Herceptin Research Today is a free monthly online journal that collates and summarizes the latest research about Herceptin, including details on side-effects, breast cancer, treatment, therapy.

Adjuvant effect of HER-2/neu-specific adenoviral vector stimulating CD8(+) T and natural killer cell responses on anti-HER-2/neu antibody therapy for well-established breast tumors in HER-2/neu transgenic mice.

Chen Y, Xie Y, Chan T, Sami A, Ahmed S, Liu Q, Xiang J

Cancer Research Unit, Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada.

Approximately one third of patients with advanced human epidermal growth factor receptor 2 (HER-2)/neu-positive breast cancer respond to trastuzumab monotherapy, a humanized anti-HER-2/neu antibody. However, de novo and acquired antibody resistance is one of the major limitations of trastuzumab therapy warranting the search for other therapeutic strategies. One of the most remarkable features of adenovirus (AdV)-based vaccine is its ability to induce exceptionally high and sustained frequencies of transgene product-specific CD8(+) T-cell responses. In this study, we constructed two recombinant AdVs (AdV(OVA) and AdV(HER-2)) expressing ovalbumin (OVA) and HER-2/neu, and assessed AdV-induced antigen-specific cellular immune responses and preventive/therapeutic antitumor immunity. We demonstrate that AdV(OVA) stimulates efficient OVA-specific CD8(+) cytotoxic T lymphocyte (CTL) and natural killer responses, leading to preventive long-term immunity against OVA-expressing BL6-10ova melanoma in wild-type C56BL/6 mice. We further demonstrate that AdV(HER-2) stimulates HER-2/neu-specific CD8(+) CTL responses, leading to a significant reduction in breast carcinogenesis in transgenic FVBneuN mice (P<0.05), but has little therapeutic effect on pre-existing Tg1-1 tumor even at early stage (15 mm(3)). In contrast, the anti-HER-2/neu antibody therapy is capable of completely inhibiting Tg1-1 tumor growth at early stage, but fails to eradicate well-established Tg1-1 breast tumor (100 mm(3)). Interestingly, a combinatorial immunotherapy of anti-HER-2/neu antibody with AdV(HER-2) vaccine was capable of curing 4 of 10 studied mice bearing well-established Tg1-1 breast tumors and significantly delaying in death of the remaining six tumor-bearing mice (P<0.05). Taken together, our results suggest an adjuvant effect of AdV(HER-2) on anti-HER-2/neu antibody therapy for well-established breast tumor in transgenic FVBneuN mice, and this combinatorial immunotherapy of trastuzumab with AdV(HER-2) vaccine may be used as a new therapeutic strategy for treatment of advanced HER-2/neu-positive breast cancer.Cancer Gene Therapy advance online publication, 13 May 2011; doi:10.1038/cgt.2011.18.

Published 13 May 2011 in Cancer Gene Ther.
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Articles on Herceptin published 11 May 2011:

A novel fully human antitumour immunoRNase targeting ErbB2-positive tumours.   Br J Cancer.

Background:ErbB2 is an attractive target for immunotherapy, as it is a tyrosine kinase receptor overexpressed on tumour cells of different origin, with a key role in the development of malignancy. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment.Methods:A novel human immunoRNase, called anti-ErbB2 human compact antibody-RNase (Erb-hcAb-RNase), made ... [Abstract] [Full-text]

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.   Clin Cancer Res.

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 ... [Abstract] [Full-text]

The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic PIK3CA Mutations.   Clin Cancer Res.

PURPOSE: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in ... [Abstract] [Full-text]

Troponin I and C-Reactive Protein Are Commonly Detected in Patients with Breast Cancer Treated with Dose-Dense Chemotherapy Incorporating Trastuzumab and Lapatinib.   Clin Cancer Res.

PURPOSE: There are no validated methods of early detection of cardiotoxicity from trastuzumab (T) following anthracycline-based chemotherapy. Currently changes in left ventricular ejection fraction (LVEF) are assessed but this approach has limited sensitivity and specificity. Within a prospective feasibility study of dose-dense (dd) doxorubicin and cyclophosphamide (AC) → weekly paclitaxel (P) with T and lapatinib (L), we included a preplanned analysis of correlative cardiac Troponin I (cTnI) ... [Abstract] [Full-text]

Articles on Herceptin published 10 May 2011:

Time to first tumor progression as a predictor of efficacy of continued treatment with trastuzumab beyond progression in human epidermal growth factor receptor 2-positive metastatic breast cancer.   Int J Clin Oncol.

BACKGROUND: Trastuzumab demonstrates significant clinical benefits in HER2-positive metastatic breast cancer (MBC), and recent clinical trials suggest that trastuzumab should be continued in combination with other chemotherapy beyond progression. There is an urgent need to assess if patients could substantially benefit from continuing trastuzumab-based therapy. METHODS: We reviewed 91 patients with HER2-positive MBC treated with trastuzumab and investigated correlations between survival and ... [Abstract] [Full-text]

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer.   Mol Cancer Ther, 10(5): 817-24.

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 ... [Abstract] [Full-text]

Articles on Herceptin published 9 May 2011:

Enhanced antiproliferative activity of Herceptin (HER2)-conjugated gemcitabine-loaded chitosan nanoparticle in pancreatic cancer therapy.   Nanomedicine.

Currently, effective drug delivery in pancreatic cancer treatment is a major challenge. Nanomedicine plays an essential role by delivering anticancer drugs in a targeted manner to the malignant tumor cells, leading to increased efficacy by reducing the toxicity of anticancer drugs to normal, sensitive sites. This study aimed for the preparation and characterization of a targeted system represented by Herceptin-conjugated gemcitabine-loaded chitosan nanoparticles (HER2-Gem-CS-NPs) for pancreatic ... [Abstract] [Full-text]

HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer.   Cancer Treat Rev.

The transmembrane protein HER2 is over-expressed in approximately 15% of invasive breast cancers as a result of HER2 gene amplification. HER2 proteolytic cleavage (HER2 shedding) generates soluble truncated HER2 molecules that include only the extracellular domain and the concentration of which can be measured in the serum fraction of blood. HER2 shedding also generates a constitutively active truncated intracellular receptor of 95kDa (p95(HER2)). Another soluble truncated HER2 protein ... [Abstract] [Full-text]

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