Metastatic Kidney Cancers clinical trials

ELR+CXCL Cytokines in Metastatic Kidney Cancers: Predictive Markers of Resistance to Sunitinib

Metastatic renal cell carcinomas (mRCC) are highly angiogenic tumors because of mutation of the pVHL gene leading to over-expression of VEGF. Therefore, mRCC represent a paradigm for the use of anti-angiogenic treatments targeting the VEGF/VEGFR pathway. Despite an increase of the time to progression these treatments, taken alone, are not curative with ineluctable progression especially for the reference treatment sunitinib a multi kinase inhibitors of VEGF, PDGF, CSF1 receptors and c-kit, FLT3 and RET. At progression on sunitinib, patients received mTOR inhibitors which is responsible, at least, of HIF1A mRNA translation, then on a third line sorafenib that inhibits VEGFR2, 3 PDGFR, c-KIT and B-RAF. The access to these different lines of treatment has finally prolonged survival but this situation is not satisfactory. Unexpected aspect associated with the use of anti-angiogenesis treatments was the diversity of the patients' response. Some patients are right away refractory and die rapidly, but the majority of patient has a transient response then progress and a few percentages of them are responder for a very long period of time. By only targeting normal endothelial cells and tumor neo-vascularization, the response should have been more homogenous, thus highlighting that the treatment induced a "Darwinian" adaptation of tumor cells and cells of the microenvironment. Two conclusions follow from these observations: 1- The need to identify predictive markers of efficacy; 2-The identification of druggable targets participating in progression on anti-angiogenic treatments. Our results have highlighted the ELR+CXCL cytokines, pro-inflammatory and pro-angiogenic cytokines as prognosis markers of survival of mRCC patients and relevant therapeutic targets on experimental tumors in mice. As VEGF/VEGFR, these cytokines are produced by tumor, endothelial and inflammatory cells. Their receptors (CXCR1, 2) are expressed physiologically by immune and endothelial cells and aberrantly by tumor cells generating at the same time autocrine proliferation loops, chronic angiogenesis and inflammation. Therefore, the CXCL/CXCR1,2 axis constitutes an independent axis of cancer development and propagation. However, the current standard of care is to administer anti-angiogenic therapies as the first line treatment. The objective of this project is linked to the identification of potent predictive markers of efficacy, easily measured in plasma samples. Deciphering the molecular mechanisms associated with the production of such cytokines by tumor cells and by cells of the microenvironment represents an interesting intellectual challenge and a relevant way to improve the current treatments by targeting, at progression on the current standard of care, other pathways than the VEGF/VEGFR axis.