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Targeted Therapy: A Giant Step Forward
Ian Krop, MD-PhD Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School May 2009 C and J asked me to talk about an exciting topics in breast cancer, the new drugs that being developed to help conquer this disease. When we saySubtypes HER2 Herceptin Lapatinib, HKI272 Pertuzumab HSP90 TDM1 TN Cisplatinum PARP inhibitors EGFR inhibitors ER AI IGF1R Bone
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“Targeted” therapy Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent Offer the promise of reduced side effects compared to less targeted drugs
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Breast cancer is family of different cancers
Triple Negative HER2+ Estrogen receptor + GENES There are two basic ways to analyze genomic data, unsupervised and supervised. In both, data is displayed in a heat map, in which expression of individual genes is displayed with red corresponding to high relative expression of a given gene and green low expression. In unsupervised analysis as was used in the perou study we ask the computer to group together samples based on similar patterns of gene expression, such as shown here with the now familiar basal, her2 and luminal subsets TUMORS 3
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Percentage of women WITHOUT recurrence
Kaplan Meier plots allow comparison of clinical outcome over time 100- Percentage of women WITHOUT recurrence Time
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Breast cancer is family of different cancers
Triple Negative HER2+ Estrogen receptor + Percentage of women WITHOUT recurrence GENES There are two basic ways to analyze genomic data, unsupervised and supervised. In both, data is displayed in a heat map, in which expression of individual genes is displayed with red corresponding to high relative expression of a given gene and green low expression. In unsupervised analysis as was used in the perou study we ask the computer to group together samples based on similar patterns of gene expression, such as shown here with the now familiar basal, her2 and luminal subsets TUMORS 5
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Breast Cancer in the U.S. 20% = 36,000 cases HER 2 + Disease
All Breast Cancer 180,000 + cases 20% = 36,000 cases HER 2 + Disease
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Amplification of the HER2 gene observed in a subset of breast cancers
FISH - FISH +
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HER2 amplification impacts prognosis
% without recurrence Time (months)
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HER2 is a cell surface signaling protein
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HER2 is a cell surface signaling protein
<10,000 HER2 proteins on normal breast cell
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HER2 gene amplification results in marked overexpression of HER2 proteins
2,000,000 HER2 proteins on cancer cell
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Herceptin (trastuzumab) is a recombinant antibody that specifically binds to the HER2 protein
HER2 binding domain
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By attaching to HER2, Herceptin prevents HER2 proteins from binding to each other, leading to inhibition of signaling
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Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer
Slamon, et al. NEJM 2001 (data originally presented 1998)
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U.S. Adjuvant Herceptin Trials (May, 2005)
Chemo+herceptin 85% ACT % Chemo alone 67% Romond, Perez et al, NEJM 2005 Years From Randomization B31/N9831
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Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer
Slamon, et al. NEJM 2001 (data originally presented 1998)
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Overcoming Herceptin resistance
From Hanahan and Weinberg, 2000 17
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HER2 is a kinase, a protein that adds phosphate to other proteins
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Lapatinib is an oral inhibitor of the HER2 kinase
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Clinical trial of lapatinib for women with HER2+ metastatic breast cancer that had progressed on Herceptin Lapatinib + Capecitabine Capecitabine alone R A N D O M I Z E
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Lapatinib improves outcome in patients with metastatic HER2+ breast cancer
Geyer CE et al. N Engl J Med 2006;355:
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HER2 Kinase inhibitors Additional inhibitors in development
Results of first study confirm role for HER2 targeted therapy after progression on Herceptin Is it better than Herceptin? Can it add to benefit of Herceptin Are there particular types of tumors that are better treated with one or the other Lapatinib being tested in adjuvant setting Additional inhibitors in development HKI272 BIBW227
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Clinical trial of Herceptin and xeloda for women with HER2+ metastatic breast cancer that had progressed on Herceptin Herceptin + Capecitabine Capecitabine alone R A N D O M I Z E
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Trastuzumab Treatment Beyond Progression in Locally Advanced or MBC
Von Minckwitz, G et al, SABCS 2007 and ASCO 2008
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Courtesy of Kenneth Bloom.
