- I have just recently started to assemble coverage of Amarin on BiotechDueDiligence (and recently bought my first shares) - here is the link to the AMRN research page under construction.
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- My notes from the webcast are below:
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Here is the link to the podcast. Get more details on ALNY research page. My quick notes:
The efficacy of varying concentrations of intravesical apaziquone on murine bladder cancer in an animal model Link Introduction and Objectives: Apaziquone is a novel bioreductive alkylating agent in development for intravesical therapy of nonmuscle invasive bladder cancer. The standard dose of apaziquone in all ongoing clinical studies is 4 mg/ 40 mL (0.1mg/mL). The objective of this study was to test the efficacy of varying concentrations of apaziquone versus placebo in an animal model of bladder cancer. Methods: A total of 1x105 MB49 cells were instilled into the bladder of C57BL/6 mice after electrocauterization to establish the tumor model. Mice bearing orthotopic tumors were administered varying concentrations of apaziquone (0.05, 0.1, 0.4, and 0.8 mg/mL) or placebo (0.85% saline) via intravesical instillation (0.1 mL) one week after tumor implantation. Instillations were continued once a week for 4 weeks. Tumor incidence, overall and median survival is reported. Results: At the end of the observation period (80 days), all animals in the control (0.85% saline) and 0.05 mg/mL groups had died (fig. 1). The median survival of mice receiving apaziquone at concentrations of 0.1 mg/mL (42.5 days); 0.4 mg/mL (40.5 days) and 0.8 mg/mL (49 days) was longer than that of mice treated with 0.05 mg/mL (30 days) and 0.85% saline (27 days). Statistically significant differences in survival were observed in control vs apaziquone-treated groups [0.1 mg/ml(P < 0.05); 0.4 mg/mL(P < 0.01); 0.8 mg/mL (P < 0.01)], and in the low concentration (0.05 mg/mL) vs 0.1 mg/mL (P < 0.05), 0.4 mg/mL (P < 0.01) and 0.8 mg/mL (P < 0.01), respectively. The median survival of the 0.1, 0.4 and 0.8 mg/mL treated groups did not differ, but 33.3% in the 0.1 mg/mL cohort, and 14.3% in the 0.4 mg/mL cohort were long-term survivors (>80 days). All other animals (n = 37) had died of cancer by the end of the observation period. Three mice did not survive anesthesia. At necropsy all mice had advanced local disease with deep invasion of the muscularis propria, and usually with multiple lung metastases. Conclusion: Apaziquone at the 0.1 mg/mL concentration demonstrates excellent antitumor activity compared to placebo or 0.05 mg/mL solutions. In this model there was no significant difference in the median survival between 0.1 mg/mL and higher concentrations of apaziquone (0.4 and 0.8 mg/mL) supporting continued development with the current clinical dose (0.1mg/mL). A critical role for the tissue distribution profile in heat shock protein (Hsp) 90 inhibitor-induced ocular toxicity in rats Link 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 Link 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 Link 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. |
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