Tanespimycin with bortezomib: Activity in relapsed/refractory patients with multiple myeloma

Dana-Farber Cancer Institute, Boston, MA 02115, USA.
British Journal of Haematology (Impact Factor: 4.96). 08/2010; 150(4):428-37. DOI: 10.1111/j.1365-2141.2010.08264.x
Source: PubMed

ABSTRACT Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open-label multicentre study, we compared 1.3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource-based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.

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    • "Detailed reviews of clinical trial data can be found in Kim et al. (2009), Taldone et al. (2008) and Holzbeierlein et al. (2010). In addition to showing initial promise as a novel therapy in isolation, 17-AAG also demonstrated synergism with a number of chemotherapeutic agents such as Bortezomib (Richardson et al. 2010), Trastuzumab (Modi et al. 2007) and Paclitaxel (Ramalingam et al. 2008). An alternative derivative of GA, 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, also known as alvespimycin) was subsequently produced, with greater solubility and showed similar initial success in phase I and II clinical trials. "
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    • "These tests showed that 17AAG can be safely administered to humans, but unfortunately, its anticancer activity in monotherapy was very limited. Much better antitumor effects were obtained when 17AAG was combined with other modern chemotherapeutics (Ramalingam et al. 2008; Richardson et al. 2010b). It is now generally accepted that multidrug, multitargeted strategies are likely to be more successful in fighting cancer comparing with single drug, single target approaches . "
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    • "GA prevents αSyninduced dopaminergic cell loss in cell culture (McLean et al., 2004) and in animal models of PD (Auluck et al., 2005; Shen et al., 2005), while the less toxic 17-AAG has also proven to be neuroprotective in PD cellular models (Danzer et al., 2011; Riedel et al., 2010) and in two animal models of PD-related neurodegenerative diseases (Fujikake et al., 2008; Waza et al., 2005). Even though 17-AAG is currently under phase-II clinical trials as an anti-tumour drug (Pacey et al., 2010; Richardson et al., 2010; Solit et al., 2008), its use in patients with neurodegenerative diseases could be hampered by its toxicity and unavailability for oral administration (Pacey et al., 2010). Another family of inhibitors of Hsp90 activity, is SNX- 2112 and its analogues, which are orally available and present improved blood brain barrier (BBB) permeability. "
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