Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma(STS).Initially developed as a small molecule inhibitor of vascula...Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma(STS).Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors,preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways.Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma,pazopanib was investigated in STS.A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes.The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts.At present,there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy,limiting the clinical effectiveness and cost-effectiveness of the drug.In this review,we summarize the preclinical and clinical data for pazopanib,outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.展开更多
Testicular germ cell tumors(TGCTs)represent the most common malignancies in young males but they also show the highest cure rate in solid tumors with more than 95%newly diagnosed TGCTs being ultimately cured[1].Singh ...Testicular germ cell tumors(TGCTs)represent the most common malignancies in young males but they also show the highest cure rate in solid tumors with more than 95%newly diagnosed TGCTs being ultimately cured[1].Singh et al.[2]recently provided precious insight into the genomic aberrations underpinning the molecular characteristics of these tumors and a clear presentation of the mechanisms underlying sensitivity/resistance to platinum.More importantly,the authors identified pre-target,on-target and post-target factors that can explain,the two sides of the same coin:the exquisite sensitivity of these cancers to platinum-based chemotherapy and at the same time,drug resistance when these factors are lacking.展开更多
Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse...Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit de novo resistance to many existing ALK inhibitors, and no clinical therapeutics to target MYCN have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which ALK upregulates MYCN transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.展开更多
文摘Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma(STS).Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors,preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways.Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma,pazopanib was investigated in STS.A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes.The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts.At present,there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy,limiting the clinical effectiveness and cost-effectiveness of the drug.In this review,we summarize the preclinical and clinical data for pazopanib,outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.
文摘Testicular germ cell tumors(TGCTs)represent the most common malignancies in young males but they also show the highest cure rate in solid tumors with more than 95%newly diagnosed TGCTs being ultimately cured[1].Singh et al.[2]recently provided precious insight into the genomic aberrations underpinning the molecular characteristics of these tumors and a clear presentation of the mechanisms underlying sensitivity/resistance to platinum.More importantly,the authors identified pre-target,on-target and post-target factors that can explain,the two sides of the same coin:the exquisite sensitivity of these cancers to platinum-based chemotherapy and at the same time,drug resistance when these factors are lacking.
基金The authors are supported by a programme grant from Cancer Research UK(C34648/A18339 and C34648/A14610).
文摘Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit de novo resistance to many existing ALK inhibitors, and no clinical therapeutics to target MYCN have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which ALK upregulates MYCN transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.
