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
ABSTRACT HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.
We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).
This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.
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ABSTRACT: ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full potential as an anti-cancer agent. Copyright © 2015. Published by Elsevier B.V.Journal of Controlled Release 02/2015; 208. DOI:10.1016/j.jconrel.2015.02.001 · 7.26 Impact Factor
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ABSTRACT: The enzyme Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin (Ig) genes, which are critically important for an effective immune response. In addition, AID seems to contribute to B cell tolerance in mice and humans by, in some still undefined way, eliminating developing autoreactive B cells. As a trade-off for the benefits brought about by its physiological roles, AID can also contribute to cellular transformation and tumor progression through its mutagenic activity. AID deaminates deoxycytidines at the Ig genes thereby generating deoxyuridine, which as part of the normal mechanism of SHM and CSR is processed by DNA repair enzymes into a larger spectrum of point mutations and also DNA double-strand breaks. Multiple mechanisms regulate AID function to minimize deleterious or pathogenic DNA damage during antibody gene diversification. Despite this, off-target AID activity still makes point mutations and initiates chromosomal translocations that affect tumor suppressor and proto-oncogenes associated with B-cell lymphoid neoplasms. Through this collateral damage, AID is etiological for the development of lymphoma in several mouse models and is expressed in many human malignancies of mature B-cell origin where it may contribute to tumor clonal evolution. Mounting evidences indicate a role for AID also in disease progression and worsening of the prognosis of Chronic Lymphocytic Leukemia (CLL) and Chronic Myelogenous Leukemia (CML). Since these leukemia are not immediately derived from germinal center B cells, normal AID regulation might not be fully functional in those cases. This review discusses recent findings on the role of AID in lymphomagenesis. We describe the multilevel regulation of AID expression and function in normal compared to tumor B cells, specially focusing on the emerging role of AID in CLL and CML.Current Immunology Reviews 11/2013; 9(2):75-85. DOI:10.2174/15733955113099990007
- Cancer Prevention - From Mechanisms to Translational Benefits, 04/2012; , ISBN: 978-953-51-0547-3