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Transcript of Biology of Cancer Principles of Systemic Therapy.
![Page 1: Biology of Cancer Principles of Systemic Therapy.](https://reader035.fdocuments.net/reader035/viewer/2022062217/56649e865503460f94b88c7d/html5/thumbnails/1.jpg)
Biology of Cancer Principles of Systemic Therapy
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• Immortality• Invasion• Loss of adherence• Autocrine
• Somatic and genetic differences • Implications for therapeutic approaches
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Objectives
• Biology of malignancy
• Definition of Terms
• Principles of Systemic Therapy
• TNM Staging Classification
• Common Chemotherapy Agents
• Targeted Therapies
• Summary
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Biology of Malignancy
Round 1
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Tumor BiologyPrinciples of Cellular Growth
• Ability to produce exact replica– essential component of life
• Lack of fidelity in cellular reproduction– creates genetic instability
• Cancer is a disease:– abnormal regulation of cellular growth– reproduction
• Control of the cell cycle progression– how processes are altered in malignant cells
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Cell Cycle-Mechanism
• Replication and division: – Functional phases
• precise copying of the DNA (S phase)• regulation/ and segregation of chromosomes (M phase)
– Preparatory phases:• G1 ( preparation for S phase)• G2 ( preparation for mitosis)
• Cells not actively dividing:– terminal differentiation– G0 (no cycling state)
• Events occur in orderly fashion
• Kinetics important in chemotherapy mechanisms
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Cell CycleExtra-cellular Signals
• Complex regulation and division not in a vacuum
• Cell integrate signals into control mechanisms:– Nutrient status– Cell to cell contact– Extra cellular peptides
• Growth factors cause cells in Go phase through cell cycle
• Continued growth factor exposure
• Cytokines: – soluble mediators of cell to cell communication
– interleukins, interferon, CSF
– bind to receptors on surface of cells
– cascade of biochemical signals activation/suppressing of genes
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Cell Cycle Check Points
• Events of cell cycle highly ordered:– different extra cellular/intracellular events
• Dependency controlled by:– regulation of gene products – mutations in checkpoints genes – progression through cell cycle
• Mutations result in altered responses:– environmental or therapeutic DNA damaging agents
increased decreased cell death – increased mutation rate or – genetic instability
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What Goes Wrong
• Potential mechanisms:
– Cellular hypoxia (outgrow blood supply)
– Decreased availability of nutrients
– Alternation in cytokine/hormonal milieu
– Accumulation in toxic metabolites
– Inhibition of cell-cell contact
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Life-cycle
• 1cm3 - >1g tumor (109) cells– 1 cm the limit of clinical detection– 30 doublings occurred prior to clinical detection
• Only 10 more doublings (3 logs)– 1kg of tumor– terminal disease
• Pre-clinical phase 75% of “life of tumor”
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Cellular Proliferation of Tumors
• Heterogeneous as a result of:– variability in blood supply/nutrients– differing degrees of differentiation within clones– constant generation of new sub clones
• Increased volume as a result:– increased lifespan– Increased number– decreased death
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Principles of Metastases
• Principle cause of death
• Mainly routes of dissemination:– via blood steam– lymphatic
• Are flow and organ specific
• Establishment of metastases is inefficient:– subpopulation/clone have the abilities to metastases– generally most malignant/aggressive
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Steps in Metastatic Cascade
• Escape
• Travel through the blood/lymphatic system
• Arrest/attachment
• Establishment of clone
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MetastasesEscape
• May be biologically facilitated by:
– ability to commit vascular invasion
– cell necrosis
– molecules of the cell surface
– protease (enzyme) secretion by tumor
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Travel
• Blood supply (angiogenesis) must be adequate
• Adequate lymphatic drainage
• Special circulatory circumstances
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Principles of Cytotoxicity
• Relationship between dose and cytotoxicity:– exponentional– drug dose– number of cells at risk/at exposure
• Principles of therapy:– multiple courses of therapy– each treatment kills same proportion
