Recent Developments in Oncology Robert H. Cassell, M.D., Ph.D. Medical Director, Cassidy Cancer Center Clinical Assistant Professor, Dept. of Medicine, University of Florida College of Medicine CASSIDY CANCER CENTER Compassion, Innovation, Trust Recent Developments in Oncology There have been many new and exciting developments in cancer • New diagnostic modalities • New ways to predict the outcome and prognosis of various cancers • New treatment advances – – – – New surgical techniques New ways of delivering radiation therapy New chemotherapy drugs New supportive therapies CASSIDY CANCER CENTER Compassion, Innovation, Trust Recent Developments in Oncology – My Favorite Use of new knowledge in science, including genetics and molecular biology, and the new fields of genomics and proteomics, to develop “rational” therapies to treat cancer CASSIDY CANCER CENTER Compassion, Innovation, Trust “CANCER” CASSIDY CANCER CENTER Compassion, Innovation, Trust “CRAB” How Do You Treat… Crabgrass -- Cut It or Tear it Out Cancer -- Surgery CASSIDY CANCER CENTER Compassion, Innovation, Trust How Do You Treat… Crabgrass -- Cut It or Tear it Out Cancer -- Surgery CASSIDY CANCER CENTER Compassion, Innovation, Trust How Do You Treat… Crabgrass -- Burn It Cancer -- Radiation Therapy CASSIDY CANCER CENTER Compassion, Innovation, Trust How Do You Treat… Crabgrass -- Burn It Cancer -- Radiation Therapy CASSIDY CANCER CENTER Compassion, Innovation, Trust How Do You Treat… Crabgrass -- Poison It Cancer -- Chemotherapy CASSIDY CANCER CENTER Compassion, Innovation, Trust How Do You Treat… Crabgrass -- Poison It Cancer -- Chemotherapy CASSIDY CANCER CENTER Compassion, Innovation, Trust What If… • You could understand what makes crab grass crab grass, so that you could do something specific to kill only the crab grass OR • You could change the crab grass, so it behaved and looked like normal grass *********** I don't think we can do this with crab grass but we are starting to be able to do this sort of thing with cancer CASSIDY CANCER CENTER Compassion, Innovation, Trust Terminology • The current buzzword in medicine is "personalized medicine." • This means treating each patient as a separate individual based on their characteristics and the characteristics of their disease(s). • In oncology, we generally use the term “targeted therapy” or, more precisely, “molecularly targeted therapy.” CASSIDY CANCER CENTER Compassion, Innovation, Trust What Makes Cancer Cells Cancerous? • 1) Increased response to growth signals and production of their own growth signals • 2) Insensitivity to anti-growth signals • 3) Evasion of apoptosis – failure to die at the right time CASSIDY CANCER CENTER Compassion, Innovation, Trust Apoptosis (Programmed Cell Death) What Makes Cancer Cells Cancerous? • 1) Increased response to growth signals and production of their own growth signals • 2) Insensitivity to anti-growth signals • 3) Evasion of apoptosis – failure to die at the right time • 4) Limitless replication potential – keep dividing indefinitely • 5) Sustained angiogenesis (new blood vessels) CASSIDY CANCER CENTER Compassion, Innovation, Trust Angiogenesis (New Blood Vessel Growth) What Makes Cancer Cells Cancerous? • 1) Increased response to growth signals and production of their own growth signals • 2) Insensitivity to anti-growth signals • 3) Evasion of apoptosis – failure to die at the right time • 4) Limitless replication potential – keep dividing indefinitely • 5) Sustained angiogenesis (new blood vessels) • 6) Tissue invasion and metastasis CASSIDY CANCER CENTER Compassion, Innovation, Trust What Makes Cancer Cells Cancerous? Other characteristics of cancer cells: • Stem cell or progenitor cell phenotype – they start out looking like normal (or benign) cells but at a primitive stage of development • Increased mutation rate • Evasion of, or resistance to, normal immune responses CASSIDY CANCER CENTER Compassion, Innovation, Trust Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1):57–70. “Targeted” Cancer Treatment How does it work? Attack targets which are specific for the cancer cell and are