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Trastuzumab
- 1. Jacob Broome jbroome2@Tulane.edu Development and Clinical Use of Trastuzumab
- 2. Trastuzumab • Monoclonal Antibody used in cancer treatment • Targets the Human Epidermal Growth Factor Receptor 2 (HER2) • Two routes of Administration Jones F. Lecture 19 2017 Slamon D, Shak S, Fuchs H, N Engl J Med 2001
- 3. HER2 • Receptor Tyrosine Kinase (RTK) • Dimerization • Most potent oncogene • Overexpressed in 30% of tumors Hudis C. N Engl J Med 2007
- 4. HER2 Activation and Overexpression • Ras Activation • Cell Proliferation • PI3K • Cell Cycle Progression • Cell Survival • Src Activation • Survival Lin N, Winer E. Clinical Cancer Research 2007
- 5. Trastuzumab Clinical Use • Binds to HER2 cell surface receptor • Activates antibody dependent cellular cytotoxicity • Disengages both PI3K and MAPK signaling Gemmete J., Mukherji S., American Journal of Neuroradiology 2011
- 6. Resistance • 40-80% of patients relapse after 1 year • Activation of mTOR • elF-4E serves as a biomarker Majewski IJ., Bernards R., Nature Med 2011
- 7. Cardiotoxicity Sandoo A., Kitas G., Carmichael A., Int J of Cancer Research and Treatment 2014
- 8. • Jones F. Molecular Biology of Cancer lectures 3, 4, 16. Tulane University. 2017 • Sloman D, Shak S, Fuchs H. Use of Chemotherapy Plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer that Overexpress HER2. New England Journal of Medicine. 2001; 344: 783-792 • Hudis CA. Trastuzumab – mechanism of action and use in clinical practice. New England Journal of Medicine. 2007; 357(1): 39-51 • Lin NU, Winer EP. Brain Metastases: The HER2 Paradigm. Clinical Cancer Research. 2007; 13(6) • Gemmete JJ, Mukherji SK. Trastuzumab (Herceptin). American Journal of Neuroradiology. 2011; 32(8): 1373-1374 • Majewski IJ, Bernards R. Taming the dragon. Genomic biomarkers to individualize the treatment of cancer. Nat Med. 2011;17:304–312 • Sandoo A, Kitas G, Carmichael A. Endothelial Dysfunction as a Determinant of Trastuzumab-mediated Cardiotoxicity in Patients with Breast Cancer. Anticancer Research. 2014; 34:1147-1152
Editor's Notes
- History Dr. Ullrich and Dr. Shepard at UCLA’s Jonsson Comprehensive Cancer Center Genentech with UCLA began trials in 1992 with 15, by 1996 expanded to over 900 Fast-tracked by FDA and gained approval in 1998 Tyrosine kinase inhibitor MAB – humanized from mouse cells Routes of Admin: intravenously or subcutaneously Administered with our without additional chemotherapy Cost - $70,000
- Dimerisation results in phosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways
- Mutations in RTKs (especially HER2) leads to activation of a series of signaling cascades which have numerous effects on protein expressions.
- Trastuzumab consists of two antigen-specific sites that bind to the juxtamembrane portion of the extraceullar domain of the HER2 receptor. Prevents the activation of intracellular tyrosine kinase. Dimerization prevention Increased endocytotic destruction of receptor, Immune activation ADCC mediated by CD56+ natural killer cells immune response
- Mammalian target of rapamycin (mTOR) Mutations result in activation of AKT and thus mTOR and commonly observed in trastuzumab resistant cells. as a result of inactivation of PTEN Phosphorylated activation of mTOR target elF-4E – phosphorylated protein that enhances translation