Monoclonal antibody to Her-2 in breast cancer

Francisco J. Esteva, Gabriel N. Hortobagyi

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

This chapter discusses the preclinical and clinical development of trastuzumab as targeted therapy for HER-2 over-expressing breast cancer receptor. HER-2 activates multiple cellular signaling pathways, including the phos-phatidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase cascades. Trastuzumab reduces signaling in these pathways and thus promotes cell-cycle arrest and apoptosis. The cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle, with a concomitant reduction in cell proliferation and reduced expression of proteins involved in sequestering p27 kip1 , including cyclin D1. This results in the release of p27 kip1, allowing it to bind and inhibit cyclin E-cdk2 complexes. The in vitro studies have shown that trastuzumab is synergistic with a variety of chemotherapeutic agents. Single-agent trastuzumab can dramatically reduce tumor size in patients with HER-2 over-expressing metastatic breast cancer. This clinical response is explained by the agent's induction of apoptosis. It is found that response rates to trastuzumab given as a single agent have ranged from 12% to 34%, depending in part on the method used to determine HER-2 status and the prior treatments received by the patients.

Original languageEnglish (US)
Title of host publicationTarget Validation in Drug Discovery
PublisherElsevier Inc.
Pages69-81
Number of pages13
ISBN (Print)9780123693938
DOIs
StatePublished - 2007

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

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