Ganetespib and Ziv-Aflibercept in Refractory Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas
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Publication
Journal: Cell
April/19/2011
Abstract
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
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Publication
Journal: Journal of Clinical Oncology
January/16/2013
Abstract
Angiogenesis has long been considered an important target for cancer therapy. Initial efforts have primarily focused on targeting of endothelial and tumor-derived vascular endothelial growth factor signaling. As evidence emerges that angiogenesis has significant mechanistic complexity, therapeutic resistance and escape have become practical limitations to drug development. Here, we review the mechanisms by which dynamic changes occur in the tumor microenvironment in response to antiangiogenic therapy, leading to drug resistance. These mechanisms include direct selection of clonal cell populations with the capacity to rapidly upregulate alternative proangiogenic pathways, increased invasive capacity, and intrinsic resistance to hypoxia. The implications of normalization of vasculature with subsequently improved vascular function as a result of antiangiogenic therapy are explored, as are the implications of the ability to incorporate and co-opt otherwise normal vasculature. Finally, we consider the extent to which a better understanding of the biology of hypoxia and reoxygenation, as well as the depth and breadth of systems invested in angiogenesis, may offer putative biomarkers and novel therapeutic targets. Insights gained through this work may offer solutions for personalizing antiangiogenesis approaches and improving the outcome of patients with cancer.
Publication
Journal: Current Medicinal Chemistry
March/5/2008
Abstract
Hsp90 is an evolutionarily conserved and ubiquitously expressed molecular chaperone that mainly modulates, along with a group of co-chaperones, the general platform of protein folding and prevents the nonspecific aggregation of misfolded or unfolded proteins. In the voluminous Hsp90 clientele, a large variety of important regulatory proteins can be identified, including many whose deregulation may lead to cancer initiation and progression, such as the oncogenic clients pp60(v-src), Bcr-Abl, mutated p53, ErbB2 (Her-2), Akt, Flt3, HIF-1alpha and B-Raf. Therefore, inhibition of Hsp90 function offers the prospect of simultaneously disrupting multiple signaling pathways directly implicated in the development of malignant phenotypes. During the last few years, there has been a major focus on the development of Hsp90 specific inhibitors. This started with the discovery that certain natural products could specifically disrupt Hsp90 chaperone activities. The benzoquinone ansamycin antibiotic geldanamycin and its less toxic derivative 17-AAG have been shown to possess strong anti-proliferative and apoptotic activity in cancer cells, whereas 17-AAG has demonstrated potent anti-tumor activity in several human xenograft models, including breast, prostate and colon cancer. In an effort to overcome difficulties with drug toxicity and solubility, a number of novel bioengineered 17-AAG analogues, such as 17-DMAG and IPI-504, and small-molecule inhibitors, including purine and pyrazole derivatives, have emerged from rational drug design followed by high-throughput screening approaches. 17-AAG was the leader inhibitor to enter and successfully complete phase I clinical trials, thus demonstrating that Hsp90 constitutes a valid drug target for cancer therapy. This review includes information on the current model of ternary interactions between Hsp90, client proteins and a vast array of co-chaperones followed by a list of characteristic inhibitors and ongoing clinical trials reported thus far.