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Herceptin

Trastuzumab (Herceptin®) is an anti-cancer therapy that acts on the HER2/neu (erbB2) receptor. "Receptors" are usually protein molecules on the surface of a cell which allow the cell to respond to hormones and other signals from other cells. Herceptin's principal use is in breast cancer in patients whose tumors overexpress (produce more than the usual amount of) this receptor. Trastuzumab is administered either once a week or once every three weeks intravenously for 30 to 90 minutes. more...

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Mechanism of action

Amplification of ErbB2 occurs in 30% of early-stage breast cancers (Bange et al 2001). It encodes the transmembrane tyrosine kinase p185-erbB2 glycoprotein. Although the signaling pathways induced by the erbB2 receptor are incompletely characterized, it is thought that activation of the PI3K/Akt pathway is important. This pathway is normally associated with mitogenic signaling involving the MAPK pathway. In cancer growth producing signals from erbB2 are constitutively transmitted, promoting invasion, survival and angiogenesis of cells (Ménard et al 2003). Furthermore overexpression can also confer therapeutic resistance to cancer therapies. Kute et al. (2004) suggest that the prime mechanism that causes increase in proliferation speed is due to induction of p27Kip1, an inhibitor of cdk2 and of cell proliferation, to remain in the cytoplasm instead of translocation in to the nucleus. This is caused by phosphorylation by Akt.

Herceptin is a monoclonal antibody which binds to its extracellular segment of the erbB2 receptor. Cells treated with Herceptin undergo arrest during the G1 phase of the cell cycle and experience a reduction in proliferation. It has been suggested that Herceptin induces some of its effect by downregulation of erbB2 leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, causing cell cycle arrest (Kute et al 2004). Also, Herceptin suppresses angiogenesis by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of erbB2 that results in the release of the extracellular domain. Herceptin has been shown to inhibit erbB2 ectodomain cleavage in breast cancer cells (Albenall et al 2003). There may be other undiscovered mechanisms by which Herceptin induces regression in cancer.

Impact

Herceptin has had a "major impact in the treatment of HER2-positive metastatic breast cancer" (Tan and Swain 2002). In combination with chemotherapy Herceptin has been shown to increase both survival and response rate in comparison to Herceptin alone (Nahta and Esteva 2003). It is possible to determine the 'erbB2 status' of a tumour, which can be used to predict efficacy of treatment with Herceptin. If it is determined that a tumour is overexpressing the erbB2 oncogene then a patient is eligible for treatment with Herceptin (Yu and Hung 2000). It is surprising that although erbB2 has great affinity for the receptor and the fact that such a high dose can be administered (due to its low toxicity) 70% of patients do not respond to treatment. In fact resistance is developed rapidly on treatment of virtually all patients. It is suggested that a mechanism of resistance is the lack p27Kip1 translocation to the nucleus in some strains, enabling cdk2 to induce cell proliferation (Kute et al., 2004).

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Speaking of people
From Ebony, 12/1/05

James D. White SAFEWAY'S SENIOR VICE PRESIDENT, CORPORATE BRANDS

James D. White is senior vice president of corporate brands for Safeway, one of the largest food and drug retailers in North America based on sales. Safeway operates 1,801 stores in the U.S. and Canada, recording annual sales of $35.8 billion in 2004. White oversees the company's entire corporate brands organization, including its marketing, manufacturing, finance and outside sales functions. Before joining Safeway, he worked at the Gillette Company, where he spent three years as senior vice president for business development for the company's North America operations. Prior to that, he spent 15 years at Nestle Purina Petcare in executive positions, and began his career at Coca-Cola, where he held various marketing and sales development positions in the mid-1980s. White received a bachelor's degree in marketing from the University of Missouri and a MBA from Fontbonne College. He is a member of the National Black MBA Association, Alpha Phi Alpha fraternity and currently serves on the board of Keane Inc., an information technology and business process company in Boston. He and his wife, Lisa, have two daughters, Krista and Jasmine.

Shirley Bridges CHIEF OPERATING OFFICER, DELTA TECHNOLOGY

Shirley Bridges is the chief operating officer and acting chief information officer at Delta Air Lines. She is responsible for managing the day-to-day operations of Delta Technology, Delta's wholly-owned subsidiary, including managing field operations, supervising the engineering department, running the project management office and producing the corporate report card. She leads a team of 2,000 technical resource workers, manages a $280 million operating budget and a $165 million capital spending plan. Prior to her new roles, Bridges served as vice president of airline operations system. Additionally, she was responsible for maintaining the technology systems that support pilot and flight attendant scheduling and communications, and monitoring corporate compliance and safety reporting systems. Before Delta, she held positions with Bridgehaus, Inc. and Norfolk Southern Railroad. She received a bachelor's degree in mathematics from Clark Atlanta University and a master's in project management from George Washington University. She resides in Jonesboro, Ga.

Dr. Ted W. Love CHAIRMAN OF THE BOARD AT NUVELO, INC.

Dr. Ted Love is chairman of the board at Nuvelo Inc., where he also serves as president and chief executive officer. Nuvelo is a San Francisco Bay area-based company that works to discover, develop and commercialize drugs for cardiovascular and cancer therapy. Dr. Love joined Nuvelo from Theravance Inc., where he worked as senior vice president of development. Previously, Dr. Love spent six years at Genentech Inc., holding a number of senior management positions in medical affairs and product development. At Genentech, Dr. Love was responsible for all drugs in development, including Herceptin and TNKase, and he was chairman of Genentech's product development committee. He earned a bachelor's degree in molecular biology from Haverford College and a medical degree from Yale Medical School. He completed his residency and fellowship training in internal medicine and cardiology at Massachusetts Generel Hospital and Harvard Medical School. Following his residency, Dr. Love joined the faculty of Massachusetts General in the department of cardiology. He serves on the California Independent Oversight Commission, which oversees the $3 billion allocation dedicated to stem cell research. Dr. Love is married with three children and lives in the San Francisco Bay area.

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