Integrating BRAF/MEK inhibitors into combination therapy for melanoma

The discovery of BRAF mutations in melanoma has not yet translated into clinical success, suggesting that BRAF/MEK inhibitors will need to be combined with other agents. In the current review, we discuss other pathways likely to be important for melanoma progression and suggest possible drug combinations for future clinical testing

Expression of drug targets in primary and matched metastatic renal cell carcinoma tumors

<p>Abstract</p> <p>Background</p> <p>Targeted therapies in renal cell carcinoma can have different effects on primary and metastatic tumors. To pave the way for predictive biomarker development, we assessed differences in expression of targets of currently approved drugs in matched primary and metastatic specimens from 34 patients.</p> <p>Methods</p> <p>Four cores from each site were embedded in tissue microarray blocks. Expression of B-Raf, C-Raf, cKIT, FGF-R1, HIF-2α, mTOR, PDGF-Rβ, VEGF-R1, VEGF-R2, VEGF-R3, VEGF, VEGF-B, VEGF-C, VEGF-D, MEK1, and ERK1/2 was studied using a quantitative immunofluorescence method.</p> <p>Results</p> <p>No significant differences were observed in global expression levels in primary and metastatic renal cell carcinoma tumors, with the exception of MEK, which had higher expression in metastatic than primary specimens. Similarly, more ki67 positive cells were seen in metastatic specimens. Correlations between marker expression in primary and metastatic specimens were variable, with the lowest correlation seen for FGF-R1 and VEGF-D. There were no significant differences in the degree of heterogeneity in primary versus metastatic tumors.</p> <p>Conclusions</p> <p>Expression of most of the studied markers was similar in primary and metastatic renal cell carcinoma tumors, suggesting that predictive biomarker testing for these markers can be conducted on either the primary or metastatic tumors for most markers.</p

Synergistic activity of letrozole and sorafenib on breast cancer cells

International audienceEstrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-expressing breast cancer cell lines. Treatment with letrozole reduced testosterone-driven cell proliferation, by inhibiting the synthesis of estrogens. Sorafenib inhibited cell proliferation in a concentration-dependent manner; this effect was not dependent on sorafenib-mediated inhibition of Raf1, but involved the down-regulation of mTORC1 and its targets p70S6K and 4E-binding protein 1 (4E-BP1). At concentrations of 5–10 μM the growth-inhibitory effect of sorafenib was associated with the induction of apoptosis, as indicated by release of cytochrome and Apoptosis-Inducing Factor into the cytosol, activation of caspase-9 and caspase-7, and PARP-1 cleavage. Combination of letrozole and sorafenib produced a synergistic inhibition of cell proliferation associated with an enhanced accumulation of cells in the G/G phase of the cell cycle and with a down-regulation of the cell cycle regulatory proteins c-myc, cyclin D1, and phospho-Rb. In addition, longer experiments (12 weeks) demonstrated that sorafenib may be effective in preventing the acquisition of resistance towards letrozole. Together, these results indicate that combination of letrozole and sorafenib might constitute a promising approach to the treatment of hormone-dependent breast cancer