Overview of Modern Oncologic Therapies
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Overview of Modern Oncologic Therapies December 8, 2014 Steven T. Rosen, M.D. Provost and Chief Scientific Officer Director, Comprehensive Cancer Center and Beckman Research Institute Irell & Manella Cancer Center Director’s Distinguished Chair City of Hope 1913 2014 Biologic Response Modifiers • Monoclonal Antibodies • • • • • • • • • • • • • • • • Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Target Antigens NH2 Fab VARIABLE REGION ANTIGEN BINDING SITE COOH Fc CONSTANT REGION EFFECTOR FUNCTIONS Antibodies in Medicine Naked mAbs Growth factors Immune based C1q Compliment Immune based Signaling mechanism based Enhance Selectivity NK Cells Bispecific T Cell Chemokine, etc.. Immune based Engineered mAbs Poison Radioactivity Prodrug Biotoxin Selective Drug Delivery Monoclonal Antibodies - Naked Year Generic/Trade Names Route Indications 1997 Rituximab/Rituxan IV B-cell NHL - CD20+ Mechanism of Action ADCC, CDC, Apoptosis 1998 Trastuzumab/Herceptin IV Breast Cancer-HER2+ Signal Inhibition 2001 Alemtuzumab/Campath IV, SC CLL - CD52+ ADCC, CDC, DC 2004 Cetuximab/Erbitux IV H&N/Colon Cancer -EGFR+ Signal Inhibition 2004 Bevacizumab/Avastin IV Colon Cancer, Adenocarcinoma Lung, RCC-VEGF Angiogenesis Inhibitor 2006 Panitumumab/Vectibix IV Colon Cancer -EGFR+ Signal Inhibition 2009 Ofatumumab/Arzerra IV CLL - CD20+ ADCC, CDC, DC 2012 Pertuzumab/Perjeta IV Breast cancer - HER2+ Signal Inhibition 2013 Obinutuzumab/Gazyva IV CLL - CD20+ ADCC, CDC, DC 2014 Ramucirumab/Cyramza IV 2014 Siltuximab/Sylvant IV Gastric Cancer - targets VEGFR2 Angiogenesis Inhibitor Castleman's Disease - antiinterleukin-6 Signal Inhibition Monoclonal Antibodies - Conjugated Year Generic/Trade Names Route Indications Mechanism of Action 2002 Ibritumomab tiuxetan/Zevalin IV B-cell NHL-CD20+ Yttrium 90 2003 Tositumomab/Bexxar IV Iodine 131 2011 Brentuximab Vedotin/Adcetris IV B-cell NHL-CD20+ Hodgkins and ALCL CD30+ 2013 Ado-trastuzumab Emtansine/Kadcyla IV Breast cancer - HER2+ Mertansine Auristatin E Biologic Response Modifiers • Monoclonal Antibodies • Recombinant Toxins • • • • • • • • • • • • • • • Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Recombinant Toxins Year Generic/Trade Names Route Indications Mechanism of Action 1999 Denileukin diftitox/Ontak IV CTCL - CD25+ Diphtheria Toxin Mechanism of Action Biologic Response Modifiers • Monoclonal Antibodies • Recombinant Toxins • Vaccines • • • • • • • • • • • • • • Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Active Cancer Vaccination Strategies Irradiated Tumor Cells Dendritic Cells Adjuvant Oral D Lactobacilus Stabilized mRNA Adapted from: Berzofsky et al, J Clin Invest. 2004;113(11):1515–1525 Vaccine Therapy Year Generic/Trade Names Route Indications Mechanism of Action 1998 BCG/TheraCys Intravesical Bladder Cancer Inflammation Prostatic Cancer Prostate Acid Phosphatase exposed dendritic cells 2010 Sipuleucel-T/Provenge IV Provenge Biologic Response Modifiers • Monoclonal Antibodies • Recombinant Toxins • Vaccines • Adoptive Immunotherapy • • • • • • • • • • • • • Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Allogeneic Bone Marrow Transplant CAR T-Cell Lymphoma Biologic Response Modifiers • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy • Immunomodulatory Drugs • • • • • • • • • • • • Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Immunomodulatory Drugs Year Generic/Trade Names Route Indications Mechanism of Action 1998 Thalidomide/Thalomid O Myeloma Immune modulation 2005 Lenalidomide/Revlimid O Myeloma, CLL 2011 Ipilimumab/Yervoy IV Melanoma Immune modulation Target CTLA - 4 Receptor, Blocks CTL Inhibition 2013 