The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

Hu, Yafang; Bobb, Daniel; He, Jie; Hill, D. Ashley; Dome, Jeffrey S.

doi:10.1080/15384047.2015.1040964

Cited by 24 publications

(19 citation statements)

References 36 publications

(45 reference statements)

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“…Drug were first solubilized in DMSO and then diluted in PBS for intraperitoneal injections. When the tumor volumes reached 100-150 mm 3 , mice were randomized (n = 5 mice for each treatment group) and 1 mg/kg bortezomib and 25 mg/kg alvespimycin intraperitoneal injections were initiated three times a week ( 18, 19 ). Control tumors were treated with 100 µ l of 5% DMSO diluted in PBS.…”

Section: Methodsmentioning

confidence: 99%

From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline

Rao

Somarelli

Altunel

et al. 2019

Preprint

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Cancer drug discovery is an inefficient process, with more than 90% of newly-19 discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a 20promising new approach to identifying personalized treatments; however, for rare cancers, such 21 as sarcomas, access to patient samples can be extremely limited, which precludes development 22of patient-derived models. To address the limited access to patient samples, we have turned to 23 pet dogs with naturally-occurring sarcomas. Although sarcomas make up less than 1% of all 24 cancers in humans, sarcomas represent at least 15% of all cancers in dogs. Dogs with naturally-25 occurring sarcomas also have intact immune systems, an accelerated pace of cancer progression, 26and share the same environment as humans, making them ideal models that bridge key gaps 27 between mouse models and human sarcomas. 28Here, we develop a framework for a personalized medicine pipeline that integrates drug 29 screening, validation, and genomics to identify new therapies. We tested this paradigm through 30the study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. By 31integrating patient-derived cancer models, in vitro drug screens, and in vivo validation we 32 identified proteasome inhibitors as a potential therapy for Teddy. After showing an initial 33 response to the proteasome inhibitor, bortezomib, Teddy developed rapid resistance, and tumor 34 growth resumed. Whole exome sequencing revealed substantial genetic heterogeneity across 35Teddy's multiple recurrent tumors and metastases, suggesting that intra-patient heterogeneity 36was responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with 37 exome sequencing revealed multiple candidate driver mutations in proteins related to the 38 proteasome pathway. Together, our results demonstrate how the comparative study of canine 39 sarcomas can offer rapid insights into the process of developing personalized medicine 40 approaches that can lead to new treatments for sarcomas in both humans and canines. 41

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Section: Methodsmentioning

confidence: 99%

From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline

Rao

Somarelli

Altunel

et al. 2019

Preprint

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“…Many clinical trials are focusing on treating OS using a variety of targeted therapies (1,25). Among them, HSP90 inhibition is a promising therapeutic strategy showing clinical activity in various tumor types, including OS (10,(26)(27)(28). Indeed, HSP90 client proteins are proteins playing crucial roles in establishing cancer cell hallmarks (29).…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic HSP90 inhibitors with improved pharmacologic properties and safety profiles might overcome some of the constraints for clinical development of the first generation of HSP90 inhibitors. For example, other novel HSP90 inhibitors (PU-H71, NVP-AUY922) were described to induce apoptosis in preclinical studies of various cancers (4), (7)(8)(9), including primary bone tumors (10,11), and are currently in clinical trials in various cancers. However, little is known regarding the potential activity of HSP90 inhibitors in sarcomas.…”

Section: Introductionmentioning

confidence: 99%

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Ory

Baud’huin

Verrecchia

et al. 2016

Clinical Cancer Research

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Purpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma.Experimental Design: The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14 þ monocytes.

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“…Drug were first solubilized in DMSO and then diluted in PBS for intraperitoneal injections. When the tumor volumes reached 100-150 mm 3 , mice were randomized (n = 5 mice for each treatment group) and 1 mg/kg bortezomib and 25 mg/kg alvespimycin intraperitoneal injections were initiated three times a week (18,19). Control tumors were treated with 100 µl of 5% DMSO diluted in PBS.…”

Section: Validation Of Top Drug Candidates In Vivomentioning

confidence: 99%

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine

et al. 2020

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Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.

show abstract

The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

Cited by 24 publications

References 36 publications

From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline

From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine

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