An Intro to Cancer Therapeutics Christopher R. Chitambar, MD Professor of Medicine Division of Hematology & Oncology Froedtert and Medical College of Wisconsin Clinical Cancer Center cchitamb@mcw.edu Intro to Cancer Therapeutics What is Cancer Therapeutics? Types of treatments used to treat cancer Cancer Treatment Modalities Local Therapy Surgery Radiation Systemic Therapy Chemotherapy Hormonal therapy Biological therapy Growth signal inhibitors Immunotherapy Angiogenesis inhibitors (target the tumor microenvironment) Tumor angiogenesis 1
Multi modality Treatment for Breast Cancer Adjuvant Surgery Chemotherapy Radiation Additional Treatment Anti HER2 Hormonal Neo adjuvant Chemotherapy Surgery Radiation Additional Treatment Anti HER2 Hormonal Chemo Metastatic breast cancer Anti HER2 +/ Hormonal +/ Chemo +/ Cancer Detection and Treatment 10 12 Detection Death 1 kilogram mass Treatment Log number of cancer cells 10 10 10 8 10 6 10 4 10 2 Symptoms / signs (Patient / Physician) 1 cm 3 mass Imaging Molecular tests Tumor size Surgery Radiation Chemotherapy Biologic therapy Micrometastatic disease elsewhere 10 0 Initiation of cancer Time Recurrence (metastases) Detection Treatment Recurrence Imaging Blood tests Symptoms Patient Physician Tumor size Surgery Radiation Chemotherapy Biologic therapy Re-treatment Symptoms Patient Physician Imaging Blood tests Molecular PCR Time Time 2
Treatment after surgery for breast cancer Who will relapse? Who should be treated? With what? For how long? Do the benefits outweigh the risks?? Treatment with chemotherapy after local therapy What is the risk of a distant recurrence? Identifying patients at risk a challenge?? Increasing recurrence risk Standard components of breast cancer pathology used in treatment decision making Histologic type (Invasive ductal, invasive lobular, others) Tumor size Tumor grade Angiolymphatic invasion, especially in node-negative Sentinel or axillary lymph node metastases Pathologic stage Estrogen receptor and Progesterone receptor HER2 expression/gene amplification 3
Chemotherapy Intravenous or oral Delivered to all areas of the body Does not cross into the central nervous system (brain and spinal cord) Dose limited by side effects Curative and/or palliative Each treatment kills a fraction of the cancer cells in a tumor (= many treatments needed) Benefits Side effects Conventional Chemotherapy Blocks Cell Division Cyclophosphamide Bleomycin Actinomycin D Vincristine, Vinblastine Paclitaxel, Docetaxel Cell Division M G 0 resting G 2 G 1 Hydrocortisone G 0 = resting phase G 1 = pre-replicative phase G 2 = post-replicative phase S = DNA synthesis M = mitosis or cell division Purine antagonists Methotrexate Cyclophosphamide 5-Fluorouracil Cytosine arabinoside Daunomycin S Actinomycin D 5-Fluorouracil Cytosine arabinoside Methotrexate 6-Mercaptopurine 6-Thioguanine Changes in genes result in abnormal proteins that stimulate the growth of cancer Normal Abnormal 4
HER2 Expression in Breast Cancer Normal (~ 20,000-50,000 receptors) HER2-positive (Up to 2 million receptor molecules) HER2 receptor HER2 receptor (IHC) HER2 gene HER2 mrna HER2 gene (FISH analysis) HER2 mrna An increase in HER2 protein occurs in about 20-25% of breast cancers HER2 is a switch that drive the growth of breast cancer HER2 = more aggressive behavior Drugs that turn off the HER2 switch block the growth of HER2 expressing breast cancer British Journal of Cancer (2014) 111, 1888-1898 doi:10.1038/bjc.2014.388 Blocking HER2 with an antibody improves outcomes in breast cancer 5
