Journal ArticleDOI
Inhibition of HSP90 molecular chaperones: moving into the clinic.
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TLDR
The current status of HSP90 inhibitors in clinical development is reviewed, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors.Abstract:
Summary Heat shock protein 90 (HSP90) is a molecular chaperone that is crucial for the stability and function of many proteins essential for cell survival. Many oncogenes, including tyrosine kinases, transcription factors, and cell-cycle regulatory proteins, are client proteins of HSP90. Inhibition of HSP90 causes client protein degradation via the ubiquitin–proteasome pathway, and is a mechanism that might simultaneously downregulate several redundant pathways crucial for cell viability and tumour development. HSP90 inhibitors are currently being developed as anticancer agents, and have shown early promising results in molecularly defined subgroups of solid tumours (eg, ALK-rearranged non-small-cell lung cancer and HER2-amplified breast cancer) and some haematological malignancies (eg, multiple myeloma). Here, we review the current status of HSP90 inhibitors in clinical development, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors. We also discuss novel strategies and future perspectives on how to optimise the therapeutic potential of this exciting new class of drugs.read more
Citations
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Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications
Jacek Zielonka,Joy Joseph,Adam Sikora,Micael Hardy,Olivier Ouari,Jeannette Vasquez-Vivar,Gang Cheng,Marcos Lopez,Balaraman Kalyanaraman +8 more
TL;DR: The physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds are described.
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The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks
TL;DR: It is now clear that aging and cancer development either share or diverge in several disease mechanisms, and aging can be considered an aging disease, though the shared mechanisms underpinning the two processes remain unclear.
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LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc.
Jiayin Tang,Tingting Yan,Yujie Bao,Chaoqin Shen,Chenyang Yu,Xiaoqiang Zhu,Xianglong Tian,Fangfang Guo,Qian Liang,Qiang Liu,Ming Zhong,Jinxian Chen,Zhi-Zheng Ge,Xiao-Bo Li,Xiaoyu Chen,Yun Cui,Ying-Xuan Chen,Weiping Zou,Haoyan Chen,Jie Hong,Jing-Yuan Fang +20 more
TL;DR: The lncGLCC1 is significantly upregulated under glucose starvation in CRC cells, supporting cell survival and proliferation by enhancing glycolysis and correlates with poor prognosis in this cancer.
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Molecular characterization and targeted therapeutic approaches in breast cancer
TL;DR: The current state of novel biological markers for BC, the evidence to demonstrate their clinical validity and utility, and the implication for therapeutic targeting are reviewed.
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Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG.
Yan Gu,Yanfang Liu,Li Fu,Lili Zhai,Jie Zhu,Yanmei Han,Yingming Jiang,Yi Zhang,Peng Zhang,Zhengping Jiang,Xiang Zhang,Xuetao Cao,Xuetao Cao,Xuetao Cao +13 more
TL;DR: A mouse model of spontaneous lymph node metastasis of breast cancer shows that primary tumors induced B cell accumulation in draining lymph nodes, identifying a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.
References
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Journal ArticleDOI
A phase I dose-escalation study of the Hsp90 inhibitor STA-9090 administered twice weekly in patients with solid tumors.
James M. Cleary,Elisabeth I. Heath,E. L. Kwak,Bruce J. Dezube,Leena Gandhi,C. Zack,R. Bradley,V. Vukovic,Geoffrey I. Shapiro,Patricia LoRusso +9 more
TL;DR: The majority of AEs reported in >20% of patients were fatigue, nausea, anemia, diarrhea, vomiting, anorexia, and headache; the majority of these AEs were mild to severe.
Journal ArticleDOI
A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma.
David Siegel,Sundar Jagannath,David H. Vesole,Ivan Borello,Amitabha Mazumder,Constantine S. Mitsiades,Jill Goddard,Joi Dunbar,Emmanuel Normant,Julian Adams,David Grayzel,Kenneth C. Anderson,Paul G. Richardson +12 more
TL;DR: The most common treatment-related adverse event was grade 1 infusion site pain (four patients), and the area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2–4 h for IPI-504 and its metabolites.
Journal ArticleDOI
Optical Imaging with HER2-targeted Affibody Molecules can monitor Hsp90 treatment response in a breast cancer xenograft mouse model
Stephanie M. W. Y. van de Ven,Sjoerd G. Elias,Carmel T. Chan,Zheng Miao,Zhen Cheng,Abhijit De,Sanjiv S. Gambhir +6 more
TL;DR: Optical imaging with an affibody can be used to noninvasively monitor changes in Her2 expression in vivo as a response to treatment with an Hsp90 inhibitor, with results similar to response measurements in positron emission tomography imaging studies.
Journal ArticleDOI
A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) for patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Melissa Lynne Johnson,Eric M. Hart,Alfred Rademaker,Bing Bing Weitner,Alexandra Urman,Hala D Simm,Leanne M Fountas,Rebekah Worden,Jyoti D. Patel,Vincent A. Miller,Gregory J. Riely +10 more
TL;DR: This phase II study combines AUY922 and E for the treatment of pts with EGFR-mutant lung cancer and RECIST-progression on 1st-line EGFR TKIs and overall response rate (ORR, CR+PR) at 8 wks.
Journal ArticleDOI
First-in-human phase I study: Results of a second-generation non-ansamycin heat shock protein 90 (HSP90) inhibitor AT13387 in refractory solid tumors.
Daruka Mahadevan,D. M. Rensvold,Sandra E. Kurtin,James M. Cleary,Leena Gandhi,John Lyons,Victoria Lock,Samantha Lewis,Geoffrey I. Shapiro +8 more
TL;DR: The primary endpoint was to determine the MTD; secondary endpoints included PK, PD, safety and tolerability, and treatment related toxicities.