New preclinical research published online today in Nature Communications suggests a potential role for Aravive-S6, a novel therapeutic candidate under development by Aravive Biologics, Inc., to increase tumour sensitivity to radiation therapy and check-point immuno-oncology agents.

Aravive-S6 is designed to selectively inhibit the AXL-signaling pathway which acts as a "survival switch" that scientists believe promotes tumour growth and metastasis, and resistance to common chemotherapeutic agents.

The new research adds to evidence that AXL over-expression also results in tumour unresponsiveness to radiation and check-point inhibitors, and further shows that inhibiting AXL signalling elicits an anti-tumour immune response and sensitises tumours to radiation and other anticancer therapies including PD-1 inhibitors and other immuno-oncology drugs.

The publication, entitled "Reprogramming the Immunologic Microenvironment through Radiation and Targeting AXL," was authored by Amato J. Giaccia, Ph.D., scientific founder and acting chief scientific officer of Aravive Biologics, and his research collaborators at Stanford University.

Dr. Giaccia commented, "Checkpoint inhibitors have demonstrated dramatic anti-tumour responses as single agents in about 10-30 percent of patients, and there is increasing clinical evidence that these agents may achieve further anti-cancer synergies in combination with radiation therapy.

Unfortunately, some tumours remain resistant to these approaches, and the aim of our research was to better understand the mechanisms underlying such resistance."

The researchers analysed genetic, tumour micro-environmental, and immunologic factors in tumours derived from a transgenic model of breast cancer.

They identified two tumours with similar growth characteristics but different responses to radiation therapy.

Profiling the tumours revealed that the AXL receptor was over-expressed in the unresponsive tumours, and that knocking out AXL resulted in slower tumour growth, increased tumour sensitivity to radiation, and an anti-tumour CD8 T-cell response that was improved with combination checkpoint immunotherapy.

"This research further increases our understanding of AXL as a key anticancer target, whose selective inhibition can overcome tumour resistance and increase the efficacy of a variety of anticancer agents, including radiation therapy and immuno-oncology approaches," said Dr. Giaccia. "Inhibiting AXL enhances MHC Class 1 expression, and recruits T-cells into the tumour by reversing the mesenchymal phenotype of the tumour to an epithelial phenotype. While the radiation and PD1/CTLA-resistant tumours were sensitive to AXL inhibition alone, the combination of anti-AXL and checkpoint inhibitors seems to work better in eliciting an anti-tumour response."

"Recently published preclinical research has shown Aravive-S6, our novel anti-AXL inhibitor, to exhibit potent preclinical activity against AML and advanced ovarian, pancreatic and breast tumours, both as a single agent and in synergy with cytotoxic drugs," said Ray Tabibiazar, M.D., President and Chief Executive Officer of Aravive Biologics. "This new research suggests that Aravive-S6 may also be a useful agent in combination with checkpoint inhibitors such as PD1, PDL1 or CTLA4 inhibitors. We look forward to continuing our development of Aravive-S6, with a goal of filing an IND by the end of 2017."

Source: Nature Communications