Combining immunotherapy with chemotherapy in lymphoma Rituximab DR CD19 slg CD20 CD22 Better survival B-lymphoma cell surface proteins Rituximab makes lymphoma cells more sensitive to chemotherapy Improved clinical response with addition of Rituximab to chemotherapy Hormonal Blockade Therapy Estrogen Action through the Estrogen Receptor (ER) HSP Growth of Breast Cancer ER ER ERE Estrogen Responsive Genes ER HSP nucleus E 2 Estrogen (estradiol) cytoplasm Blocking Estrogen stimulation of the estrogen receptor SERMS Tamoxifen & analogues Stop Growth of Breast Cancer Oophorectomy Aromatase E 2 estradiol Testosterone AIs Anastrozole Letrozole Exemestane ER Inappropriate shape Nuclear shuttling ER synthesis SERDS Fulvestrant E+ER mrna ERE at Estrogen Responsive Genes 6
Turning off tumor blood supply Angiogenesis is stimulated by growth factors Tumor Blood vessels Tumor Many different proteins (factors) regulate tumor angiogenesis through complex pathways Angiogenesis Inhibitor (VEGFR inhibitor) Chemotherapy + angiogenesis inhibition improves outcomes in metastatic colon cancer N Engl J Med 2004;350:2335-2342 Bevacizumab = Vascular Endothelial Growth Factor inhibitor A New Era in Cancer Drug Development Use knowledge of specific genomic changes in cancers to guide drug development and drug choices Personalized medicine Precision medicine Specific treatment for groups of patients 7
Genomic analysis reveals that there are 4 major subtypes of breast cancer No correlation With subtypes Overall survival Basal Luminal subtype A Luminal subtype B ERBB2 (HER2) Basal subtype Normal-breast like Luminal A Luminal B HER2 ER+ ER- Months Timelines of biologic breast cancer subclassification Harbeck N, and Rody A JCO 2012;30:686-689 Genomic Profiling of Breast Cancer as a prognostic & predictive tool 8
A 21 Gene Assay To determine whether chemotherapy should be given in addition to anti estrogen therapy Genes Genes Genes Genes Genes OncotypeDx (21-gene assay) Oncotype DX test Chemotherapy benefit based on recurrence score Benefit from Chemotherapy 9
Clinical scenarios Patient 1 Patient 2 49-year-old patient with 1.0-cm tumor Menopausal Status: Perimenopausal Tumor Type: Infiltrating Ductal Carcinoma Tumor Size: 1.0 cm Estrogen Receptor: Positive Progesterone Receptor: Positive HER2: Negative Histologic Grade: 3 Lymph Node Status: Negative 58-year-old patient with 1.0-cm tumor Menopausal Status: Postmenopausal Tumor Type: Infiltrating Ductal Carcinoma Tumor Size: 1.0 cm Estrogen Receptor: Positive Progesterone Receptor: Positive HER2: Negative Histologic Grade: 3 Lymph Node Status: Negative Clinical scenarios, cont d. Patient 1 - RESULTS Recurrence Score = 33 CLINICAL EXPERIENCE Patients with a score of 33 in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 22% ( 95% CI: 17%-27%). Patient 2 - RESULTS Recurrence Score = 12 CLINICAL EXPERIENCE Patients with a score of 12 in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 8% ( 95% CI: 5%-10%). Changes in genes result in abnormal proteins that stimulate the growth of cancer Normal Abnormal 10
We are discovering how abnormal proteins produced by genomic function in in cancer cells Melanoma Cutaneous Melanoma The Future Develop drugs that target specific abnormal proteins produced by genomic changes The Road to Drug Discovery and Development PRE-DISCOVERY Drug Discovery Preclinical 5,000 10,000 compounds 250 3 6 YEARS IND SUBMITTED Clinical Trials 5 Phase Phase 1 2 Phase 3 Number of Volunteers 20-100 100-500 1,000-5,000 6-7 YEARS NDA SUBMITTED FDA Review LG Scale MFG 0.5-2 YRS One FDAapproved drug Phase 4, Post-Marketing Surveillance Source: Drug Discovery and Development brochure. www.innovation.org 11
Take home message In the future, genomic changes in a patient s cancer will be used to develop the best drugs for cancer treatment? Questions?? Thank you for coming! 12