Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
The human endogenous retrovirus K family (HERV-K) comprises 30 to 50 closely related proviruses, most of which are defective. In contrast to all other human endogenous retroviruses, some HERV-K proviruses have maintained open reading frames for all viral proteins. In addition to the structural proteins Gag and Env and the reverse transcriptase, two regulatory proteins (Rec and Np9) have been described. Malignant melanoma has the highest mortality among skin cancers and is particularly aggressive. To study the expression of HERV-K, a set of seven primers was developed that allows discrimination between full-length and spliced mRNA and mRNA from deleted and undeleted proviruses. Expression of full-length mRNA from deleted and undeleted proviruses was detected in all human cells investigated. Expression of spliced env and rec was detected in a teratocarcinoma cell line, in 45% of the metastatic melanoma biopsies, and in 44% of the melanoma cell lines. In normal neonatal melanocytes, spliced rec was detected but not spliced env. Viral proteins were shown to be expressed in primary melanomas, metastases, and melanoma cell lines by immunohistochemistry, immunofluorescence, and Western blot analyses using specific antisera. For the first time, antibodies against HERV-K were found in melanoma patients. Melanomas are, in addition to teratocarcinomas and human breast cancer, the third tumor type with enhanced expression of HERV-K. (Cancer Res 2005; 65(10): 4172-80)
Background Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. Objectives This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. Methods Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. Results The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0Á2-36) for mBCC in the 200-mg group and 46Á1% (95% CI 37Á2-55Á1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. Final 42-month efficacy and safety results from the BOLT study, R. Dummer et al. 1373Fig 3. Objective response rates by central review across all BOLT (Basal Cell Carcinoma Outcomes with LDE225 Treatment) analyses in patients receiving sonidegib 200 mg daily. 17,19,20 Results are for the intent-to-treat population. BCC, basal cell carcinoma; laBCC, locally advanced BCC; mBCC, metastatic BCC; ORR, objective response rate. Fig 4. Kaplan-Meier plots of duration of response per central review in patients receiving sonidegib 200 mg daily (responders only). BCC, basal cell carcinoma; laBCC, locally advanced BCC; mBCC, metastatic BCC; mo, months. 1374 Final 42-month efficacy and safety results from the BOLT study, R. Dummer et al. The data are presented as n (%). Results are for the safety population. AE, adverse event; BOLT, Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment; SAE, serious AE. Final 42-month efficacy and safety results from the BOLT study, R. Dummer et al. 1375 Fig 6. Adverse events in ≥ 20% of patients treated with sonidegib 200 mg and 800 mg daily CK, creatine kinase.
The human endogenous retrovirus-K encodes two potential tumor proteins, Rec and Np9. Rec is related to the Rev protein of HIV-1 and has been shown to be associated with tumor development in nude mice. Having shown the expression of human endogenous retrovirus-K in human melanomas and melanoma cell lines, tools were developed to allow the expression of the transmembrane envelope, Rec and Np9 mRNA and proteins to be studied in more detail. The expression of spliced env, rec and np9 was investigated by reverse transcriptase-polymerase chain reaction using a set of primers developed to discriminate between full-length and spliced mRNA. Env-specific, Rec-specific and Np9-specific antisera were produced, characterized and used to study protein expression in melanomas and melanoma cell lines by immunohistochemistry, immunofluorescence and Western blot analyses. Existence of human endogenous retrovirus-K Rec and Np9-specific antibodies in the sera of melanoma patients were analyzed by Western blot of immunofluorescence studies. The expression of both spliced env and rec mRNA was detected in 39% of the melanomas and in 40% of the melanoma cell lines and np9 mRNA was detected in 29 and 21%, respectively. In normal neonatal melanocytes, spliced rec mRNA was detected in the absence of spliced env mRNA. Using antisera specific for Rec and Np9, Rec protein was found in 14% of the melanomas but Np9 in none. In addition, cell surface expression of the putatively immunosuppressive transmembrane envelope protein and release of virus particles were shown. Antibodies specific for neither Rec nor Np9 were detected. The transmembrane envelope protein, Rec and Np9 proteins are expressed in melanoma cells with a pattern similar to that seen in teratocarcinoma cell lines. Additional experiments are needed to determine their involvement, if any, in cell proliferation and tumor progression.
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