoing issue, even as novel targeted agents continue to be approved," said Steven L. Warner, Ph.D., Vice President of Discovery and Development at Tolero. "Our data suggest that AXL represents a novel mechanism by which cancer cells acquire resistance to targeted agents and that this mechanism involves crosstalk to retinoic acid signaling. TP-0903 provides a novel approach to reverse this mechanism and we look forward to evaluating this molecule in the clinic."

In the study, TP-0903 treatment of multiple leukemia cell lines increased levels of CYP26, a known RA response gene. In preclinical models of leukemia, TP-0903 as a single agent strongly inhibited tumor volumes by up to 100% at multiple dose levels and treatment schedules. These data support the continued development of TP-0903 as a single agent treatment as well as in combination with targeted agents in multiple cancer types.

About TP-0903 and AXL Kinase Inhibitors

TP-0903 is a small molecule inhibitor of AXL kinase. AXL, along with other members of the TAM family of kinases, are key regulators of the mesenchymal phenotype of cancer cells. Mesenchymal cancer cells have increased invasion and migratory properties, enhanced cell survival characteristics in stressed environments, and critically, increased resistance to both targeted and traditional chemotherapies. Consequently, targeting AXL kinase with TP-0903 is an attractive way to overcome resistance to chemotherapy by targeting mesenchymal cancer cell populations.

About Tolero

Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with serious oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias and anemia as well as important targets of drug resistance and transcriptional control.