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Herceptin
- 1. HERCEPTIN Presented by: Shubhda Roy Sh
- 2. Interesting Facts about Breast Cancer • Does lump in the breast imply Breast Cancer (BC) ? • Is Pain a common symptom for BC ? • Is BC main cause of cancer death in US ? • Where is the highest concentration of BC in US ? • Where is lowest incidence of Breast Cancer in US ? http://www.rxlist.com/quiz_breast_cancer/quiz.htm
- 3. Gene amplification and/or overexpression of HER2 Gene • Amplified HER2 gene J Pathol 2001; 195: 422–428.Slides from Molecular Target lecture Chromosome 17 • Normal HER2 gene • 2 copies
- 4. What is HER2+ breast cancer cells • Amplification of HER 2 Gene increase Her 2 Protein • More HER2 receptors on surface of breast cells. o Human Epidermal growth factor receptor 2 positive • More cancer cells grow & divide faster • More HER2 cancer cells are formed • HER2+ breast cancer cells are considered aggressive https://www.youtube.com/watch?v=nXtKboH2S38
- 5. About Herceptin • First therapeutic antibody to receive FDA approval o targeted at a cancer-related molecular marker • Chemical name: trastuzumab • Regular Name: Herceptin, based on human epidermal growth receptor or HER 2 • Treatment after surgery for HER2-positive breast cancer • Improved 5-year disease free survival of stage 1–3 HER2- positive breast cancers to about 87% o (overall survival 95%) http://www.herceptin.com/breast/herceptin;jsessionid=AD4E35010F5B2708B847206379507D8E.gxe501c-m1
- 6. 2 Lines Treatment • First line: o In combination with chemotherapy drugs • Adriamycin, Cytoxan and Taxotere "AC→TH." • Taxotere and carboplatin”TCH.“ • Second line: o Alone after treatment with multiple other therapies for metastatic cancer
- 8. Slides from Molecular Target lecture
- 9. Resistance to Herceptin • Upregulation of the PI3K pathway • Increased signaling from HER family receptors & IGF-1R • Accumulation of p95-HER2
- 10. Adverse reactions • Cardiac issues • Fever • Nausea • Vomiting • Infusion reactions • Diarrhea • Infections increased cough, • Headache • Fatigue • shortness of breath • Rash • low white and red blood cells • muscle pain.
- 11. Lipinski Rules Molecular Mass : 145531.5 g/mol This is a mono clonal antibody. Lipinski rules do not apply C6470H10012N1726O2013S42
- 12. Developmental Times http://www.gene.com/media/product-information/herceptin-development-timeline 1979 - Cancer Researcher Robert Weinberg identified gene HER-2 1984 - Genentech Scientist Alex Ullirich - Protein produced HER2 Protein from gene 1986 - Dumb luck - Met Dennis Slamon in Denver airport. Oncologist, cancer researcher 1987- Published paper together, overexpression HER-2 cause cancer. Reached to out Genentech, who had abandoned cancer research. Staff disbanded. 1989 – Mother of a Genentech's VP's got breast cancer. He convinced HER-2 was worth investing. 1989 - Michael Shepard, Axel Ullrich and their teams at Genentech developed mouse 4D5, the parent of Herceptin, 1990 - Len Presta, Paul Carter and Michael Shepard of Genentech create Herceptin by humanizing the 4D5 mouse antibody directed at HER2 1992 – IND filed 1997 - Phase III trials completed 1998 - Genentech submitted BLA for Herceptin. DAKO submitted PMA for Diagnostic Hercep test. July 1998 - Genentech signed a deal with Roche September- 1998 - FDA approval October 2008 - More than 430,000 women with HER2 + have been treated world wide October 2010 - FDA Approval of Herceptinin use HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma
- 13. Competitors• Lapatinib (Tykerb, GSK) – ATP Inhibitor • Neratinib – Irreversible – ATP Inhibitor • Pertuzumab (Perjeta) - binds to a different epitope of HER2 than trastuzumab • HSP90- (Tanespimycin)Heat shock protein 90 (HSP90) is a molecular chaperone • PI3K pathway inhibitors • TDM-1 - antibody–drug conjugate to deliver cytotoxic therapy to antigen-expressing tumors http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092522
- 14. Referecnes • http://www.gene.com/media/product-information/herceptin-development- timeline • http://www.breastcancer.org/treatment/targeted_therapies/herceptin • http://livertox.nlm.nih.gov/Trastuzumab.htm#structure • http://chem.sis.nlm.nih.gov/chemidplus/rn/180288-69-1 • https://en.wikipedia.org/wiki/Trastuzumab • http://www.gene.com/media/product-information/herceptin-breast • http://www.herceptin.com/breast/herceptin;jsessionid=97BDBFF77449057A 2C76288C4E9CD90D.gxe501c-m1 • /
Editor's Notes
- Scarring or cysts Invasive ductal carcinoma (IDC)
- Diverse mechanisms by which Herceptin mediates its effects on cell survival and proliferation
- Lapatinib is a dual EGF receptor (EGFR)/HER2 tyrosine kinase inhibitor approved for use in trastuzumab-refractory patients. Neratinib is an irreversible tyrosine kinase inhibitor of EGFR/HER2. (B) Pertuzumab, a monoclonal antibody to HER2, binds to HER2 at a distinct epitope from where trastuzumab binds and prevents ligand-induced heterodimerization with HER3. Dysregulated activation of the PI3K–AKT–mTOR pathway can mediate trastuzumab resistance, and molecular therapies aimed at directly inhibiting PI3K, AKT and mTOR are therefore in development. (C) HSP90 inhibitors promote HER2 degradation by blocking the activity of HSP90, a chaperone protein that protects HER2 from proteasomal degradation. (D) TDM-1, the antibody–drug conjugate of trastuzumab and maytansine, allows for delivery of a potent microtubule inhibitor selectively into HER2-overexpressing cells.
- HER2–HER3–PI3K–AKT–mTOR signaling Drug dosage For use in the treatment of metastatic breast cancer: Administer trastuzumab, alone or in combination with paclitaxel. Initial dose: 4 mg/kg IV infusion over 90 minutes Subsequent therapy: 2 mg/kg IV infusion over 30 minutes once weekly until disease progression US$70,000 for