(not number) of cells– small decrease in drug dose results in large increase
in cell survival– e.g.: 3 log killed 1010 to 107
1 log regrowth between cycles
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Gompertzian Growth Curve
LogKill
Time
Standard of Care
↓ Dose
Delayed Schedule
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Summary-Biology• Cell Cycle kinetics:
– highly ordered – critical for both normal as well as aberrant growth
• Relationship between dose & cell survival:– generally exponential – drug dosing– number of cells at risk for exposure
• Resistance result of the selection pressure:– instability of tumor– size of tumor
• Metastases:– flow and organ specific– escape/travel/arrest/establishment
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Definition of Terminology
Round 2
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Principles of Systemic TherapyDefinition of Terms
• Neoadjuvant: – prior to definitive surgery– advanced/locally advanced disease– organ preservation
• Adjuvant:– post surgical/pathological staging– statistical possibility of micrometastatic disease– efficacy of therapy in tumor site
• Metastatic:– Curable (testes)– Incurable (prostate, lung)
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Continued
• Induction Chemotherapy:– setting of biopsy proven metastatic disease– may be curable (testes)– incurable (renal)
• Direct Instillation:– site directed installation or perfusion– primary target/organ (bladder)– sanctuary sites (brain)
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Principles of Systemic Therapy
Round 3
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Principles ofCombination Systemic Therapy
• Objectives:– biochemical interactions between drugs
– maximum cell kill as tolerated by host
– broader range of coverage of resistant cell lines
– slows development of resistant cell lines
• Optimum dose and schedule
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Gompertzian Growth Curve
LogKill
Time
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Mechanisms of Resistance
• Drug exposure/Selection pressure– chemotherapeutic agents selects for resistant cells– Goldie-Coldman hypothesis
• Resistance within a tumor a function of:– inherent genetic instability of a tumor– size of tumor ( # cells)
• Tumor sanctuaries
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Toxicity of Chemotherapy
Drug Anthracycline Vincas Antibiotics Taxanes Alkylators
Cardio X X X
CNS X X X
Edema X
Fibrosis X X
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Meta-Analysis: CHF Anthracycline Dose
Epirubicin (n=9144)
Est
ima
ted
pro
ba
bilit
y o
f d
eve
lop
ing
CH
F
0.20Doxorubicin (n=3941)
Cumulative dose (mg/m2)
0.10
0.05
0
0 200 400 600 800 1000 1200
0.15
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Functional Impairments Caused by Cancer Therapy
Deficit Surgery Chemo Rads Immuno
Atrophy X X X X
Contracture X X
Joint X X X
Edema X X X X
Neuropathy X X
Pain X X X X
Cardiac X
CNS X X X
Gait X X X
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Summary
• Goal of therapy:– stage dependent– tumor type specific– incorporating host factors
• Selection of therapy:– single versus combination chemotherapy– combined versus single modality of therapy
• Toxicity of therapy:– overlapping/non-overlapping
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Staging Principles
TNM Classification
Round 4
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Staging Principles
• Stage I– Organ confinement
• Stage II– Organ plus regional lymph nodes
• Stage III– Locally advanced
• Stage IV– Metastatic
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Common Chemotherapeutic Agents
Round 5
Drug Classification
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Alkylating Agents
• Mechanism of Action:– disrupts DNA
• Indications:– tumors with low growth potentials– low grade lymphomas– number of sites where they can interact – dose important
• Agents include:– Metchlorethamine (MOPP)– Cyclophosphamide (CHOP/CMF/FAC/AC)– Chlorambucil (CLL/low grade lymphoma)
• Toxicity:– myelosuppression
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Anti-tumor Metabolites• Mechanism of action:
– topoisomerase inhibitor (breaking coiling strands)– free radical formation
• Indications:– Breast cancer– Hodgkin's Disease
• Agents:– Adriamycin, Epirubicin, Mitozantrone (FAC)– Bleomycin (ABVD)
• Toxicity:– myelosuppression– pulmonary fibrosis– Left ventricular dysfunction
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Anti-tumor Metabolites-2
• Mechanism of action:– substitutes a metabolite into the DNA/RNA
• Indications:– Colon cancer (5FU-FA)– Breast cancer (CMF)
• Agents:– 5FU– Methotrexate– Capecitabine– Gemcitabine
• Toxicity:– mucositis– myelosuppression
