Trastuzumab

Trastuzumab (Herceptin®) is an anti-cancer therapy that acts on the erbB2 receptor. Its principal use is in breast cancer. Patients in whom the cancer is found to express this receptor, trastuzumab is administered once a week intravenously for 30 to 60 minutes.

Contents

1 Mechanism of action 2 Impact 3 History 4 References 5 Further reading

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., 2000).

History

The biotech company Genentech gained FDA approval for Trastuzumab in September 1998. The drug was jointly developed by that company, where the antibody was first discovered by scientists that included Dr Axel Ullrich, and the Jonsson Cancer Center at UCLA, where Dr Dennis Slamon subsequently worked further on trastuzumab's development.

In the clinical trials leading up to trastuzumab's approval 42% of percent taking Herceptin in combination with the chemotherapy drug paclitaxel had significance responses. The comparable rate for the taxane alone was only 16%.

References

• Albanell J, Codony J, Rovira A, Mellado B, Gascon P. (2003). Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv Exp Med Biol, 532:253-268
• Bange J, Zwick E, Ullrich A. (2001). Molecular targets for breast cancer therapy and prevention. Nature Medicine, 7:548-552
• Kute T, Lack CM, Willingham M, Bishwokama B, Williams H, Barrett K, Mitchell T, Vaughn JP. (2004). Development of Herceptin resistance in breast cancer cells. Cytometry, 57A:86-93
• Ménard S, Pupa SM, Campiglio M, Tagliabue E. (2003). Biologic and therapeutic role of HER2 in cancer. Oncogene, 22:6570-6578
• Nahta R, Esteva1 FJ. (2003). HER-2-Targeted Therapy – Lessons Learned and Future Directions. Clinical Cancer Research, 9:5078-5048
• Tan AR, Swain SM. (2002). Ongoing adjuvant trials with trastuzumab in breast cancer. Semin Oncol. 30:(5 Suppl 16)54-64
• Yu D, Hung M. (2000). Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene, 19:6115-6121

Further reading

• Bazell, Robert. Her-2: the making of Herceptin, a revolutionary treatment for breast cancer. Random House, 1998. 214 pages. ISBN 067945702X.fr:Trastuzumab