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Final Report Summary - VELYMPH (Investigation of VEGF-C involvement in acquired metastatic properties of renal cell carcinoma following anti-angiogenesis treatments)

Abnormal vascular network formation is a prerequisite for tumor growth. This phenomenon has prompted the development of therapies targeting molecules involved in the formation of pathological blood vessels such as vascular endothelial growth factor (VEGF) and its receptors. Although some patients benefited from such an approach, the majority had a poor outcome, the transient decrease of the tumor/metastases being accompanied by the selection of more aggressive tumor cells.

Renal cell carcinoma (RCC) is the most common and lethal type of kidney cancer in adults, and represents a paradigm for anti-angiogenic treatments. A common problem of cancer patients, including RCC patients under anti-angiogenic therapy, is the recurrence of metastases and even the development of new metastatic niches. Therefore, we postulated that the over-expression of VEGF-C, a growth factor for vascular and lymphatic endothelial cells, is responsible for the acquired metastatic properties of RCC following failed anti-angiogenic treatment with sunitinib, an anti-angiogenic therapy given as a first line treatment for RCC. We thus proposed that VEGF-C may constitute both a predictive marker of escape to current anti-angiogenic therapies and a new therapeutic target in RCC.

Another type of cancer for which the discovery of predicative markers of treatment efficiency and the development of more efficient combination therapies are needed, is the head and neck squamous cell carcinoma (HNSCC). Conventional radiotherapy with photons (X) in HNSCC remains difficult, due to the proximity of numerous organs at risk. Recent studies have shown an advantage of proton (P) beam therapy, over X radiotherapy, in inducing lower toxicities and lower dose delivery to organs of risk in HNSCC patients. Therefore, we hypothesized that the two different radiation types would lead to different intrinsic and extrinsic biological responses, allowing the adaptation of HNSCC cells. In addition, we hypothesized that VEGF-C might be responsible for disease progression post-irradiation, therefore explaining in part the post-irradiation relapse seen in HNSCC patients.

Indeed, our results showed that sunitinib stimulated a VEGF-C dependent development of lymphatic vessels in RCC experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels in 70% of neoadjuvant treated patients. Thus, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may contribute to failure of anti-RCC treatment. In addition, increased lymphangiogenesis and a transcriptomic analysis in favor of a more aggressive phenotype were observed in xenofgrafts generated with X-, as compared to P-irradiated HNSCC cells. Increased detection of lymphatic vessels in relapsed HNSCC tumors from patients receiving conventional X radiotherapy was consistent with these results.

Although sunitinib and radiotherapy have revolutionized the care of patients, their efficiency may be improved by targeting key molecules involved in the development of the lymphatic network, such as VEGF-C. Our data set the basis for the establishment of improved treatment approaches for RCC and HNSCC patients, leading to better clinical outcomes and reduced costs associated to patient care.

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