Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introducti...Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.展开更多
Objective： The triple negative （TN） metastatic breast cancer （MBC） patients are known to have worse prognosis, shorter progressive free survival （PFS）, and overall survival （OS）, that mandates using aggressiv...Objective： The triple negative （TN） metastatic breast cancer （MBC） patients are known to have worse prognosis, shorter progressive free survival （PFS）, and overall survival （OS）, that mandates using aggressive chemotherapy regimens. This phase II study aimed at investigating the efficacy and safety of using cisplatin and docetaxel in patients with triple negative metastatic breast cancer, and the possibility of using breast cancer susceptibility genel （BRCA1） expression as a predictive marker of chemotherapy response, and epidermal growth factor receptor （EGFR） as prognostic marker. Method： Between January 2006 and March 2009, 40 eligible patients with TN MBC were included in the study. We examined BRCA1 expression and EGFR protein in their specimens using immunohistochemistry. The patients were treated with cisplatin 75 mg/m2 and docetaxel 75 mg/m2 every 3 weeks, TN measurable MBC patients previously treated with anthracycline in their adjuvant or neo adjuvant settings were included in the study. Results： The median age of the treated patients was 43.5 years. Nearly half of the patients had an ECOG performance status of 0 or 1, and about third of them had one metastatic site. These metastatic sites were predominantly visceral in 80% of the patients. Fifty-five percent of TNMBC stained positive for BRCA1 and sixty-five percent for EGFR. Positivity for both markers was significantly associated with grade III tumors （P = 0.004）, OS, and PFS （P = 0.001 and 0.009） respectively. Overall, the regimen was well tolerated as Gill vomiting and neurological side effects were observed in 20% of the patients. Other toxiciUes were generally mild and medically manageable; with no treatment mortality was recorded. The overall disease control rate （ODCR） was 60%; the median PFS was 8 months, with a median overall OS of 17.5 months; while the median OS among responders was 23 months （95% CI 21.35 to 25.32）. The patients with negative EGFR had a significantly better OR, PFS, and OS than EGFR positive cases. There was no significant difference concerning OR, PFS, and OS, between positive and negative BRCA1 cases, which could be attributed to the better efficacy of cisplatin in the positive BRCA1 cases. Conclusion： This chemotherapy regimen is effective with tolerable toxicity profile, our results point out the importance of BRCA1 expression as predictive marker of chemotherapy response, and EGFR as prognostic marker, which could identify a certain group of patients with more aggressive disease who might benefit from using anti EGFR targeted therapy plus cisplatin.展开更多
Tumor metastasis emerges as a crucial target for tumor therapy. In this study, a tumor metastasis targeting peptide（TMT） was conjugated to a lipid material（PEG-DSPE） to obtain the targeting compound（TMT-PEG-DSPE...Tumor metastasis emerges as a crucial target for tumor therapy. In this study, a tumor metastasis targeting peptide（TMT） was conjugated to a lipid material（PEG-DSPE） to obtain the targeting compound（TMT-PEG-DSPE）, which was used to construct the targeted liposomal doxorubicin（TMT-LS-DOX）. We showed that TMT-LS-DOX presented satisfactory pharmaceutical characteristics. This metastasis-specific delivery system was tested in two highly metastatic breast cancer cell lines（MDA-MB-435S and MDA-MB-231） with a non-metastatic breast cancer cell line（MCF-7） as the control. The free TMT peptide itself showed no cytotoxicity even at the concentration of 100 μg/mL. Importantly, the enhanced cellular uptake of TMT-LS-DOX to both MDA-MB-435S and MDA-MB-231 cell lines was demonstrated as compared to MCF-7 cells, via a TMT-mediated mechanism demonstrated by a receptor competition study. In conclusion, the TMT modified nanocarriers might provide a strategy to enhance the specificity of chemotherapeutic agents to highly metastatic breast cancer.展开更多
基金NIH grants 1K08CA160692-01A1,U54CA163125-01 and the generous philanthropic support of several families whose lives have been affected by melanoma
文摘Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.
文摘Objective： The triple negative （TN） metastatic breast cancer （MBC） patients are known to have worse prognosis, shorter progressive free survival （PFS）, and overall survival （OS）, that mandates using aggressive chemotherapy regimens. This phase II study aimed at investigating the efficacy and safety of using cisplatin and docetaxel in patients with triple negative metastatic breast cancer, and the possibility of using breast cancer susceptibility genel （BRCA1） expression as a predictive marker of chemotherapy response, and epidermal growth factor receptor （EGFR） as prognostic marker. Method： Between January 2006 and March 2009, 40 eligible patients with TN MBC were included in the study. We examined BRCA1 expression and EGFR protein in their specimens using immunohistochemistry. The patients were treated with cisplatin 75 mg/m2 and docetaxel 75 mg/m2 every 3 weeks, TN measurable MBC patients previously treated with anthracycline in their adjuvant or neo adjuvant settings were included in the study. Results： The median age of the treated patients was 43.5 years. Nearly half of the patients had an ECOG performance status of 0 or 1, and about third of them had one metastatic site. These metastatic sites were predominantly visceral in 80% of the patients. Fifty-five percent of TNMBC stained positive for BRCA1 and sixty-five percent for EGFR. Positivity for both markers was significantly associated with grade III tumors （P = 0.004）, OS, and PFS （P = 0.001 and 0.009） respectively. Overall, the regimen was well tolerated as Gill vomiting and neurological side effects were observed in 20% of the patients. Other toxiciUes were generally mild and medically manageable; with no treatment mortality was recorded. The overall disease control rate （ODCR） was 60%; the median PFS was 8 months, with a median overall OS of 17.5 months; while the median OS among responders was 23 months （95% CI 21.35 to 25.32）. The patients with negative EGFR had a significantly better OR, PFS, and OS than EGFR positive cases. There was no significant difference concerning OR, PFS, and OS, between positive and negative BRCA1 cases, which could be attributed to the better efficacy of cisplatin in the positive BRCA1 cases. Conclusion： This chemotherapy regimen is effective with tolerable toxicity profile, our results point out the importance of BRCA1 expression as predictive marker of chemotherapy response, and EGFR as prognostic marker, which could identify a certain group of patients with more aggressive disease who might benefit from using anti EGFR targeted therapy plus cisplatin.
基金National Natural Science Foundation of China(Grant No.81130059)the National Research Fund for Fundamental Key Project(Grant No.2009CB930300)
文摘Tumor metastasis emerges as a crucial target for tumor therapy. In this study, a tumor metastasis targeting peptide（TMT） was conjugated to a lipid material（PEG-DSPE） to obtain the targeting compound（TMT-PEG-DSPE）, which was used to construct the targeted liposomal doxorubicin（TMT-LS-DOX）. We showed that TMT-LS-DOX presented satisfactory pharmaceutical characteristics. This metastasis-specific delivery system was tested in two highly metastatic breast cancer cell lines（MDA-MB-435S and MDA-MB-231） with a non-metastatic breast cancer cell line（MCF-7） as the control. The free TMT peptide itself showed no cytotoxicity even at the concentration of 100 μg/mL. Importantly, the enhanced cellular uptake of TMT-LS-DOX to both MDA-MB-435S and MDA-MB-231 cell lines was demonstrated as compared to MCF-7 cells, via a TMT-mediated mechanism demonstrated by a receptor competition study. In conclusion, the TMT modified nanocarriers might provide a strategy to enhance the specificity of chemotherapeutic agents to highly metastatic breast cancer.
