J Clin Oncol. 2009 Nov 2. [Epub ahead of print]
Understanding the Mechanisms Behind Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.
Spector NL,
Blackwell KL.
Duke Translational Research Oncology Program, Duke University Hospital, Department of Medicine, Division of Medical Oncology; and Department of Medicine/Medical Oncology, Duke University Medical Center, Durham, NC.
PURPOSE: Targeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) -positive breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clinical benefit also is discussed. METHODS: An extensive literature review of trastuzumab and proposed mechanisms of action was performed. RESULTS: At least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclinical setting. These include
activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, reduction of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clinical benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated.
The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway.
Targeting both HER2, with various approaches, and other pathways may enhance the clinical benefit observed with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1). CONCLUSION: Trastuzumab is the foundation of care for patients with HER2-positive BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clinical benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.
PMID: 19884552 [PubMed - as supplied by publisher]
Cancer Res. 2009 Nov 3. [Epub ahead of print]
{beta}1-Integrin Circumvents the Antiproliferative Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer.
Lesniak D,
Xu Y,
Deschenes J,
Lai R,
Thoms J,
Murray D,
Gosh S,
Mackey JR,
Sabri S,
Abdulkarim B.
Departments of Experimental Oncology, Laboratory Medicine and Pathology, Radiation Oncology, Statistics and Epidemiology, and Medical Oncology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada.
Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2-positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. beta(1)-Integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of beta(1)-integrin expression in HER-2-positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of beta(1)-integrin is an independent negative prognostic factor for tumor progression of HER-2-positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of beta(1)-integrin, its small interfering RNA-induced knockdown or treatment with a beta(1)-integrin-blocking antibody in HER-2-positive breast cancer cells, identified a strong inverse relationship between expression level of beta(1)-integrin and in vitro sensitivity to trastuzumab. Notably, beta(1)-integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that beta(1)-integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2-positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab. [Cancer Res 2009;69(22):8620-8].
NOTE:
tanespimycin (below) development appears to have been dropped due to expiring patent.
http://www.myelomabeacon.com/news/20...opment-halted/
Maybe other HSP90 inhibs will make it
Clin Cancer Res. 2011 May 10. [Epub ahead of print]
HSP90 Inhibition is Effective in Breast Cancer: A Phase 2 Trial of Tanespimycin (17AAG) plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab.
Modi S,
Stopeck AT,
Linden HM,
Solit DB,
Chandarlapaty S,
Rosen N,
D'Andrea G,
Dickler MN,
Moynahan ME,
Sugarman S,
Ma W,
Patil S,
Norton L,
Hannah AL,
Hudis C.
LINK
Source
Medicine, Memorial Sloan-Kettering Cancer Center.
Abstract
PURPOSE:
Hsp90 is a chaperone protein required for the stability of a variety of client proteins.
17-AAG is a natural product that binds to Hsp90 and inhibits its activity, thereby inducing the degradation of these clients. In pre-clinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. Based on these data and activity in a phase 1 study, we conducted a phase 2 study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2 positive breast cancer.
EXPERIMENTAL DESIGN:
We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab.
All patients received weekly treatment with tanespimycin at 450mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by RECIST criteria.
RESULTS:
Thirty-one patients were enrolled with a median age of 53 years and a median 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 (CR + PR + SD) 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).
CONCLUSIONS:
This is the first phase 2 study to definitively show RECIST-defined responses for 17-AAG in solid tumors.
Tanespimycin plus trastuzumab has significant anti-cancer 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.
- PMID:
- 21558407
- [PubMed - as supplied by publisher]
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