A critical role for the tissue distribution profile in heat shock protein (Hsp) 90 inhibitor-induced ocular toxicity in rats
In addition to regulating a number of oncogenic client proteins, the Hsp90 molecular chaperone also controls the folding of key signaling molecules required to maintain normal cell function in many organs, including the retina. In human clinical trials Hsp90 inhibition has been associated with visual disorders including blurred vision, flashes, delayed light/dark accommodation, and photophobia [including a new disclosure for MPC3100 from MYRX]. These adverse effects involving injury to the retina may be attributable to photoreceptor degeneration and cell death, as previously reported in dogs following repeated doses of PF-04929113 [aka SNX-5422]. In contrast, ganetespib, a potent Hsp90 inhibitor currently in phase II/III trials, has demonstrated promising clinical activity without manifesting ocular toxicity. This difference in vision deficits between ganetespib and other Hsp90 inhibitors likely depends on a number of contributing factors.
In this study, we examined the relationship between retinal drug distribution profiles and photoreceptor degeneration in male SD rats treated with17-DMAG, 17-AAG, and STA-9056 (an Hsp90 inhibitor with comparable in vitro activity to 17-DMAG) [But I don't know how this drug compares structurally to ganetespib aka STA-9090]. All compounds were tested in short-term studies at 1-3 dose levels administered i.v.. At necropsy, eyes were dissected and processed for histopathological examination. In subsets of animals, the retinal tissues, along with plasma and cerebrospinal fluid (CSF) samples, were collected for analysis.
Our results indicate that all compounds evaluated showed greater exposure in the retinal tissue compared to plasma and CSF. 17-DMAG, for which visual changes have been reported in clinical subjects, produced marked photoreceptor cell death and was associated with a slow elimination rate (at 6 hrs post-dose, 50% of the drug present at 30 min remained in the retina) and a high retina/plasma (R/P) ratio. In contrast, and consistent with the absence of clinically-reported visual changes, 17-AAG at the maximum tolerated dose did not produce detectable photoreceptor injury. At 6 hr post dose, 94% of 17-AAG had been eliminated from the retina resulting in a low R/P ratio. Finally, STA-9056 showed 79% drug elimination at 6 hrs and an R/P ratio that was moderately low. Photoreceptor degeneration was not observed at doses of STA-9056 that are active in animal tumor models, and only minimal degeneration was seen at a higher dose. Our findings suggest that the R/P exposure ratio and elimination rate profiles play crucial roles in ocular toxicity and can be used as indicators of potential Hsp90 inhibitor-induced damage in rats.
In summary, Hsp90 plays an important role in the retina and prolonged Hsp90 inhibition can lead to vision disorders. However, ocular toxicity may be successfully minimized by administration of Hsp90 inhibitors with favorable drug properties that include, although not necessarily limited to, lower retina/plasma exposure ratios and faster retinal elimination.
Ganetespib, a unique resorcinolic Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile in preclinical models
Targeted inhibition of the molecular chaperone heat shock protein 90 (Hsp90) results in the simultaneous blockade of multiple oncogenic signaling pathways and has thus emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (STA-9090) is a unique resorcinolic inhibitor of Hsp90 currently in clinical trials for a number of human cancers. Here we describe the key interaction of ganetespib with a number of amino acid residues in the ATP binding pocket of Hsp90 which results in high affinity binding. Ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematological tumor cell lines. By using a novel isotope-labeling scheme and LC-MS/MS detection technique, we have determined that Hsp90 occupancy by ganetespib in cancer cells is relatively fast under saturating conditions, reaching equilibrium within 5 minutes of ganetespib exposure. In vivo, ganetespib demonstrated strong single-agent activity in solid and hematological xenograft models, as evidenced by significant tumor growth inhibition and/or regression. Of note, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Most importantly, ganetespib showed no evidence of cardiac or liver toxicity and exhibited minimal potential risk for CNS or ocular toxicities. Taken together, this preclinical activity profile suggests that ganetespib may have broad application for a variety of human malignancies and mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.
