Phase II trial of the Hsp90 inhibitor tanespimycin (Tan) + trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC)

Modi, Shanu; Sugarman, Steven; Stopeck, A.; Linden, HM; Ma, Wen; Kersey, Kathryn; Johnson, Robert G.; Rosen, Neil; Hannah, Alison L.; Hudis, C.

doi:10.1200/jco.2008.26.15_suppl.1027

Cited by 51 publications

(33 citation statements)

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“…Despite these advances, resistance to anti-HER2 agents is frequent and new anti-HER2 therapies are being explored (36). Among these novel approaches, Hsp90 inhibitors have been considered as potential agents because they result in decreased HER2 expression, and there is already some evidence of antitumor activity with these agents (23,37).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Scaltriti

Serra

Normant

et al. 2011

Molecular Cancer Therapeutics

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Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer. Mol Cancer Ther; 10(5); 817-24. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Scaltriti

Serra

Normant

et al. 2011

Molecular Cancer Therapeutics

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“…Two anti-HSP90 agents that have been combined with trastuzumab in early-stage clinical trials are geldanamycin and tenespimycin (17-AAG; Kosan Biosciences, Hayword, CA). Reports of a trial of tenespimycin combined with trastuzumab in advanced pretreated MBC have shown good safety and tolerability [359] and early indications of significant clinical activity in HER-2-positive disease [360].…”

Section: Trastuzumab Plus Heat Shock Protein 90 Inhibitorsmentioning

confidence: 99%

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

et al. 2009

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1. Contrast the current strengths and limitations of the three main slide-based techniques (IHC, FISH, and CISH) currently in clinical use for testing breast cancer tissues for HER-2 status.2. Compare the efficacy of trastuzumab-and lapatinib-based regimens in the adjuvant and metastatic settings as reported in published clinical trials and regulatory approval databases.3. Contrast the list of biomarkers that have been associated with clinical resistance to trastuzumab and lapatinib and describe their current level of validation.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTThe human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ

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“…The most advanced class of HSP90 inhibitors, including tanespimycin and other 17-AAG derivatives, are now in phase II/phase III clinical trials for solid and hematologic malignancies. A combination of tanespimycin and trastuzumab has shown encouraging results in a phase II trial for trastuzumab refractory breast cancer (16). However, significant clinical limitations of these 17-AAG derivatives have been reported, including poor solubility, potential liver toxicity, substrate for the P-glycoprotein multidrug resistance efflux pump, quinine reductase NQO1 dependence, and limited oral bioavailability (17)(18)(19).…”

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confidence: 99%

CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

Bao

Lai

Qü

et al. 2009

Clinical Cancer Research

103

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Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types. Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.Results: CUDC-305 shows high affinity for HSP90α/β (IC 50 , ∼100 nmol/L) and HSP90 complex derived from cancer cells (IC 50 , 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC 50 , 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross bloodbrain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dosedependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.

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Phase II trial of the Hsp90 inhibitor tanespimycin (Tan) + trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC)

Cited by 51 publications

References 0 publications

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

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