critical for its survival or for its malignant behavior Why is it better than chemotherapy? More specific for cancer cells – chemotherapy hits rapidly growing cells not all cancer cells grow that rapidly some normal cells grow rapidly Possibly more effective CASSIDY CANCER CENTER Compassion, Innovation, Trust Cancer Targets From National Cancer Institute, US National Institutes of Health. Cancer Targets From National Cancer Institute, US National Institutes of Health. Cancer Targets From National Cancer Institute, US National Institutes of Health. Targets • The targets currently being used are those that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. • The focus is on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, how a cell responds to specific external stimuli, and even cell death. • We use the term “signal transduction” to refer to the actions of these proteins. CASSIDY CANCER CENTER Compassion, Innovation, Trust Tumor Cell Stimulation ATP TK TK ATP + Survival Gene Transcription Metastases Cell Cycle Progression Antiapoptosis Cell Proliferation Angiogenesis Targeted Therapy • The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation. CASSIDY CANCER CENTER Compassion, Innovation, Trust Therapy Targeted at the Estrogen Receptor • Selective estrogen receptor modulators (SERMs) – tamoxifen (Nolvadex) – toremifene (Fareston) • Estrogen receptor inhibitor and destroyer – fulvestrant (Faslodex) • Estrogen synthesis inhibitors – aromatase inhibitors (AIs) – anastrozole (Arimidex) – letrozole (Femara) – Exemestane (Aromasin) CASSIDY CANCER CENTER Compassion, Innovation, Trust Strategies to Inhibit Signaling tyrosine kinase Anti- mAbs inhibitors “-mab” “-ibs” ATP TK - Anti-ligand mAbs “-mab” TK TK - - Philadelphia Chromosome Philadelphia Chromosome (BCR-ABL Translocation) BCR-ABL Translocation Oncogenes c-met RAS BRAF PI3K PTE N CRAF MEK AKT p16 Cyclin D ERK CDK2 CDK4 mTor Targeted inhibitors c-met in development XL880 RAS BRAF R115777 SCH66336 Sorafenib RAF-265 PLX4032 MEK PI3K SF1126 XL147 GSK690693 VQD-002 PD0325901 AZD6244 PD332991 CYC202 p1 6 Cyclin D ERK BMS-387032 CDK2 CDK4 PTE N AKT temsirolimus everolimus AP23573 mTor Signal Pathways in the Cancer Cell The “Nibs” Small molecule tyrosine kinase inhibitors (or TKIs) – generic names end in “-nib” Generally oral Side effects vary, depending on which enzymes they inhibit (what their target is) Eight are FDA-approved, numerous others are in development Several are effective against cancers resistant to most previous therapies CASSIDY CANCER CENTER Compassion, Innovation, Trust FDA-Approved TKIs Generic Name Brand Name Cancer Imatinib Gleevec CML, GIST, others Dasatinib Sprycel CML, ALL Nilotinib Tasigna CML Gefitinib Iressa Lung Erlotinib Tarceva Lung, Pancreas Lapatinib Tykerb Breast Sorafenib Nexavar Kidney, Liver Sunitinib Sutent Kidney Monoclonal Antibodies Another type of targeted therapy – they are large molecules produced through genetic engineering They usually have to be given IV Side effects can include reactions to non-human proteins They can cause cell damage in several ways, most often by attacking cell-surface receptors CASSIDY CANCER CENTER Compassion, Innovation, Trust Tumor NRPs TGFβ bFGF PDGF VEGF Ang HGF RAS BRAF PI3K MEK AKT Endothelial cell & Pericyte ERK mTor Eph Trastuzumab • Monoclonal antibody against epidermal growth factor receptor 2 (EGFR2, HER-2) • Very effective against breast cancers in which HER-2 is “over-expressed” (more than usual amount per cell) (about 20% of all breast cancers) • Often used in combination with chemotherapy CASSIDY CANCER CENTER Compassion, Innovation, Trust Cetuximab • Monoclonal antibody against epidermal growth factor receptor 1 (EGFR1) • Effective in colon cancer and head and neck cancer; possibly useful in lung cancer • Used with chemotherapy and with radiation therapy CASSIDY CANCER CENTER Compassion, Innovation, Trust Bevacizumab • Monoclonal antibody against vascular endothelial growth factor (VEGF), which stimulates angiogenesis (growth of new blood vessels into tumor) • Deprives tumors of the blood supply they need for growth