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
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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
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•
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
•
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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
•
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•
•
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•
•
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
•
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•
Monoclonal Antibodies
Recombinant Toxins
Vaccines
Adoptive Immunotherapy
• Immunomodulatory Drugs
•
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•
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
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Monoclonal Antibodies
Recombinant Toxins
Vaccines
Adoptive Immunotherapy
Immunomodulatory Drugs
• Interferons and Cytokines
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•
•
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
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Monoclonal Antibodies
Recombinant Toxins
Vaccines
Adoptive Immunotherapy
Immunomodulatory Drugs
Interferons and Cytokines
• Hormonal Agents
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•
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
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Monoclonal Antibodies
Recombinant Toxins
Vaccines
Adoptive Immunotherapy
Immunomodulatory Drugs
Interferons and Cytokines
Hormonal Agents
• Signal Transduction Modifiers
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•
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•
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•
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
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Monoclonal Antibodies
Recombinant Toxins
Vaccines
Adoptive Immunotherapy
Immunomodulatory Drugs
Interferons and Cytokines
Hormonal Agents
Signal Transduction Modifiers
• Transcriptional Regulators
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•
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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
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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
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Monoclonal Antibodies
Recombinant Toxins
Vaccines
Adoptive Immunotherapy
Immunomodulatory Drugs
Interferons and Cytokines
Hormonal Agents
Signal Transduction Modifiers
Transcriptional Regulators
Anti-sense Compounds
• Angiogenesis Inhibitors
•
•
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•
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
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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
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•
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•
•
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
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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
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•
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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
•
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•
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•
•
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•
•
•
•
•
•
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
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•
•
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
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