Abstract 4155: Regulation of MDSC trafficking and function in RCC by CXCR4 in the presence of a VEGF-R antagonist
Authors: Panka David J. , Arbeit Robert D. , Mier James W. 
Published: July 2016

Abstract
Using a murine model of 786-0 and A498 RCC xenografts, we have previously demonstrated that acquired resistance to sunitinib treatment was associated with a marked increase in the infiltration of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC). These cells have also been implicated in the development of resistance to other anticancer therapies. Further, we observed that both the influx of MDSC and resistance to VEGF-targeted therapies could be prevented by concurrent administration of an HDM2 antagonist, a drug whose biological effects are mediated primarily through the up regulation of p53. MDSC trafficking into tumor tissue is regulated by chemokines, many of which (e.g. SDF-1/CXCL-12) are produced in response to HIF-2 expression. p53 is known to directly repress CXCL12 transcription, and we have shown that HDM2 blockade suppresses HIF-2 expression, suggesting that the drug has both direct and indirect effects on CXCL12 expression. Western blot analysis of tumor lysates confirmed that HDM2 antagonism mediates its effects on MDSC through the suppression of chemokine production, including CXCL12. These findings suggested that the ability of HDM2 antagonism to prevent sunitinib resistance might be due, at least in part, to the suppression of CXCL12 production and MDSC recruitment. Consequently we hypothesized that agents that block CXCL12/CXCR4 signaling directly would duplicate the effects of HDM2 blockade on MDSC trafficking and prevent resistance to VEGF-targeted therapies.
Mice were inoculated with 786-0 and A498 RCC xenografts, the tumors permitted to grow to ∼300 mm3, and then treatment initiated with the CXCR4 inhibitor X4P-001 (AMD11070), axitinib, both agents in combination, or saline (control). Whereas either drug alone either had no (axitinib) or modest (X4P-001) effects on tumor growth, the combination of X4P-001 and axitinib had additive (synergistic) anti-tumor effects. Specifically, combination treatment resulted in massive tumor cell death, with the established implants actually regressing in size - an effect not previously seen with VEGFR-targeted drugs given as single agents. IHC staining demonstrated, as previously, that mice treated with axitinib alone had an increase in Ki-67 positive tumor cells. This effect was not observed in mice that received both X4P-001 plus axitinib, suggesting an anti-proliferative effect of the combination. Finally, the tumors from mice receiving axitinib alone had extensive MDSC infiltration, whereas the tumors from mice receiving either X4P-001 alone or the axitinib/X4P-001 combination had significantly less MDSC infiltration. These pre-clinical findings support both the role that MDSCs play in resistance to VEGF-R antagonists and the use of X4P-001 in combination with axitinib in upcoming clinical trials.
Citation Format: David J. Panka, Robert D. Arbeit, James W. Mier. Regulation of MDSC trafficking and function in RCC by CXCR4 in the presence of a VEGF-R antagonist. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4155.