Vemurafenib and ipilimumab: A promising combination? Results of a case series.

The purpose of combining targeted agents and immunotherapy is to achieve a chance of long-term tumor control in highly advanced patients. Between April 2012 and December 2013, 10 patients with metastatic melanoma were treated with a combination treatment of vemurafenib and ipilimumab as an individual treatment decision after detailed information and giving written informed consent. All the patients had advanced symptomatic disease, seven with elevated serum lactate dehydrogenase (LDH) levels and six with brain metastases on MRI. After clinical improvement under vemurafenib monotherapy (median 11.5 weeks), four cycles of ipilimumab were administered additionally. Combination treatment was tolerated well, with only two patients developing ≥ grade 3 elevation of transaminases; this was asymptomatic and resolved on cessation of BRAF inhibitor treatment. Staging 12 weeks after initiation of ipilimumab revealed partial response for five patients, stable disease for two, and disease progression for three. Of the seven patients with disease control, we stopped vemurafenib for five, to determine whether ipilimumab treatment led to disease control. Two revealed progressive disease 2 mo later, and received vemurafenib again, but for three the disease was controlled for at least a year, and two are still in partial remission without any further treatment. Progression-free survival was a median of 8.0 mo (95% CI 4.8-11.2), overall survival (OS) was 13.0 mo (95% CI 5.0-21.0), and four patients are still alive. In conclusion, the combination of vemurafenib and ipilimumab was well tolerated and clinical outcome was promising. The combination of targeted and immunotherapies is currently addressed in clinical trials.

L1-CAM expression in ccRCC correlates with shorter patients survival times and confers chemoresistance in renal cell carcinoma cells.

Conflicting data exist about the expression of L1 cell adhesion molecule (L1-CAM) in clear cell renal cell carcinoma (ccRCC). To determine the clinical usefulness of L1-CAM as a therapeutic or prognostic marker molecule in renal cancer patients, we analyzed its expression on a cohort of 282 renal cell carcinoma (RCC) patients. L1-CAM expression was found in 49.5% of 282 renal cancer tissues. Importantly, L1-CAM expression in patients with ccRCC was associated with significantly shorter patient survival time. We further present evidence that L1-CAM was involved in the resistance against therapeutic reagents like rapamycin, sunitinib and cisplatin. The downregulation of L1-CAM expression decreased renal cancer cell proliferation and reduced the expression of cyclin D1. In addition, we found out that Von Hippel-Lindau (VHL) deficiency was accompanied by a downregulation of the transcription factor PAX8 and L1-CAM. In normal renal tissue, PAX8 and L1-CAM were co-expressed in collecting duct cells. Importantly, the downregulation of PAX8 by small interfering RNA increased the expression of L1-CAM and concomitantly induced the migration of renal cancer cells. Furthermore, we observed in 65.3% of 282 RCC patients a downregulation of PAX8 expression. With chromatin immunoprecipitation analysis, we additionally demonstrate that PAX8 can bind to the promoter of L1-CAM and we further observed that the downregulation of PAX8 was accompanied by increased L1-CAM expression in a high fraction of ccRCC patients. In summary, we show that VHL and PAX8 are involved in the regulation of L1-CAM in renal cancer and L1-CAM represents an important therapeutic and prognostic marker protein for the treatment of ccRCC.

ADAM10 is upregulated in melanoma metastasis compared with primary melanoma.

ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo. Immunohistochemical analysis on tissue microarrays indicated that ADAM10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas.