Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer.

Modi, Shanu; Saura, Cristina; Henderson, Charles A.; Lin, Nu; Mahtani, R; Goddard, Jill; Ródenas, Eduardo; O’Shaughnessy, Joyce; Baselga, José

doi:10.1200/jco.2011.29.15_suppl.590

Cited by 12 publications

(6 citation statements)

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“…Among the 20 patients evaluable for efficacy, 1 PR was observed and 1 patient had SD for 6 months. Thus, there was modest clinical activity but the trial did not meet the prespecified criteria for trial expansion [68]. …”

Section: Clinical Studies With Hsp90 Inhibitors In Cancersmentioning

confidence: 99%

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Jhaveri

Taldone

Modi

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

410

426

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Hsp90 is an ATP dependent molecular chaperone protein which integrates multiple oncogenic pathways. As such, Hsp90 inhibition is a promising anti-cancer strategy. Several inhibitors that act on Hsp90 by binding to its N-terminal ATP pocket have entered clinical evaluation. Robust pre-clinical data suggested anti-tumor activity in multiple cancer types. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma. In breast cancer, proof-of-concept was demonstrated by first generation Hsp90 inhibitors in combination with trastuzumab mainly in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer. There are a multitude of second generation Hsp90 inhibitors currently under investigation. To date, however, there is no FDA approved Hsp90 inhibitor nor standardized assay to ascertain Hsp90 inhibition. This review summarizes the current status of both first and second generation Hsp90 inhibitors based on their chemical classification and stage of clinical development. It also discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors. Ultimately, these efforts will aid in maximizing the full potential of this class of agents.

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Section: Clinical Studies With Hsp90 Inhibitors In Cancersmentioning

confidence: 99%

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Jhaveri

Taldone

Modi

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

410

426

View full text Add to dashboard Cite

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“…A phase II trial of 4 in combination with trastuzumab in patients with HER2-positive MBC was also reported . 5% ORR and 70% SD were observed in heavily pretreated patients previously exposed to trastuzumab.…”

Section: Targeting Hsp90 As a Promising Strategy To Combat Tyrosine K...mentioning

confidence: 99%

Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90–Kinase Interactions

et al. 2016

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Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.

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“…Retaspimycin (IPI-504) was combined with trastuzumab in 26 patients with advanced, HER-2 positive breast cancer who had progressed on trastuzumab 164. Among the 20 evaluable patients, there was 1 PR and SD in 14.…”

Section: Heat Shock Protein 90 (Hsp 90)mentioning

confidence: 99%

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

et al. 2013

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For many years, the medical treatment of breast cancer was reliant solely on cytotoxic chemotherapy. However, over the past twenty years, treatment has evolved to a more target-directed approach. We now employ tailored therapy based on the presence or absence of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2). We expect this trend to continue, as agents that use novel approaches to target HER2, as well as targeting different portions of the HER signaling pathway, are in various stages of development. Notably, pertuzumab, a humanized monoclonal antibody that binds to a different domain of the extracellular portion of the HER2 receptor than trastuzumab, was recently approved for use, as was lapatinib, a small-molecule tyrosine kinase inhibitor. Patients with triple negative breast cancer, particularly those with the BRCA mutation, have more limited treatment options and carry a worse prognosis than those who are hormone receptor positive. However, recent data has shown that PARP inhibitors may have significant anti-tumor effect in those with this subtype of breast cancer. Novel agents that inhibit mTOR, PI3K, the insulin-like growth factor, heat shock protein 90, and histone deacetylase have shown promise in phase I-III trials and offer exciting new possibilities for the treatment of this often fatal disease. As we are presented with an ever increasing number of treatment options, the timing and combinations of therapeutic agents used becomes ever more complex in the age of personalized care, but we are hopeful that ultimately this will lead to improved patient outcomes.

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Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer.

Cited by 12 publications

References 0 publications

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90–Kinase Interactions

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

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