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Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma.

Suzuki R, Hideshima T, Mimura N, Minami J, Ohguchi H, Kikuchi S, Yoshida Y, Gorgun G, Cirstea D, Cottini F, Jakubikova J, Tai YT, Chauhan D, Richardson PG, Munshi NC, Utsugi T, Anderson KC - Leukemia (2014)

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.

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Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells: Akt (PI3K/Akt pathway), IL-6R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), CDK4, 6, 9 (cell cycling), and IκB kinases (NF-κB pathway)... The expression of HSP90 is upregulated (2- to 10-fold) in tumor cells compared with normal cells, reflecting multiple oncogenic pathways and maintenance of homeostasis within tumor cells... Significant degradation of HSP90 client proteins was triggered by TAS-116 in a dose-dependent manner in MM.1S cells (Supplementary Figure S1E)... Importantly, more significant degradation of phosho-C-Raf and phospho-MEK1/2, HSP90 client proteins and key RAS/RAF/MEK pathway regulators, was triggered by TAS-116 than 17-AAG in INA6 and NCI-H929 MM cells (Supplementary Figure S2D, 2E)... Taken together, these results indicate that TAS-116 induces cytotoxicity selectively and potently in MM cell lines and patient MM cells, even in NALM-6 cells, without toxicity in normal PBMNCs; potently targets HSP90 client proteins including C-Raf and MEK1/2; as well as inhibits upregulation of HSP27 and overcomes 17-AAG resistance mechanisms in MM cells... The OS was significantly prolonged in the combination group compared with either monotherapy cohort (P = .004 in TAS-116 vs the combination, and P = .0004 in BTZ vs the combination; Figure 1C)... These treatments were well tolerated, and no significant body weight loss was observed (Figure 1D)... In addition, we assessed the cytotoxicity of TAS-116 or HSP90 inhibitor PF-04928473 (SNX-2112) in combination with BTZ in ARPE-19 cells... Surprisingly, low-dose BTZ significantly ameliorated the cytotoxicity induced by TAS-116, compared with PF-04928473 (SNX-2112) (Figure 2B)... We next investigated the ocular toxicity profile of TAS-116 using an in vivo murine xenograft model... Importantly, TAS-116 15 mg/kg–treatment (maximum tolerated dose) did not induce ocular toxicity in mice, in contrast to PF-04929113 (SNX-5422) 40 mg/kg, which was associated with increased photoreceptor cell death in all retinal layers (Figure 2C)... TAS-116 also enhanced bortezomib (BTZ)-induced MM cytotoxicity, due to inhibition of BTZ-triggered canonical NF-κB activation and enhancing endoplasmic reticulum stress... We confirmed that TAS-116, alone and in combination with BTZ, was well tolerated; triggered significant tumor growth inhibition; and prolonged host survival in a murine xenograft model of human MM... Importantly, TAS-116 showed lower ocular toxicity, a known toxicity of HSP90 inhibitors, than PF-04929113 (SNX-5422)... Taken together, our studies show that TAS-116 blocks MM cell growth both in vitro and in vivo, and is well tolerated, providing the framework for its clinical evaluation to improve patient outcome in MM.

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TAS-116 inhibits human MM cell growth and enhances bortezomib-induced cytotoxicity in vivo(A–G) SCID mice were injected subcutaneously with 5 × 106 MM.1S cells and treated with 10 mg/kg oral TAS-116 5 days a week (n = 10; green line); 15 mg/kg oral TAS-116 5 days a week (n = 10; blue line); 0.5 mg/kg subcutaneous BTZ twice a week (n = 8; purple line); or 0.5 mg/kg subcutaneous BTZ twice a week and 10 mg/kg oral TAS-116 5 days a week (n = 10; red line) for 28 days. A vehicle control group received oral vehicle only and subcutaneous saline (n = 9; black line).(A) Tumor volume was calculated from caliper measurements every other day, and data represent mean ± SD.(B) Representative whole-body images from a mouse treated for 29 days with control vehicle (bottom panel) or for 31 days with TAS-116 (10 mg/kg; top panel).(C) Survival was evaluated from the first day of treatment using Kaplan-Meier curves.(D) Change of body weight was expressed from the first day of treatment. Data represent mean ± SD.(E) Tumors harvested from TAS-116- (15 mg/kg) and vehicle control- treated mice after 3 days of treatment were subjected to immunohistochemical analysis for cleaved caspase-3 and TUNEL staining.
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Figure 1: TAS-116 inhibits human MM cell growth and enhances bortezomib-induced cytotoxicity in vivo(A–G) SCID mice were injected subcutaneously with 5 × 106 MM.1S cells and treated with 10 mg/kg oral TAS-116 5 days a week (n = 10; green line); 15 mg/kg oral TAS-116 5 days a week (n = 10; blue line); 0.5 mg/kg subcutaneous BTZ twice a week (n = 8; purple line); or 0.5 mg/kg subcutaneous BTZ twice a week and 10 mg/kg oral TAS-116 5 days a week (n = 10; red line) for 28 days. A vehicle control group received oral vehicle only and subcutaneous saline (n = 9; black line).(A) Tumor volume was calculated from caliper measurements every other day, and data represent mean ± SD.(B) Representative whole-body images from a mouse treated for 29 days with control vehicle (bottom panel) or for 31 days with TAS-116 (10 mg/kg; top panel).(C) Survival was evaluated from the first day of treatment using Kaplan-Meier curves.(D) Change of body weight was expressed from the first day of treatment. Data represent mean ± SD.(E) Tumors harvested from TAS-116- (15 mg/kg) and vehicle control- treated mice after 3 days of treatment were subjected to immunohistochemical analysis for cleaved caspase-3 and TUNEL staining.

