Clin Cancer Res
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Chemokines, small proinflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 [stromal cell-derived factor-1 (SDF-1)] binds primarily to CXC receptor 4 (CXCR4; CD184). ⋯ The CXCL12/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is a target for therapeutics that can block the CXCL12/CXCR4 interaction or inhibit downstream intracellular signaling.
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Review
An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics.
Phase I clinical trials represent the first step in bringing promising new treatments from the laboratory to the clinic. Although the importance of phase I clinical trials is widely recognized, there is currently no consensus among the scientific, medical, and statistical communities on how best to do these studies in humans. With the advent of targeted therapies, it has become evident that we need to tailor the design of phase I studies for the particular drug class under investigation and any endpoints that are being defined. ⋯ The primary focus included (1) efficient trial designs, (2) phase I drug combinations, and (3) appropriate statistical and correlative endpoints. In this CCR Focus series, articles summarize key aspects and recommendations on phase I studies (including combination trials), such as design, use of biomarkers, the European Union and Japanese perspectives on design, requirements for first-in-human and other phase I studies, and ensuring regulatory and International Conference on Harmonization (ICH) compliance. A final article summarizes recommendations for the design and conduct of phase II studies.
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Review
Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now?
Hepatocellular carcinoma (HCC), once considered an orphan disease in the West, has become a global health concern. It is the third leading cause of cancer death worldwide, and its incidence continues to increase. Historically, the development of new systemic agents for advanced HCC has been lacking despite no clear benefit with traditional cytotoxic therapies. ⋯ These clinical studies are founded on a growing body of basic and translational science that has identified several potential molecular targets in HCC. The successful development of such targeted agents in the future will be linked to our ability to appropriately select patients for treatment based on their clinical stage (including extent of liver disease and extent of tumor) and on potential predictive markers of response. Here, we review these data in the context of rational drug development in HCC in the front-line setting and in previously treated patients.
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Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During recent years, considerable research efforts have focused on the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in cancer cells, and the identification of pharmacologic agents that modulate gene expression via inhibition of HDACs. The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clinical implications of HDAC inhibition as a strategy for cancer therapy.
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Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development and those for which further evaluation should be halted. Although definitive phase III trials use progression-free or overall survival to confirm clinical benefit, earlier endpoints are preferable for phase II trials. Traditionally, tumor shrinkage of a predetermined degree (response) has been used as a surrogate of eventual survival benefit based on the observation that high response rates (RR), and particularly complete responses, in the phase II setting resulted in survival benefit in subsequent phase III trials. ⋯ Numerous alternate or complementary endpoints have been explored, incorporating multinomial endpoints (including progression and response), progression-free survival, biomarkers, and, more recently, evaluation of tumor size as a continuous variable. In this review, we discuss the current status of phase II endpoints and present retrospective analyses of two international gastrointestinal cancer studies showing the potential utility of one novel approach. Alternate endpoints, although promising, require additional evaluation and prospective validation before their use as a primary endpoint for phase II trials.