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Vinca Alkaloids
• Mechanisms:– inhibits microtubule formation during M phase
• Indications:– Lung cancer (vinorelbine)– Lymphomas (vincristine)
• Agents:– Vincristine (CHOP)– Vinblastine– Vinorelbine (Cisplatin/Vinorelbine)
• Toxicity:– myelosuppression– neuropathy
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Antimicrotubule Mechanism of Action
Inhibition of Polymerization:
Inhibition of Depolymerization:
MicrotubuleTubulin
• docetaxel• paclitaxel
• vinblastine• vinorelbine
Vinca alkaloids
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Other Agents-Cisplatin
• Mechanism:– Interferes with DNA replication without affecting
normal RNA and protein synthesis
• Indications:– Lung Cancer (Cisplatin/vinorelbine)– Ovarian Cancer (Cisplatin/taxol)
• Analogues:– Carboplatin– Oxaloplatin
• Toxicity:– myelosuppression– neuropathy
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Cisplatinum®
Mechanism of action
Pt
– Herce
ptin®
+ Herceptin ®
DNA repair, reversal of resistance
PtPt
Pt
Pt
Pt
Pt Pt
Pt
Pt
DNA repair/platinum resistance
Pt
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Taxanes
• Mechanism:– Interfere with structure and function
of the microtubules
• Indication:– Breast– Lung– Ovarian
• Analogues:– Taxol (TAC)– Taxotere
• Toxicity:– myelosuppression– neuropathy
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SummaryCommon Agents
• Agents may be:– cell cycle dependent or independent– oral or intravenous– bolus or continuous infusion
• Specific toxicities:– nonoverlapping/overlapping– facilitate combination chemotherapy
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Targeted Therapies
Round 6
Receptors HER-2 proteins
Antiangiogenesis
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Treatment Options for Women with HER2 Positive Breast Cancer
“The Herceptin Story”
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HER-2 Terminology
Human Epidermal Growth Factor Receptor-2
HER2/neu-2 oncogene encoding production HER2 receptor
Also known neu (rat gene) c-erbB-2
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erb-b1EGFRHER1
neu Erb-b2HER2
Erb-b3HER3
Erb-b4HER4
TG
F
EG
F
HR
G(N
RG
1)
Ep
i
-ce
l
HB
-E
GF
Am
p
Ep
i
HB
-GF
NR
G1
NR
G2
NR
G3
NRG4
Tyrosinekinase
domain
Ligandbindingdomain
Transmembrane
The EGFR/HER Family
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• Targets HER2 protein
• High affinity (Kd = 0.1 nM)
• High specificity95% human, 5% murineDecreases potential
for immunogenicity
HER2 epitopes recognized by hyper variable murine
antibody fragment
Human IgG-1
Trastuzumab:Humanized Anti-HER2 Antibody
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Transmembrane Structure of HER2 Receptor
Extracellular domain(632 amino acids)Ligand-binding site
Intracellular domain(580 amino acids)Tyrosine kinase activity
Transmembrane domain(22 amino acids)
Cytoplasm
Plasmamembrane
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HER2 Receptor Transmembrane Signal Transduction Pathway
Signaltransductionto nucleus
Nucleus
Binding site
Tyrosinekinase activity
Cytoplasm
Plasmamembrane
Growth factor
Gene activationCELL
DIVISION
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Role of HER2 in Breast Cancer
A HER2-positive status: predictor of poor prognosis multivariate analysis
• HER2 was a strong independent predictor:• relapse (p=0.001)• overall survival (p=0.02)
The HER2 receptor provides: Extracellular target specific anticancer treatment Herceptin
Slamon DJ et al. Science 1987;235:177–82
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Indicators of Increased HER2 Production
1 = gene copy number2 = mRNA transcription3 = cell surface receptor protein expression4 = release of receptor extracellular domain
A = HER2 DNAB = HER2 mRNAC = HER2 receptor protein
Normal Amplification/overexpression
Nucleus
Cytoplasm
Cytoplasmicmembrane
1
2
3
4
C
B
A
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Disease-Free Survival
87%87%85%85%
67%
75%
N EventsACT 1679 261ACTH 1672 134
%
HR=0.48, 2P=3x10-12
ACACTHTH
ACT
Years From Randomization B31/N9831
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Angiogenesis
• This concept first put forward by Folkman
• VEGF one of the most important mediators
• Endothelial cell specific mitogen
• Interacts with VEGFR-1 and VEGFR-2
• Essential for normal embryonic vasculogenesis
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Vascular Endothelial Growth Factor(VEGF)
• Transformed cell lines secrete VEGF
• VEGF mRNA :– high levels in many human tumours
• Increased microvessel density– poor prognostic factor
• VEGF felt to be:– major tumour angiogenesis factor in epithelial cancers
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VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