Mentions: We next examined the in vivo efficacy of TAS-116 in combination with BTZ using a murine xenograft model of human MM. Mice treated with TAS-116 (10 mg/kg and 15 mg/kg), BTZ, or TAS-116 plus BTZ showed significantly enhanced growth inhibition versus the vehicle control group (P = .004 and P = .0012, P = .003, and P < .0001, respectively; Figure 1A). Representative images of tumor growth inhibition by TAS-116 (10 mg/kg) are demonstrated in Figure 1B. The delay in tumor growth was greater in the combination-treated group compared with either monotherapy cohort (P = .0014 in TAS-116 vs the combination and P = .0001 in BTZ vs the combination; Figure 1A). Median overall survival of treated animals (TAS-116 10 mg/kg = 33 days, 15 mg/kg = 37 days, BTZ = 36 days, and the combination = 56.5 days) was significantly longer than vehicle control (29 days; P = .0064, P < .0001, P = .0009, and P < .0001, respectively; Figure 1C). The OS was significantly prolonged in the combination group compared with either monotherapy cohort (P = .004 in TAS-116 vs the combination, and P = .0004 in BTZ vs the combination; Figure 1C). These treatments were well tolerated, and no significant body weight loss was observed (Figure 1D). Importantly, immunohistochemical analysis of harvested human MM confirmed a significant increase in cleaved caspase-3- and TUNEL-positive cells in TAS-116 15 mg/kg-treated mice (Figure 1E). These results indicate that TAS-116 triggers enhanced in vivo anti-MM activities, both alone and in combination with BTZ, with a favorable safety profile.


Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma.

Suzuki R, Hideshima T, Mimura N, Minami J, Ohguchi H, Kikuchi S, Yoshida Y, Gorgun G, Cirstea D, Cottini F, Jakubikova J, Tai YT, Chauhan D, Richardson PG, Munshi NC, Utsugi T, Anderson KC - Leukemia (2014)

