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Compartmentalized Cancer Drug Discovery Targeting Mitochondrial Hsp90 Chaperones Oncogene (2009) 28, 3681–3688 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW Compartmentalized cancer drug discovery targeting mitochondrial Hsp90 chaperones BH Kang and DC Altieri Prostate Cancer Discovery and Development Program, Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA There is a plethora of attractive drug targets in cancer, the past decade (Schein and Scheffler, 2006). These but their therapeutic exploitation proved more difficult disappointments have not gone unnoticed, and patient than expected, and only rarely truly successful. One advocacy groups and media organizations (Leaf, 2004; possibility not often considered in drug discovery is that Kolata, 2009) are urging new venues to improve cancer cancer signaling pathways are not randomly arranged in drug discovery, and produce, if not the ‘cure’, at least cells, but orchestrated in specialized subcellular compart- meaningful advances in patient survival. ments. The identification of heat shock protein-90 (Hsp90) chaperones in mitochondria of tumors, but not most normal tissues, provides an example of a compartmenta- Pathway-oriented drug discovery and the Hsp90 lized network of cell survival, opening fresh prospects for chaperone network novel, subcellularly targeted cancer drug discovery. Oncogene (2009) 28, 3681–3688; doi:10.1038/onc.2009.227; A fresh approach to these challenges is to take published online 3 August 2009 advantage of systems biology tools, and model cancer pathways in their globality (Rajasethupathy et al., Keywords: Hsp90; mitochondrial permeability transi- 2005). Connectivity maps (Lamb et al., 2006) linking tion; CypD; protein folding; cancer therapy multiple signaling pathways may more accurately recapitulate tumor heterogeneity, uncover redundancy and buffering, and ultimately identify nodal proteins, hub molecules integrating multiple downstream mechanisms of cell proliferation, survival and adapta- Cancer drug discovery in the post-Imatinib era tion (Butcher, 2005; Rajasethupathy et al., 2005). Nodal proteins, for instance the epidermal growth factor The improved knowledge of cancer genes (Vogelstein and receptor (Citri and Yarden, 2006), offer prime oppor- Kinzler, 2004), coupled with the feasibility of disabling tunities for cancer drug discovery, as their antagonists specific molecular lesion(s) in tumors (O’Dwyer and may provide genuine pathway inhibitors, disabling Druker, 2000), ushered the era of ‘targeted’ drugs entire signaling network(s), instead of a single target, (Sawyers, 2004): molecular ‘magic bullets’ that would and thus suited to overcome tumor heterogeneity (Wood change forever the landscape of cancer care. Unfortu- et al., 2007). nately, this expectation met a much harsher reality. The The molecular chaperone heat shock protein-90 extraordinary complexity of most malignancies with (Hsp90) is another example of a nodal protein hundreds of mutated or deregulated gene pathways (McClellan et al., 2007), intersecting multiple signaling (Wood et al.,2007),theastronomicalcostsandlow networks (Zhao and Houry, 2007). Hsp90 and Hsp90- success rate (typically 0.0001%) of ‘target-centric’ drug like molecules (see below) oversee protein folding discovery (van der Greef and McBurney, 2005), and the quality control (Young et al., 2001), trafficking of herculean task of fulfilling hundreds of regulatory steps signaling molecules at the plasma membrane (Garcia- and decision points to bring new agents to the clinic Cardena et al., 1998), delivery of preproteins to (Steensma, 2009), have greatly hampered the advent of mitochondria (Young et al., 2003), assembly and molecular cancer therapeutics. As a result, oncology trial disassembly of cytoskeletal proteins in the cytosol design all too often pursues small, and at times clinically (Barral et al., 2002), and disassembly of transcriptional insignificant gains, over 50% of the largest (and costliest) complexes in the nucleus (Freeman and Yamamoto, oncology phase III trials fails to produce benefit, and new 2002). These functions require sequential cycles of cancer drug registration has actually fallen by 40% over ATPase activity (Prodromou et al., 1997), and recruit- ment of cochaperones, including Hsp70, p50cdc37, Aha1, Correspondence: Dr DC Altieri, Department of Cancer Biology, p60hop and p23 (Pearl and Prodromou, 2000). Differ- LRB428, University of Massachusetts Medical School, 364 Plantation ently from Hsp70, which controls folding of all newly Street, Worcester, MA 01605, USA. E-mail: [email protected] synthesized proteins (Schmid et al., 1994), Hsp90 Received 4 June 2009; revised 30 June 2009; accepted 1 July 2009; oversees the maturation and/or stability of client published