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VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X
X(1)
X(2)
X(3)
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Inhibiting Angiogenesis
• Deplete VEGF
• Block VEGF receptor:– Extracellular = monoclonal antibodies
– Intracellular = tyrosine kinase inhibitor
• Target immature endothelial cells
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VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X(1)
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Bevacizumab(Avastin)
• Humanized monoclonal antibody against VEGF:– Direct anti-angiogenic effect– Decreases vascular permeability
• Given via IV every two weeks
• Rare serious adverse effects:– Hypertension– Bleeding/Thrombosis
• Established benefit in CRC– Studies in renal, prostate and breast
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Colorectal Cancer
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Cetuximab(Erbitux)
• Monoclonal antibody targeting EGFR
• Blocks binding of ligand to the EGFR
• Leads to receptor internalization
• ADCC, complement activation
• Activity in:– colorectal cancer and SCCHN
• In vitro synergistic with radiation and chemo
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VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X(2)
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• Inherited RCC– Von Hippel-Lindau syndrome– Germ line mutation of chromosome 3p
• Non-inherited RCC: – VHL gene tumor suppressor gene inactivation– Expression of oxygen-regulated transcription factor
(HIFa)– Induction of hypoxia-inducible genes
• including vascular endothelial growth factor (VEGF)
• VEGF overexpression promotes tumor angiogenesis
Biology of RCC
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Mechanism of Action in RCC
RCC pathogenesis and progression
↑ VEGF ↑ PDGF
Vascularpermeability
Cell survival, proliferation, migration
Vascularformation, maturation
Loss of VHL Protein Function
VEGFR PDGFRVEGFVEGF PDGFPDGF
Vascular Endothelial CellVascular Endothelial Cell Pericyte/Fibroblast/Vascular Smooth Muscle
Pericyte/Fibroblast/Vascular Smooth Muscle
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Mechanism of Action in RCC
Inhibition of RCC pathogenesis and progression
↑ VEGF ↑ PDGF
Vascularpermeability
Cell survival, proliferation, migration
Vascularformation, maturation
Loss of VHL Protein Function
VEGFR PDGFRVEGFVEGF PDGFPDGF
Vascular Endothelial CellVascular Endothelial Cell Pericyte/Fibroblast/Vascular Smooth Muscle
Pericyte/Fibroblast/Vascular Smooth Muscle
SunitinibSorafenibSunitinibSorafenib
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Lung CancerGefitinib & Erlotinib
• In initial phase I (safety) trials of gefitinib– patients with NSCLC responded
• This led to phase II trials:– Gefitinib (Iressa)– Erlotinib (Tarceva)
• Response rates:– 10 – 15 % as single-agent– Females, non-smokers, adenocarcinoma– ? More likely to respond if get a rash?
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VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X(3)
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Inhibition of Growth Signals
• Prototype drug is Imatinib:– Gleavec– Binds to the tyrosine kinase domain of the
bcr-abl fusion protein in CML
• Leads to extremely high rates – complete responses– cytogenetic responses
• Also inhibits the TK of KIT, PDGFR
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GIST
• GIST:– Rare– chemoresistant sarcoma
• Often has gain-of-function mutations in KIT– Leads to constitutive activation– Driving force in oncogenesis of this tumor
• Imatinib leads to prolonged:– durable remissions in the majority of pts– Must express express KIT
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Putting it all Together
…welcome to my world!!
Knockout
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Principles of Oncology
• Stage and cell type
• Additional Factors: – patient characteristics:
•age•co-morbid conditions •psychological profile
– treatment related factors:•treatment intent/curative vs palliative•toxicity profile of therapy
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Principles ofCombination Systemic Therapy
• Objectives:– biochemical interactions between drugs
– maximum cell kill as tolerated by host
– broader range of coverage of resistant cell lines
– slows development of resistant cell lines
• Optimum dose and schedule
• Optimum combination of therapeutic drugs
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Summary
• Goal of therapy:– stage dependent– tumor type specific– incorporating host factors
• Selection of therapy:– single versus combination chemotherapy– combined versus single modality of therapy
• Toxicity of therapy:– overlapping/non-overlapping