Biomarkers that predict sensitivity to heat shock protein 90 inhibitors (HSP90i).

10618 Background: HSP90 is an attractive target in tumors as it mediates the maturation and stabilization of client oncoproteins. HSP90i are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset to date. Predictive biomarkers could identify patients (pts) and/or tumors with sensitivity to HSP90i improving the therapeutic index. We explored potential biomarkers across multiple studies of HSP90i. Methods: Archived pre-treatment tumor specimens from pts treated with any of several HSP90i (17-AAG, 17-DMAG, CNF2024, retaspimycin & ganetespib) on 8 phase I/II trials at MSKCC from 1999 to 2011 were identified. The following antibodies were validated at MSKCC and tumor tissue was tested by immunohistochemistry (IHC) with results defined for each as: ER, PR & AR: >1% pos & <1% neg; HSP90 & HSP70: 0, 1+ neg & 2+, 3+ pos; PTEN: 0, 1+ neg & 2+ pos; HER2: 0, 1+ neg, 2+ equivocal, 3+ pos; EGFR: 0 neg & 1+, 2+, 3+ pos. Clinical response was correlated with IHC using Fishe...

[1]  G. Chiosis,et al.  Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions , 2014, Expert opinion on investigational drugs.

[2]  C. Hudis,et al.  A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer , 2013, Breast Cancer Research and Treatment.

[3]  C. Hudis,et al.  A Phase I Dose-Escalation Trial of Trastuzumab and Alvespimycin Hydrochloride (KOS-1022; 17 DMAG) in the Treatment of Advanced Solid Tumors , 2012, Clinical Cancer Research.

[4]  K. Jhaveri,et al.  HSP90 inhibitors for cancer therapy and overcoming drug resistance. , 2012, Advances in pharmacology.

[5]  G. Giaccone,et al.  A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas , 2011, Clinical Cancer Research.

[6]  Alison Stopeck,et al.  HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab , 2011, Clinical Cancer Research.

[7]  S. Chandarlapaty,et al.  Protocol for PTEN Expression by Immunohistochemistry in Formalin-fixed Paraffin-embedded Human Breast Carcinoma , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[8]  J. Baselga,et al.  Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Jill L. Johnson,et al.  Hsp90 and co-chaperones twist the functions of diverse client proteins. , 2010, Biopolymers.

[10]  S. Chandarlapaty,et al.  Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth , 2009, Oncogene.

[11]  G. Giaccone,et al.  Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. , 2010, European journal of cancer.

[12]  Sarat Chandarlapaty,et al.  SNX2112, a Synthetic Heat Shock Protein 90 Inhibitor, Has Potent Antitumor Activity against HER Kinase–Dependent Cancers , 2008, Clinical Cancer Research.

[13]  C. Hudis,et al.  Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  G. Mills,et al.  A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. , 2007, Cancer cell.

[15]  Yuval Kluger,et al.  High HSP90 expression is associated with decreased survival in breast cancer. , 2007, Cancer research.

[16]  S. Larson,et al.  Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer , 2007, Clinical Cancer Research.

[17]  R. Nahta,et al.  HER2 therapy: Molecular mechanisms of trastuzumab resistance , 2006, Breast Cancer Research.

[18]  Neal Rosen,et al.  Hsp90: a novel target for cancer therapy. , 2006, Current topics in medicinal chemistry.

[19]  S. Lindquist,et al.  HSP90 and the chaperoning of cancer , 2005, Nature Reviews Cancer.

[20]  P. Workman,et al.  Pharmacokinetic-Pharmacodynamic Relationships for the Heat Shock Protein 90 Molecular Chaperone Inhibitor 17-Allylamino , 17-Demethoxygeldanamycin in Human Ovarian Cancer , 2005 .

[21]  David Cameron,et al.  Identification of molecular apocrine breast tumours by microarray analysis , 2005, Oncogene.

[22]  S. Lakhani,et al.  Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  D. Rimm,et al.  Automated subcellular localization and quantification of protein expression in tissue microarrays , 2002, Nature Medicine.

[24]  N. Rosen,et al.  Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function* , 2002, The Journal of Biological Chemistry.

[25]  N. Rosen,et al.  Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. , 2002, Cancer research.

[26]  N. Rosen,et al.  Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2 , 2002, Oncogene.

[27]  T. H. van der Kwast,et al.  The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters. , 1996, European journal of cancer.