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Small-molecule protein tyrosine kinase inhibitors for the treatment of metastatic prostate cancer.

ABSTRACT: The microenvironment is critical to the growth of prostate cancer (PCa) in the bone. Thus, for clinical efficacy, therapies must target tumor-microenvironment interactions. Several protein tyrosine kinases have been implicated in the development and growth of PCa bone metastasis. In this review, specific protein tyrosine kinases that regulate these complex interactions, including PDGFR, the EGFR family, c-Src, VEGFR, IGF-1R, FGFR and c-Met will be discussed, with an emphasis on why these kinases are promising therapeutic targets for metastatic PCa treatment. For each of these kinases, small-molecule inhibitors have reached clinical trials. Current results of these trials and future prospects for the use of tyrosine kinase inhibitors for the treatment of PCa bone metastases are also discussed.

SUBMITTER: Gallick GE

PROVIDER: S-EPMC3285098 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Small-molecule protein tyrosine kinase inhibitors for the treatment of metastatic prostate cancer.

Gallick Gary E GE Corn Paul G PG Zurita Amado J AJ Lin Sue-Hwa SH

Future medicinal chemistry 20120101 1

The microenvironment is critical to the growth of prostate cancer (PCa) in the bone. Thus, for clinical efficacy, therapies must target tumor-microenvironment interactions. Several protein tyrosine kinases have been implicated in the development and growth of PCa bone metastasis. In this review, specific protein tyrosine kinases that regulate these complex interactions, including PDGFR, the EGFR family, c-Src, VEGFR, IGF-1R, FGFR and c-Met will be discussed, with an emphasis on why these kinases ...[more]

PMID: 22168167

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Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Dataset Information

Small-molecule protein tyrosine kinase inhibitors for the treatment of metastatic prostate cancer.

Publications

Small-molecule protein tyrosine kinase inhibitors for the treatment of metastatic prostate cancer.

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