TAS-116 inhibits human MM cell growth and enhances bortezomib-induced cytotoxicity in vivo(A–G) SCID mice were injected subcutaneously with 5 × 106 MM.1S cells and treated with 10 mg/kg oral TAS-116 5 days a week (n = 10; green line); 15 mg/kg oral TAS-116 5 days a week (n = 10; blue line); 0.5 mg/kg subcutaneous BTZ twice a week (n = 8; purple line); or 0.5 mg/kg subcutaneous BTZ twice a week and 10 mg/kg oral TAS-116 5 days a week (n = 10; red line) for 28 days. A vehicle control group received oral vehicle only and subcutaneous saline (n = 9; black line).(A) Tumor volume was calculated from caliper measurements every other day, and data represent mean ± SD.(B) Representative whole-body images from a mouse treated for 29 days with control vehicle (bottom panel) or for 31 days with TAS-116 (10 mg/kg; top panel).(C) Survival was evaluated from the first day of treatment using Kaplan-Meier curves.(D) Change of body weight was expressed from the first day of treatment. Data represent mean ± SD.(E) Tumors harvested from TAS-116- (15 mg/kg) and vehicle control- treated mice after 3 days of treatment were subjected to immunohistochemical analysis for cleaved caspase-3 and TUNEL staining.
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Figure 1: TAS-116 inhibits human MM cell growth and enhances bortezomib-induced cytotoxicity in vivo(A–G) SCID mice were injected subcutaneously with 5 × 106 MM.1S cells and treated with 10 mg/kg oral TAS-116 5 days a week (n = 10; green line); 15 mg/kg oral TAS-116 5 days a week (n = 10; blue line); 0.5 mg/kg subcutaneous BTZ twice a week (n = 8; purple line); or 0.5 mg/kg subcutaneous BTZ twice a week and 10 mg/kg oral TAS-116 5 days a week (n = 10; red line) for 28 days. A vehicle control group received oral vehicle only and subcutaneous saline (n = 9; black line).(A) Tumor volume was calculated from caliper measurements every other day, and data represent mean ± SD.(B) Representative whole-body images from a mouse treated for 29 days with control vehicle (bottom panel) or for 31 days with TAS-116 (10 mg/kg; top panel).(C) Survival was evaluated from the first day of treatment using Kaplan-Meier curves.(D) Change of body weight was expressed from the first day of treatment. Data represent mean ± SD.(E) Tumors harvested from TAS-116- (15 mg/kg) and vehicle control- treated mice after 3 days of treatment were subjected to immunohistochemical analysis for cleaved caspase-3 and TUNEL staining.
Mentions: We next examined the in vivo efficacy of TAS-116 in combination with BTZ using a murine xenograft model of human MM. Mice treated with TAS-116 (10 mg/kg and 15 mg/kg), BTZ, or TAS-116 plus BTZ showed significantly enhanced growth inhibition versus the vehicle control group (P = .004 and P = .0012, P = .003, and P < .0001, respectively; Figure 1A). Representative images of tumor growth inhibition by TAS-116 (10 mg/kg) are demonstrated in Figure 1B. The delay in tumor growth was greater in the combination-treated group compared with either monotherapy cohort (P = .0014 in TAS-116 vs the combination and P = .0001 in BTZ vs the combination; Figure 1A). Median overall survival of treated animals (TAS-116 10 mg/kg = 33 days, 15 mg/kg = 37 days, BTZ = 36 days, and the combination = 56.5 days) was significantly longer than vehicle control (29 days; P = .0064, P < .0001, P = .0009, and P < .0001, respectively; Figure 1C). The OS was significantly prolonged in the combination group compared with either monotherapy cohort (P = .004 in TAS-116 vs the combination, and P = .0004 in BTZ vs the combination; Figure 1C). These treatments were well tolerated, and no significant body weight loss was observed (Figure 1D). Importantly, immunohistochemical analysis of harvested human MM confirmed a significant increase in cleaved caspase-3- and TUNEL-positive cells in TAS-116 15 mg/kg-treated mice (Figure 1E). These results indicate that TAS-116 triggers enhanced in vivo anti-MM activities, both alone and in combination with BTZ, with a favorable safety profile.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells: Akt (PI3K/Akt pathway), IL-6R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), CDK4, 6, 9 (cell cycling), and IκB kinases (NF-κB pathway)... The expression of HSP90 is upregulated (2- to 10-fold) in tumor cells compared with normal cells, reflecting multiple oncogenic pathways and maintenance of homeostasis within tumor cells... Significant degradation of HSP90 client proteins was triggered by TAS-116 in a dose-dependent manner in MM.1S cells (Supplementary Figure S1E)... Importantly, more significant degradation of phosho-C-Raf and phospho-MEK1/2, HSP90 client proteins and key RAS/RAF/MEK pathway regulators, was triggered by TAS-116 than 17-AAG in INA6 and NCI-H929 MM cells (Supplementary Figure S2D, 2E)... Taken together, these results indicate that TAS-116 induces cytotoxicity selectively and potently in MM cell lines and patient MM cells, even in NALM-6 cells, without toxicity in normal PBMNCs; potently targets HSP90 client proteins including C-Raf and MEK1/2; as well as inhibits upregulation of HSP27 and overcomes 17-AAG resistance mechanisms in MM cells... The OS was significantly prolonged in the combination group compared with either monotherapy cohort (P = .004 in TAS-116 vs the combination, and P = .0004 in BTZ vs the combination; Figure 1C)... These treatments were well tolerated, and no significant body weight loss was observed (Figure 1D)... In addition, we assessed the cytotoxicity of TAS-116 or HSP90 inhibitor PF-04928473 (SNX-2112) in combination with BTZ in ARPE-19 cells... Surprisingly, low-dose BTZ significantly ameliorated the cytotoxicity induced by TAS-116, compared with PF-04928473 (SNX-2112) (Figure 2B)... We next investigated the ocular toxicity profile of TAS-116 using an in vivo murine xenograft model... Importantly, TAS-116 15 mg/kg–treatment (maximum tolerated dose) did not induce ocular toxicity in mice, in contrast to PF-04929113 (SNX-5422) 40 mg/kg, which was associated with increased photoreceptor cell death in all retinal layers (Figure 2C)... TAS-116 also enhanced bortezomib (BTZ)-induced MM cytotoxicity, due to inhibition of BTZ-triggered canonical NF-κB activation and enhancing endoplasmic reticulum stress... We confirmed that TAS-116, alone and in combination with BTZ, was well tolerated; triggered significant tumor growth inhibition; and prolonged host survival in a murine xenograft model of human MM... Importantly, TAS-116 showed lower ocular toxicity, a known toxicity of HSP90 inhibitors, than PF-04929113 (SNX-5422)... Taken together, our studies show that TAS-116 blocks MM cell growth both in vitro and in vivo, and is well tolerated, providing the framework for its clinical evaluation to improve patient outcome in MM.

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Related in: MedlinePlus