Pomalidomide/Pomalyst O Myeloma Immune modulation 2014 Blinatumomab/BITE IV ALL 2014 Pembrolizumab/Keytruda IV Melanoma Anti-CD19, Anti-CD3 Target PD-1 Receptor, Blocks CTL Inhibition Thalidomide/Lenalidomide/Pomalidomide T/L/P T/L/P T/L/P T/L/P T/L/P T/L/P CTLA - 4 Receptor (Immune Checkpoint Inhibitor) Blinatumomab • Bispecific (CD19 and CD3) T-cell engaging Ab; continuous IV • Ph 2: MRD+ B-ALL, n = 21 • 16 pts of 20 evaluable pts became MRD neg after 1 cycle (80% ORR) • RFS probability 78% at median followup of 405 days • After median followup of 33 months, RFS of the 20 evaluable pts was 61% 65% in 9 pts who went to allo 67% in 6 pts with PH neg MRD responders with no further treatment Topp MS, et al. J Clin Oncol 2011 Topps MS, et al. Blood 2012 Biologic Response Modifiers • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs • Interferons and Cytokines • • • • • • • • • • • Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Interferons-Cytokines Year Generic/Trade Names Route 1992 Aldesleukin/Proleukin IV 1997 Interferon Alfa-2b/Intron A DC, SC 1999 Interferon Alfa-2a/Roferon A DC, SC Indications Mechanism of Action Melanoma and Renal Cell Cancer - target IL2 Receptor Immune modulation Follicular non-Hodgkin's Lymphoma, Hairy Cell Leukemia, CML, CTCL, Melanoma, Kaposi's Sarcoma - target Interferon Receptor Immune modulation Hairy Cell Leukemia, Philadelphia chromosome, Cutaneous T-cell lymphoma, Follicular non-Hodgkin's lymphoma, Renal cell carcinoma Immune modulation IFNa Jak kinases IRS-proteins Stat-pathway p38 Map kinase pathway Crk-pathway PI-3K mTOR p70S6K 4E-BP1-P gene transcription mRNA translation growth inhibitory/antitumor effects Rap1 Biologic Response Modifiers • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines • Hormonal Agents • • • • • • • • • • Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Biologic Response Modifiers Hormonal Therapies Year Generic/Trade Names Route Indications Mechanism of Action 1977 Tamoxifen Citrate/Nolvadex O Breast Cancer Anti-estrogen 1996 Goserelin/Zoladex IM Prostate Cancer LHRH Agonist 1996 Anastrozole/Arimidex O Breast Cancer Aromatase Inhibitor 1996 Nilutamide/Nilandron O Prostate Cancer Anti-androgen 1998 Letrozole/Demara O Breast Cancer Aromatase Inhibitor 1999 Targretin/Bexarotene O CTCL Rexinoid 1999 Exemestane/Aromasin O Breast Cancer Aromatase Inhibitor 2000 Triptorelin/Trelstar IM Prostate Cancer LHRH Agonist Hormonal Therapies Year Generic/Trade Names Route Indications Mechanism of Action 2001 Flutamide/Eulexin O Prostate Cancer Anti-androgen 2002 Fulvestrant/Faslodex IM Breast Cancer Anti-estrogen 2007 Raloxifene Hydrochloride/Evista O Breast Cancer Anti-estrogen 2008 Degarelix/Firmagon IM Prostate Cancer LHRH Antagonist 2009 Leuprolide/Lupron IV Prostate Cancer LHRH Agonist 2009 Bicalutamide/Casodex O Prostate Cancer Anti-androgen 2011 Abiraterone Acetate/Zytiga O Prostate Cancer CYP17A1 Inhibitor 2012 Enzalutamide/Xtandi O Prostate Cancer Inhibits Androgen Receptor Biologic Response Modifiers • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents • Signal Transduction Modifiers • • • • • • • • • Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Cancer Targets Signal Transduction Inhibitors Year Generic/Trade Names Route Indications Mechanism of Action 2001 Imatinib / Gleevec O CML, GIST Bcr-Abl, C-Kit 2003 Gefitinib/Iressa O EGFR 2004 Trametinib/Mekinist O NSCLC Metastatic melanoma with BRAF V600E or V600K mutations 2005 Erlotinib/Tarceva O NSCLC, Pancreatic Cancer EGFR, JAK2 VEGFR, PDGFR, BRAF, C-Kit BRAF 2005 Sorafenib/Nexavar O RCC, HCC 2005 Dasatinib/Sprycel O CML 2006 Sunitinib/Sutent O RCC, GIST Bcr-Abl, STC, C-Kit PDGFR, VEGFR, C-Kit, RET, CS-1R, Fit3 2007 Lapatinib /Tykerb O HER2 (ErbB2) HER2 2007 Temsirolimus/Torisel IV RCC mTORC1 2007 Nilotinib/Tasigna O CML, (Ph+ CML) Bcr-Abl 2009 Everolimus/Afinitor/Zortress O RCC, SEGA, PNET mTORC1 Signal Transduction Inhibitors Year Generic/Trade Names Route Indications 2009 Pazopanib/Votrient O RCC, Soft Tissue Sarcoma Mechanism of Action PDGFR, C-Kit 2011 Vandetanib/Caprelsa O 2011 Vemurafenib/Zelboraf O Symptomatic or progressive medullary VEGFR, EGFR, RET, BRK thyroid cancer Treatment of unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDABRF approved test. 2011 Crizotinib/Xalkori O ALK+NSCLC ALK, HGFR, C-MET 2011 Ruxolitinib/Jakafi O Myelofibrosis 2012 Axitinib/Inlyta O RCC JAK VEGFR, PDGFR, C-Kit 2012 Vismodegib/Erivedge O Metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma SMOR 2012 Ziv-aflibercept/Zaltrap IV mCRC VEGF O Ph+ chronic myelogenous leukemia (CML) Bcr-Abl 2012 Bosutinib/Bosulif Signal Transduction Inhibitors Year Generic/Trade Names Route Mechanism of Action O Indications Metastatic colorectal cancer (CRC)/GIST 2012 Regorafenib/Stivarga 2012 Cabozantinib/Cometriq O MTC 2012 Ponatinib/Iclusig O 2013 Dabrafenib/Tafinlar O CML Metastatic melanoma with BRAF V600E mutation/ Metastatic melanoma with BRAF V600E or V600K C-MeT, VEGFR Bcr-Abl, BEGFR, PDGFR, FGDR, EPH, SRC, C-KiT, RET, TIE2, FLT3 2013 Afatinib/Gilotrif O NSCLC ErbB 2013 Ibrutinib/Imbruvica O MCL, CLL BTK 2014 Ceritinib/Zykadia O ALK+NSCLC ALK 2014 Zydelig/Idelalisib O Follicular Lymphoma, CLL PI3 Kinase Inhibitor RET, VEGFR, PDGFR BRAF Biologic Response Modifiers • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers • Transcriptional Regulators • • • • • • • • Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses DNA Methylation in Eukaryotes X Promoter with CpG island Exon I Exon II Exon III Azacitidine: MDS, AML Decitabine: MDS, AML Reversible Histone Acetylation Regulates Gene Expression HAT Transcriptional Factors Histone acetylation Pol2 Ac- AcAcCore histones mRNA Ac- Histone deacetylation HDACs Cofactors AcAc- Ac- AcRepressed Chromatin (hypo-acetylated histones) Activated Chromatin (hyper-acetylated histones) Repressed Chromatin Yoo CB and Jones PA. Nat Rev Drug Discov. 2006;5:37. Transcription/Translation Regulation Year Generic/Trade Names Route Indications Mechanism of Action 2006 Decitabine/Dacogen IV MDS DNA Methylation Inhibitor 2006 Vorinostat/Zolina O CTCL HDAC Inhibitor 2009 Romidepsin/Istodax IV CTCL HDAC Inhibitor 2012 Omacetaxine Mepesuccinate/Synribo SC CML Protein translation 2014 Belinostat/Beleodaq O PTCL HDAC Inhibitor Biologic Response Modifiers • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators • Anti-sense Compounds • • • • • • • Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Antisense Oligonucleotide Activity Biologic Response Modifiers • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds • Angiogenesis Inhibitors • • • • • • Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Angiogenesis Inhibitors Year Generic/Trade Names Route 2004 Bevacizumab/Avastin IV 2005 Sorafenib/Nexavar O 2006 Sunitinib/Sutent O 2011 Vandetanib/Caprelsa O 2012 Axitinib/Inlyta O 2012 Ziv-aflibercept/Zaltrap IV 2012 Regorafenib/Stivarga 2012 Cabozantinib/Cometriq 2014 Ramucirumab/Cyramza Indications Mechanism of Action Colon Cancer, Adenocarcinoma Lung, RCC-VEGF, Metastatic cervical cancer Angiogenesis Inhibitor VEGFR, PDGFR, BRAF, RCC, HCC C-Kit PDGFR, VEGFR, C-Kit, RET, RCC, GIST CS-1R, Fit3 Symptomatic or progressive VEGFR, EGFR, RET, BRK medullary thyroid cancer VEGFR, PDGFR, C-Kit RCC VEGF O mCRC Metastatic colorectal cancer (CRC)/GIST O MTC C-MeT, VEGFR IV Gastric Cancer - targets VEGFR2 Angiogenesis Inhibitor RET, VEGFR, PDGFR Biologic Response Modifiers • • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors • Proteasome Inhibitors • • • • • Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses The 26S proteasome and its function • Present in all cells • Ubiquitin-proteasome pathway – Essential role in regulating intracellular concentration of specific proteins – Control of protein homeostasis in the cell • Ubiquitin “tags” proteins for degradation by the proteasome NEJM Proteasome Inhibitors Year Generic/Trade Names Route Indications Mechanism of Action 2003 Bortezomib/Velcade IV/SC Myeloma/MCL Proteasome Inhibitor 2012 Carfilzomib/Kyprolis IV Myeloma Proteasome Inhibitor Biologic Response Modifiers • • • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors • Metabolism Inhibitors • • • • DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs Oncolytic Viruses Tumor Cell Metabolism Glycolysis http://www.uams.edu/radiology/info/clinical/pet/images.asp Adapted from: Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. “Brick by brick: metabolism and tumor cell growth.” Curr. Opin. Genet. Dev. 2008, Feb; 18(1):54-61. Biologic Response Modifiers • • • • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors • DNA Repair Inhibitors • Apoptosis Inducers • RNA Based Analogs • Oncolytic Viruses DNA Damage Biologic Response Modifiers • • • • • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors • Apoptosis Inducers • RNA Based Analogs • Oncolytic Viruses Apoptosis Induction Biologic Response Modifiers • • • • • • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers • RNA Based Analogs • Oncolytic Viruses RNA-Directed Nucleoside Analogues NH N N O OH N N Cl HO NH 2 2 N OH 8-Chloro-adenosine N NH2 HO N O OH N OH 8-Amino-adenosine Metabolism of 8-Cl-Adenosine 8-Cl-Adenosine Ado Deaminase 8-Cl-Inosine Ado Kinase 8-Cl-AMP 8-Cl-ADP ATP Synthase 8-Cl-ATP (Cytotoxic Metabolite) Generation of the cytotoxic metabolite requires activity of adenosine kinase and ATP synthase. Intracellular Accumulation of 8-Cl-ATP 500 100 8-Cl-ATP, µM 75 300 200 50 100 25 0 ATP, % of control 400 0 0 2 4 6 8 10 12 Hours Conclusion: By 6 hours of incubation, myeloma cells accumulate high levels (300 mM) of the 8-Cl-ATP while endogenous ATP falls leading to reduced energy sources Inhibition of RNA Synthesis DNA DNA % of control 100 75 50 RNA RNA 25 0 0 2 4 6 8 10 12 Hours Conclusion: 8-Cl-Ado inhibits RNA but not DNA synthesis which may be a more effective way to kill slow growing cancer cells such as myeloma or CLL. Drug Sensitivity Score of 8-chloro-adenosine in AML Patient Samples Biologic Response Modifiers • • • • • • • • • • • • • • • • Monoclonal Antibodies Recombinant Toxins Vaccines Adoptive Immunotherapy Immunomodulatory Drugs Interferons and Cytokines Hormonal Agents Signal Transduction Modifiers Transcriptional Regulators Anti-sense Compounds Angiogenesis Inhibitors Proteasome Inhibitors Metabolism Inhibitors DNA Repair Inhibitors Apoptosis Inducers RNA Based Analogs • Oncolytic Viruses Oncolytic Viruses Virus Measles Killing Cancer Supportive Care Year Generic/Trade Names Route Indications Mechanism of Action 1991 Neupogen/Filgrastim SC Neutropenia G CSF 1991 Leukine/Sargramostim SC Neutropenia GM CSF 1997 Neumega/Oprelvekin SC Thrombocytopenia ILII 2002 Neulasta/ Pegfilgrastim SC Neutropenia PEG-G-CSF 2002 Elitek/ Rasburicase IV Hyperuricemia urate oxidase 2004 Kepivance/Palifermin IV Oral mucositis Keratinocyte Growth Factor 2008 Romiplostim/Nplate SC Thrombocytopenia Thrombopoietin 2008 Eltrombopag/ Promacta O Thrombocytopenia c-Mpl Receptor Agonist 2008 Plerixafor/Mozobil SC Enhance stem cell mobilization Blocks CXCR4 2010 Denosumab/Prolia/Xgeva SC Osteoporosis Inhibits RANKL Personalized Medicine Cancer Diagnostic Market is Rapidly Evolving Questions?