Cancer-selective mitochondrial copper transport by elesclomol results in potent single agent efficacy in multiple tumor types
Elesclomol is a first-in-class investigational drug that exerts potent anticancer activity through the elevation of reactive oxygen species (ROS) levels and is currently under clinical evaluation as a novel anticancer therapeutic. We recently demonstrated that elesclomol preferentially binds extracellular copper (Cu) and selectively transports this metal ion to the mitochondria of tumor cells to promote mitochondrial ROS generation and subsequent apoptosis. Here we report that elesclomol-induced copper transport and apoptosis is tumor selective. Comparative analysis using human PBMCs and the promyelocytic tumor cell line HL-60 demonstrated increased Cu levels in the mitochondrial fraction of HL-60 cells following elesclomol-Cu treatment, but not in donor PBMCs. Further, elesclomol-Cu induces ROS in HL-60-derived mitochondria but not in those isolated from PBMCs. These results suggest that elesclomol-Cu selectively targets cancer cell mitochondria to ultimately produce critical elevations in oxidative stress. To evaluate increased exposure to elesclomol-Cu in vivo, elesclomol was administered continuously to tumor-bearing mice using an Alzet pump at a clinically relevant dose. Upon release, elesclomol immediately chelates copper from the blood to form an elesclomol-Cu complex, achieving 10-fold higher levels of elesclomol-Cu compared to those following bolus injection. Even with this increased formation of elesclomol-Cu in situ, no signs of toxicity have been observed. In five different tumor xenograft models tested, elesclomol consistently demonstrated marked single agent activity with significant tumor growth suppression, indicating that increased elesclomol-Cu levels result in selective and enhanced antitumor efficacy. These findings highlight a unique mechanism of action of elesclomol and support potential single agent activity of this compound in a variety of tumor types.
European Multidisciplinary Cancer Congress - September 23-27, 2011 - Stockholm, Sweden.
A Phase 1 and Pharmacokinetic Study of Ganetespib (STA-9090), a Heat Shock Protein 90 Inhibitor, in Combination With Docetaxel in Subjects With Advanced Solid Tumour Malignancies
R.D. Harvey1, C.M. Lewis1, J.S. Kauh1, T.K. Owonikoko1, A. Akintayo1, M. Karol2, F. Teofilovici2, J.M. Lufkin2, F.R. Khuri1, S.S. Ramalingam1 1Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta GA, USA ; 2Synta Pharmaceuticals, Clinical Development, Lexington MA, USA
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. Ganetespib has been well tolerated and has shown promising single-agent antitumour activity in early trials in multiple cancers. Based on preclinical synergy between ganetespib (G) and docetaxel (D), a phase I pharmacokinetic (PK) and feasibility study was initiated with the combination.
Materials and Methods: Patients (pts) with advanced solid tumour malignancies and ECOG performance status (PS) 0–2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) administered as an 1-hr separate infusion in a 3-week cycle. PK sampling was performed on days 1/8 of cycle 1. The primary endpoint was determination of optimal doses of the two agents for combination therapy.
Results: Thirteen pts were enrolled in the dose escalation phase. Median age-63 (44–72); 2-M, 11-F; ECOG PS 0–1, 1, 12. At dose levels 1 (D-60mg/m2, G-150mg/m2) and 2 (D-75mg/m2, G-150mg/m2), none of 6 pts initially treated had a DLT. Two of 4 pts at dose level 3 (D-75mg/m2, G-200mg/m2) had DLTs (g4 febrile neutropenia and one g4 neutropenia of >7 days), requiring expansion of dose level 2. As no other DLTS were observed; level 2 was the expansion cohort. Common AEs included neutropenia (n=10), diarrhea, anemia and fatigue (n=4 each), nausea and febrile neutropenia (n=3 each). Common g 3/4 AEs included neutropenia (n=10) and febrile neutropenia (n=3). The median number of cycles received is 4 (1–8), with 6 pts still on study. Among 10 pts evaluable for response, 7 had disease stabilization following cycle 2 (6 weeks), 4 pts to 12 weeks and 1 pt to 18 weeks. PK data from dose level 1 indicates PK similarity between G administered alone and G administered prior to D. No drug accumulation was observed following once-weekly dosing which is consistent with other studies where G was administered alone. Additional PK data will be presented.
Conclusions: The combination of docetaxel and ganetespib is well tolerated at the recommended doses of 75mg/m2 and 150mg/m2. Promising anti-cancer activity was noted, and a randomized phase II study of the combination has been initiated in advanced NSCLC.
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