CXCR4 Inhibitor Drugs May Help Combat Resistance in RCC

Promising new preclinical data are suggesting a novel way to combat resistance to treatment with axitinib, a vascular endothelial growth factor receptor (VEGF-R) antagonist, in patients with renal cell carcinoma (RCC). 

Researchers from X4 Pharmaceuticals in Cambridge, Mass., have been developing novel CXCR4 inhibitor drugs to improve immune cell trafficking and increase the ability for T cells to track and destroy cancer.  At the EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium held in Munich, Germany (November 29–December 2), researchers reported on the company’s lead drug candidate for treating RCC.

The findings in preclinical models of RCC elucidated the molecular mechanism that directs the trafficking of key immune cells in the tumor microenvironment that result in synergistic antitumor effect of X4P-001 and axitinib. The data also showed that X4P-001 blocks the critical escape mechanism that leads to resistance to treatment with axitinib.

“While treatment with VEGF-R antagonists is first-line therapy, it can be hindered by acquired resistance,” said senior study author James Mier, MD, an Associate Professor of Medicine at the Beth Israel Deaconess Medical Center, Boston, Massachusetts. “These data show clear evidence that by inhibiting CXCR4, X4P-001 blocks a critical mechanism of this resistance, resulting in a synergistic anti-tumor effect which may ultimately lead to improved patient outcomes.”

Mier presented a poster at this meeting, entitled “MDSC trafficking and function in RCC by CXCR4 in the presence of a VEGF-R antagonist is dependent on HIF-2a expression,” and it showed that CXCR4 inhibition with X4P-001 blocks the primary pathway that leads to resistance to VEGF-R cancer therapies in RCC. Acquired resistance of tumors to VEGF-R antagonists is dependent on HIF-2a, CXCR4/CXCL12, and the infiltration of myeloid derived suppressor cells (MDSCs) into the tumor. CXCR4 inhibition with X4P-001 blocks communication between the tumor and MDSCs and this suppresses HIF-2a expression.  This appears to reduce MDSC tumor infiltration and improve the anti-tumor effects.

Paula Ragan, PhD, Founder, President and CEO of X4, said these data demonstrate the potential of X4P-001 in combination with approved therapies as a potential new treatment approach to achieve impactful clinical responses for patients with advanced RCC.  She said the data provide additional compelling rationale for the company’s ongoing phase I/II clinical study evaluating the combination of X4P-001 and axitinib in patients with advanced RCC.

X4P-001 is an oral, small molecule inhibitor of CXCR4, the receptor for the chemokine CXCL12. Recent studies demonstrated that CXCR4/CXCL12 is a primary receptor-ligand pair that cancer cells and surrounding stromal cells express and use to block normal immune function and promote angiogenesis. X4P-001 has been tested in more than 70 subjects in four clinical trials and was shown to be well tolerated.