Breast Cancer- a Genetic Disease

The Charles B. Huggins Lectures, 2007 ―Personalized Medicine for Cancer‖ R. Stephanie Huang, Ph.D. (rhuang@medicine.bsd.uchicago.edu) The University of Chicago Key Points from Lecture 1 The goal(s) of personalized medicine is to: A. Develop better drugs B. Improve individuals’ quality of life and health C. Decrease overall health care cost D. All of the above Key Points from Lecture 1 Personalized medicine is about A. Disease prevention B. Disease detection C. Disease treatment D. All of the above Key Points from Lecture 1 Personalized medicine is necessary and feasible TRUE FALSE Personalized Medicine for Cancer • Personalized medicine IS being practiced in the current medical field • We are still at the beginning of this new era The Charles B. Huggins Lectures, 2007 Saturdays from 11:00 AM – 12:00 PM January 13th. Overview of personalized medicine and cancer treatment January 20th. Pharmacology of cancer treatment February 10th. Human Genome Project and its relationship to pharmacology February 17th. A great set of cell line tools— Family pedigrees, International HapMap cell lines and NCI60 cell lines February 24th. Ethical issue in personalized treatment January 27th. Molecularly targeted approach to cancer treatment February 3rd. Success in applying genetics and genomics in optimized treatment March 3rd. Future Medicines for Cancer What is Cancer? • Originated from normal cells • Grow continuously (usually fast and do not undergo normal cell death) • Lack of normal function Cancer Treatment History Overview 1728-1793 Scottish surgeon John Hunter 460-370 BC Greek physician Hippocrates Origin of word Cancer Non-invasive tumor is moveable 1956 first cure of metastatic cancer by methotrexate 1990s Emerge of Early 20th century personalized Wilhelm medicine term Roentgen World war II X-ray Discovery of Nitrogen mustard Chemotherapy and Biologic (Immuno-) therapy 1846 Available of Anesthesia Radiation Time Surgery Personalized medicine Hormone Therapy 1761 Giovanni Morgagni of Padua 1600BC Egypt Edwin Smith Papyrus There is no treatment Autopsies to relate the patient’s illness to the pathologic findings Late 19th century Thomas Beatson Removal of ovaries benefits breast cancer patients Mid 20th century Mid 20th century Charles Huggins James Watson and Francis Crick Discovery of DNA structure Removal of the testes resulted in regression of metastatic prostate cancer Ways to Treat Cancer • Local treatment: Treatment that affects cells in the tumor and the area close to it Surger y Radiation • Systemic: Affecting the entire body (To kill the minimal residual disease and prevent recurrent and metastasis of cancer) Radiation Chemotherapy Hormonal therapy Biologic (immuno) therapy Chemotherapy Chemical Treatment • Treatment involving the use of chemical agents to stop cancer cells from growing • Include cytotoxic agents and monoclonal antibodies Chemotherapy Related Toxicity • Each drug usually is associated with multiple side effects • Toxicities can be acute (short-term), chronic (long-term), or permanent • They may cause inconvenience, discomfort, and even death • Dose-limiting toxicity (DLT): Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment Cytotoxic Agents • Inhibit fast growing cells G0 M G0 G2 G1 S Common Adverse Effects • • • • Nausea/vomiting/diarrhea Hair loss (alopecia) Mouth sore (mucositis) Bone marrow suppression (myelosuppresion) [low white blood cell count (neutropenia), low red blood cell count (anemia), low platelet count (thrombocytopenia)] How do Cytotoxic Agents Work? • Compete with DNA/RNA building blocks • Affect enzymes in DNA/RNA synthesis • Prevent cells from dividing Drugs that Compete with DNA/RNA Building Blocks • Alkylating agents: Add bulky groups to DNA or crosslink DNA • Platinum: Form intra- and inter-strand crosslinks in DNA • Antimetabolites: Mimic the structure of DNA/RNA building blocks and incorporate into DNA/RNA to prevent DNA synthesis and transcription Normal DNA from Replication Alkylating Agents: Mechanism of Function -- Preventing DNA from Replication Add bulky group to DNA Normal repair enzymes “correct error” Fragmented DNA Crosslink DNA Prevent DNA from being separated for synthesis Alkylating Agents Usage • Used to treat both solid tumors and blood malignancies (eg: lymphomas and leukemias) – Cyclophosphamide (Cytoxan®, Neosar®) – Ifosfamide (Ifex®) – Melphalan (Alkeran®) Alkylating Agents – Adverse Effects • • • • • DLT -- Myelosuppression Nausea/vomiting Alopecia Neurotoxicity (cyclophosphamide, ifosfamide) Hemorrhagic cystitis (cyclophosphamide, ifosfamide) • Pulmonary fibrosis • GI and oral mucosal damage Platinum Compounds Cisplatin (Platinol®) Carboplatin (Paraplatin®) Oxaliplatin (Eloxatin® Intra-and interstran dcrosslink DNA NH3 P t NH3 Prevent DNA from being separated for synthesis NH3 P t NH3 Platinum Compounds • Cisplatin is approved for treatment of testicular, ovarian and bladder cancer and it is highly toxic – – – – – Nephrotoxicity Ototoxicity Peripheral neuropathy Nausea/vomiting Anemia • Carboplatin is approved for treatment of ovarian cancer and the dose-limited toxicity is hematologic toxicities • Oxaliplatin is approved for treatment of colorectal cancer DNA/RNA building blocks Thymine Uracil Antimetabolites 5-Fluorouracil (5-FU) Cytarabine Deoxycytidine Gemcitabine Antimetabolites: Mechanism of Function Block DNA synthesis U U U U Block RNA synthesis 5-Fluorouracil (Adrucil®, Carac®, Efudex®, Fluoroplex® V) • Used to treat solid tumors – breast, colon rectal, stomach, pancreas, ovary, cervix, bladder and prostate • IV bolus 5-FU  myelosuppression • Infusional 5-FU  mucosal damage (diarrhea) Cytidine Analogs • Cytarabine (Cytosar-U®) – Acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL) and chronic myelocytic leukemia (CML) – DLT = myelosuppression • Gemcitabine (Gemzar®) – Active against many solid tumors – pancreas, lung and ovary – Mild myelosuppression – May cause rash and peripheral edema DNA/RNA building blocks Guanine Antimetabolites 6-mercaptopurine S Deoxyadenine Fludarabine F HO OH Purine Analogs • 6-Mercaptopurine (Purinethol®) – Acute lymphocytic leukemia (ALL) – DLT = myelosuppression • Fludarabine (Fludara®) – Chronic lymphocytic leukemia (CLL), nonHodgkin’s lymphoma and acute leukemia – DLT = myelosuppression Folic Acid Analogs • Folates are required for purine and thymidylic acid synthesis • Antifolates inhibit dihydrofolate reductase, which is required to convert dietary folates to a usable form X • Prevents DNA synthesis DNA Methotrexate (Rheumatrex®, TrexallTM) • Used to treat hematologic and solid tumors • Also used for management of rheumatoid arthritis, prevention of graft-versus-host disease • Most common toxicities are mucositis and bone marrow suppression • May also cause liver, renal, pulmonary, and neural toxicities Drugs that Affect Enzymes for DNA/RNA Synthesis -Topoisomerase inhibitors Topoisomerase • Causes breaks in DNA • Prevents supercoiling of DNA during replication and transcription http://www.meds.com/colon/camptosar/usx4766.html Topoisomerase Inhibitors • Etoposide (VePesid®, Toposar®, Etopophos®) • Teniposide (Vumon®) • Irinotecan (Camptosar®) • Topotecan (Hycamtin®) http://www.meds.com/colon/camptosar/usx4766.html Etoposide and Teniposide • Etoposide is used for a variety of hematologic and solid tumors • Teniposide used in treatment of ALL • DLT -- Myelosuppression Irinotecan and Topotecan • Irinotecan is FDA approved for the treatment of metastatic colon and rectal cancer • Topotecan is used in treatment of ovarian, cervical and small-cell lung cancer • Irinotecan DLT – Diarrhea and neutropenia • Topotecan DLT – Myelosuppression Anthracyclines (Doxorubicin, Daunorubicin and Idarubicin) • Mechanism of action: Inhibition of DNA and RNA synthesis – Intercalate in DNA – Interference with topoisomerase – Produce free radicals • Used to treat a broad spectrum of solid and hematologic malignancies • DLT -- myelosuppression • Cardiac toxicity – Acute: Rhythm disturbances – Chronic: Congestive cardiomyopathy The Cell Cycle G0 M G0 G2 G1 S Mitosis Microtubule Inhibitors -- Vinca Alkaloids • Inhibit assembly of microtubules by binding to tubulin • Vincristine (Oncovin®, Vincasar®) used to treat leukemias, lymphomas and solid tumors • Vinblastine (Velban®, Alkaban-AQ®) is useful against lymphomas, testicular, and bladder cancers • Vinorelbine (Navelbine®) approved for non-small cell lung cancer Vinca Alkaloids – Adverse Effects • Vincristine  neurotoxicity • Vinblastine  bone marrow suppression • Vinorelbine  neutropenia Microtubule Inhibitors -Taxols • Accelerated microtubule formation and stabled of established microtubules by inhibiting microtubule depolymerization • Paclitaxel (Taxol®) used to treat breast, non-small cell lung and Kaposi’s sarcoma • Docetaxel (Taxotere®) is useful against breast, nonsmall cell lung, prostate and gastric cancers Taxols • DLT – Bone marrow suppression (neutropenia) • Nausea/vomiting • Cumulative neurotoxicity • Hypersensitivity reactions • Alopecia Hormonal Agents • Block hormonal stimulation of cancer cell growth • Important in the treatment of breast, ovarian, endometrium and prostate cancers Selective Estrogen Receptor Modulators (SERMs) Bind Estrogen Receptors but Do not Promote Transcription E SERM (Tamoxifen, Raloxifene) Cell membrane ER + ER ER + Nuclear membrane ER ER ER ERE (transcriptionall y inactive) (transcriptionall y activation) Dr. Fackenthal 2006 Selective Estrogen Receptor Modulators (SERMs) • Tamoxifen (Nolvadex) – Anti-estrogenic effects in breast but estrogenic properties in other tissues – Adjuvant therapy with tamoxifen reduces risk of developing contralateral breast cancer – Also used for prevention of breast cancer • Low toxicity, side effects include increased risk of blood clots and endometrial cancer Aromatase Inhibitors Block the Synthesis of Estrogen in Postmenopausal Women • Aromatase expressed in liver, muscle, and adipose tissues as well as in breast and the ovaries of premenopausal women • Exemestane (Aromasin) • Anastrozole (Arimidex) • Letrozole (Femara) • Side effects: Osteoporosis and bone fractures AstraZeneca Oncology www.breastcancerprofessional.com Dr. Fackenthal Key Points • Cytotoxic agents target fast growing cells – Substituting DNA/RNA building blocks – Inhibiting DNA/RNA synthesis enzymes – Preventing cell divide • Cytotoxic agents are in general more toxic to human body due to less specificity towards cancer • Combination therapy? Key Points • Major side effects of cytotoxic agents are… – Nausea, vomiting, diarrhea – Hair loss – Bone marrow suppression Key Points • Hormonal agents block hormonal stimulation of cancer cell growth – Blocking estrogen/male sex hormones action – Reducing amount of estrogen/androgen • Hormonal agents tend to be less toxic What is Next? • Treatments that target cancers but do not affect normal cells • Improve the utility of cytotoxic drugs by identifying patients at risk and design care accordingly Resources http://benmay.bsd.uchicago.edu/bmi2/news/huggins_lectures/hugg ins_lectures.html Resources National Cancer Institute: http://www.cancer.gov Resources National Cancer Institute: http://www.cancer.gov Resources National Cancer Institute: http://www.cancer.gov Resources http://www.cancer.gov/cancertopi cs/treatment/types-of-treatment Resources American Cancer Society: http://www.cancer.org http://www.cancer.org/docroot/ETO/ETO_1.as p Thank you See you next Saturday!