The HER Family HER2 can dimerize with itself or other HER family members Courtesy of Kenneth Bloom. Intracellular
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Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain
Hubbard 2005
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HSP90 is a chaperone for proteins like HER2
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Trastuzumab-DM1, a novel antibody drug conjugate
Herceptin DM1 Her2 by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents Delivers high concentrations of drug to tumor Spares normal tissue from toxicity 28
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Trastuzumab-DM1, a novel antibody drug conjugate
Herceptin DM1 Her2 by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents Delivers high concentrations of drug to tumor Spares normal tissue from toxicity 29
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Trastuzumab-DM1, a novel antibody drug conjugate
Herceptin DM1 Her2 by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents Delivers high concentrations of drug to tumor Spares normal tissue from toxicity 30
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HER2 A Good ADC Target Tumor expression >>> Normal-tissue expression Absolute Expression levels very high Internalized without down regulation “A novel exploitation of HER2 biology” The green fluorophore Alexa-488 was conjugated to trastuzumab BT474 cells incubated with 488trastuzumab +/- were incubated 1 micromolar GA for 3h and then imaged by fluorescence microscopy Austin et al. (2004) Mol Biol Cell 15,
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Trastuzumab-DM1, a novel antibody drug conjugate
Results of early studies of TDM1 encouraging Response rate ≈40% in patients whose tumors had progressed on Herceptin Side effects minimal (validates strategy of antibody–drug conjugate) Larger trials are underway
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PI3-kinase may be an important target in breast cancer
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Targeting HER2+ Tumors Antibody conjugates Moderate receptor
Inhibit Dimerization Moderate receptor expression Inhibit Kinase activity Inhibit downstream effects Interactions between Trastuzumab and Tumor Cells. HER2 serves as a coreceptor with related members of the HER family of tyrosine kinase-associated growth factors. Acquired amplification of the HER2/neu gene on chromosome 17 in HER2-positive breast cancer leads to marked overexpression of HER2 on the cell surface, which alters normal signaling function. Trastuzumab is a humanized monoclonal antibody that binds to HER2 and inhibits tumor-cell growth through a variety of intracellular, and possibly extracellular, mechanisms. Burstein, H. J. N Engl J Med 2005;353:
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Breast cancer is family of different cancers
Triple Negative HER2+ Estrogen receptor + Percentage of women WITHOUT recurrence GENES There are two basic ways to analyze genomic data, unsupervised and supervised. In both, data is displayed in a heat map, in which expression of individual genes is displayed with red corresponding to high relative expression of a given gene and green low expression. In unsupervised analysis as was used in the perou study we ask the computer to group together samples based on similar patterns of gene expression, such as shown here with the now familiar basal, her2 and luminal subsets TUMORS 35
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The link between BRCA1 associated breast cancer and basal like cancers
Inherited mutations in the BRCA1 gene account for a small percentage of breast cancers 80% of BRCA1 associated breast cancers are basal like (triple negative)
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The link between BRCA1 associated breast cancer and basal like cancers
BRCA1 associated breast cancers have a fundamental defect in DNA repair Evolving data suggest that spontaneous TN breast cancers share this defect
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Basal-like Tumors Show DNA Damage Sensitivity
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© 2001 Macmillan Magazines Ltd
NATURE REVIEWS | GENETICS VOLUME 2 | JUNE 2001 | 447 © 2001 Macmillan Magazines Ltd NATURE REVIEWS | GENETICS VOLUME 2 | JUNE 2001 | 447
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Platinum Damages DNA
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04-183 Preoperative Cis-Platinum in Triple Negative Breast Cancer
SURGERY Women with newly diagnosed ER-/PR- /HER2- breast cancer Standard Treatment CisPlatinum x 4 doses Research Biopsy, Blood Tissue for Research
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Redundant Mechanisms of DNA Repair
X Homologous Recombination Base excision repair
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Base excision repair requires PARP
Huber et al. DNA Repair 3 (2004) 1103–1108
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Redundant Mechanisms of DNA Repair
X Homologous Recombination Base excision repair
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Hereditary ovarian cancer summary
AZD2281 – PARP inhibitor Hereditary ovarian cancer summary Total number of patients No. of evaluable patients Platinum resistant Ongoing response GCIG CA125 and/or RECIST radiological response 13 11 7/11 5/11 6/11
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Women with newly diagnosed ER-/PR-/HER2- breast cancer
Next Step SURGERY Women with newly diagnosed ER-/PR-/HER2- breast cancer CisPlatinum/PARP INHIBITOR x 4 doses Standard Treatment Research Biopsy, Blood Tissue for Research
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Cancers are dependent on new blood vessel growth (angiogenesis)
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Blocking VEGF with Avastin leads to loss of tumor vasculature and tumor regression
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Blocking VEGF may also lead to “normalization” of blood vessels
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ECOG 2100: Trial Design Patients enrolled Dec. 2001- March 2004
Doubling of RR (14% vs 28%) Nearly 5 month improvement in median PFS (6.1 vs 11 months) Preliminary improvement in overall survival Patients enrolled Dec March 2004 First interim analysis with data cut-off Feb with 355 events Miller KD ASCO 2005
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Progression Free Survival
*Benefit the same in ER+ and ER- patients Miller KD ASCO 2005
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Cancer stem cell model of therapeutic resistance
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Novel strategies for estrogen receptor expressing cancers
Hormonal therapy + therapies targeting growth factor receptors Avastin and other anti-angiogenic drugs seem to work well in ER+ breast cancer Currently, major advance is observation that for many women, prolonged adjuvant therapy (>5yr) can offer additional benefit
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How long does it take?
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Conclusion The number of new drugs in development is increasing quickly Targeted therapy’s promise of improved effectiveness and decreased side effects is being fulfilled If a good target is identified, the drugs will come Participation in clinical trials in needed to accelerate the pace of drug development
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