and invasion • Effective against cancers of colon, lung, breast, kidney, and brain CASSIDY CANCER CENTER Compassion, Innovation, Trust Monoclonal Antibodies FDA-Approved “Naked” (Non-Conjugated) MoAbs Generic Name Brand Name Target Cancer(s) Alemtuzumab Campath CD52 CLL Bevacizumab Avastin VEGF Multiple Cetuximab Erbitux EGFR1 Colon, H&N Panitumumab Vectibix EGFR1 Colon Rituximab Rituxan CD20 Lymphomas Trastuzumab Herceptin HER-2 Breast CASSIDY CANCER CENTER Compassion, Innovation, Trust Monoclonal Antibodies • Conjugated antibodies currently approved – Radio-conjugated antibodies • Tositumomab (Bexxar) • Ibritumomab (Zevalin) • Both used against refractory lymphomas – Toxin-conjugated antibody • Gemtuzumab ozogamicin (Mylotarg) • Used against AML CASSIDY CANCER CENTER Compassion, Innovation, Trust Monoclonal Antibodies In Development • • • • • • • • • • Epratuzumab Matuzumab Nimotuzumab Zalutumumab Pertuzumab Mapatumumab Lexatumumab Volociximab Pemtumomab Labetuzumab CASSIDY CANCER CENTER Compassion, Innovation, Trust • • • • • • • • • ch806 CP-751,871 IMC-A12 VEGF-Trap IMC-18F1 IMC-1121B IMC-3G3 Vitaxin CNTO 95 Types of MoAbs Structure % Human Example Comments Mouse 0 Tositumomab, Ibritumomab Radioconjugates Chimeric 65 Cetuximab, Rituximab Humanized 95 Trastuzumab Human 100 Panitumumab CASSIDY CANCER CENTER Compassion, Innovation, Trust Transgenic mice Nomenclature of MoAbs • Last syllable is always –mab • Next to last syllable -u- human (100%) : Panitumumab -zu- humanized (95%) : Trastuzumab -xi- chimeric (65%) : Rituximab -o- mouse, -a- rat, -e- hamster, -i- primate : Tositumomab • Previous syllable – -tu(m)- for tumor in general [-ma(r)- breast, -pr(o)- prostate, co(l)- colon, etc.] – -ci(r)- for circulatory : Bevacizumab CASSIDY CANCER CENTER Compassion, Innovation, Trust New Directions • Combination of different targeted therapies (multiple TKIs, TKI with MoAb; occasionally multiple MoAbs) • Combination with standard chemotherapy or with radiotherapy • Targeted agents to “clean up” after surgery • Use with other novel agents CASSIDY CANCER CENTER Compassion, Innovation, Trust Other Novel Types of Cancer Therapies Now in Use • Proteasome inhibitors (Bortezomib) • mTOR inhibitors (Temsirolimus, Everolimus) • DNA demethylating agents (Azacytidine, Decitabine) • Histone deacetylase inhibitors (Vorinostat) • Translocation targeters (retinoic acid) • Antiangiogenic agents (Thalidomide, Lenalidomide) CASSIDY CANCER CENTER Compassion, Innovation, Trust Other Novel Types of Cancer Therapies in Development • • • • • • • • Integrin inhibitors (Volociximab) “Death” receptor stimulants Telomerase inhibitors Apoptosis promoters DNA repair inhibitors (PARP inhibitors, etc.) Heat shock protein targeters Antagonists of specific gene mutations Antisense agents CASSIDY CANCER CENTER Compassion, Innovation, Trust Biotherapeutic Agents • • • • • • • Interferons Interleukins Cancer Vaccines Immunomodulatory agents Colony stimulating factors Monoclonal antibodies Gene therapy CASSIDY CANCER CENTER Compassion, Innovation, Trust Take Home Points • Molecularly targeted therapy is a new way of approaching cancer treatment • It is based on recent scientific advances in molecular biology, chemistry, and genetics • It involves the rational selection of drugs which target specific processes in cancer cells that make them different from normal cells • A number of targeted therapies are currently available and many others are in development • Targeted therapies are frequently effective but are not perfect: There are side effects to the treatments, and there may be development of resistance • Targeted therapies are increasingly being used in combination with other targeted therapies or with other treatment modalities • We definitely will be hearing much more about targeted therapies for cancer in the future CASSIDY CANCER CENTER Compassion, Innovation, Trust Thank You for your Attention Cassidy Cancer Center Winter Haven Hospital 200 Ave. F, NE Winter Haven, FL 33881-4131 863-292-4670 www.winterhavenhospital.com/facilities/CCC CASSIDY CANCER CENTER Compassion, Innovation, Trust