online 3 August 2009 proteins implicated in hormone and growth factor Subcellularly directed cancer drug discovery BH Kang and DC Altieri 3682 receptor signaling, cell-cycle progression and cell survi- drug efficacy, whether Hsp90 is as nodal a target as it val (Pearl and Prodromou, 2000; Young et al., 2003). was hoped, or, rather, whether other aspects of Hsp90 This pathway is exploited in cancer, where Hsp90 biology needed to be uncovered to unlock the full chaperoning (Whitesell and Lindquist, 2005) contributes therapeutic potential of these agents. to drug resistance (Cowen and Lindquist, 2005), metastasis (Eustace et al., 2004), tumor cell survival (Rodina et al., 2007) and transcriptional mechanisms of Compartmentalization of Hsp90 chaperones in tumor transformation (Dai et al., 2007). mitochondria At least one of the missing aspects of Hsp90 biology that Targeting Hsp90 for novel cancer therapeutics: clinical may influence the response to therapy is its novel experience and unanswered questions subcellular localization to mitochondria. Originally noted in a global survey of the mitochondrial proteome In addition to these nodal properties, other features (Mootha et al., 2003), Hsp90 is abundantly present in make Hsp90 an almost ideal cancer drug target (Isaacs mitochondria, and sorted to both the organelle inter- et al., 2003). Its ATPase pocket can accommodate small membrane space and the matrix (Kang et al., 2007). molecule inhibitors (Isaacs et al., 2003), and Hsp90 An Hsp90-like chaperone, tumor necrosis factor recep- protein levels (Neckers, 2002), as well as ATPase activity tor-associated protein-1 (TRAP-1) is also a mitochon- (Kamal et al., 2003) are increased in tumors, compared drial protein (Cechetto and Gupta, 2000; Felts et al., to normal tissues, suggesting that Hsp90 therapeutics 2000), localized to the organelle matrix (Kang et al., may have desirable selectivity (Isaacs et al., 2003). 2007), as well as the intermembrane space (Pridgeon Accordingly, multiple small molecule Hsp90 antagonists et al., 2007), in vivo. This subcellular localization is have been developed from 17-allylaminogeldanamycin selective, in that both Hsp90 chaperones are differen- (17-AAG), a less toxic derivative of the benzoquinone tially expressed in mitochondria of tumor cells, although ansamycin antibiotic, geldanamycin (GA; Isaacs et al., undetectable or expressed at very low levels in the 2003) or, more recently, from purine or resorcinol organelles of most normal tissues (see below), in vivo structures (Solit and Chiosis, 2008). These agents (Kang et al., 2007). The basis for this tumor preference competitively inhibit the Hsp90 ATPase activity, shut has not been determined, but it may have to do with off the chaperone function and induce degradation of changes in mitochondrial trafficking in transformed multiple client proteins (Isaacs et al., 2003). In turn, this cells. Accordingly, deregulation of cancer signaling exerts anticancer activity, predominantly through cell- pathways, for instance Akt, has been associated with a cycle arrest, followed by variable degrees of apoptosis, more avid mitochondrial preprotein import machinery especially in ‘sensitive’ cell types (Isaacs et al., 2003; (Wright et al., 2008), and Ras transformation of model Solit and Chiosis, 2008). Despite this promising back- fibroblasts, but not glucose deprivation, was sufficient to ground, the response to Hsp90 antagonists in the clinic upregulate Hsp90 levels in mitochondria (Kang et al., has been in general disappointing (Table 1), certainly 2007). inferior to what was expected from potential ‘pathway Once in mitochondria, Hsp90 and TRAP-1 bind the inhibitors’ (Drysdale et al., 2006). These less-than- matrix immunophilin, cyclophilin D (CypD; Kang et al., impressive clinical data (Table 1) raised questions about 2007). These interactions are direct, recapitulated in Table 1 Clinical experience with current small molecule Hsp90 antagonists Drug Trial Patients Regimen Outcome Citation 17-AAG Phase I 21 Single agent NR J Clin Oncol, 23:1078 17-AAG Phase I 19 Single agent 3 SD J Clin Oncol, 23:1885 17-AAG Phase I 30 Single agent 2 SD J Clin Oncol, 23:4152 17-AAG Phase I 45 Single agent NR Clin Cancer Res, 11:3385 17-AAG Phase I 13 Single agent NR Clin Cancer Res, 12:6087 17-AAG Phase II (RCC) 20 Single agent NR Invest New Drugs, 24:543 17-AAG Phase I 54 Single agent NR Clin Cancer Res, 13:1775 17-AAG Phase I 44 Single agent NR Clin Cancer Res, 13:1769 17-AAG Phase I 15 (Ped) Single agent NR Clin Cancer Res, 13:1783 17-AAG Phase I 17 (Ped) Single agent NR, 5 SD Clin Cancer Res, 13:1789 17-AAG Phase I 25 Plus trastuzumab 1 PR, 4 MR 4 SD J Clin Oncol, 25:5410 17-AAG Phase I 25 Plus paclitaxel NR, 6 SD Clin Cancer Res, 14:3456 17-AAG Phase
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