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Biology of Cancer Principles of Systemic Therapy
• Immortality• Invasion• Loss of adherence• Autocrine
• Somatic and genetic differences • Implications for therapeutic approaches
Objectives
• Biology of malignancy
• Definition of Terms
• Principles of Systemic Therapy
• TNM Staging Classification
• Common Chemotherapy Agents
• Targeted Therapies
• Summary
Biology of Malignancy
Round 1
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
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
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
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
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
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”
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
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
Steps in Metastatic Cascade
• Escape
• Travel through the blood/lymphatic system
• Arrest/attachment
• Establishment of clone
MetastasesEscape
• May be biologically facilitated by:
– ability to commit vascular invasion
– cell necrosis
– molecules of the cell surface
– protease (enzyme) secretion by tumor
Travel
• Blood supply (angiogenesis) must be adequate
• Adequate lymphatic drainage
• Special circulatory circumstances
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
Gompertzian Growth Curve
LogKill
Time
Standard of Care
↓ Dose
Delayed Schedule
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
Definition of Terminology
Round 2
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)
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)
Principles of Systemic Therapy
Round 3
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
Gompertzian Growth Curve
LogKill
Time
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
Toxicity of Chemotherapy
Drug Anthracycline Vincas Antibiotics Taxanes Alkylators
Cardio X X X
CNS X X X
Edema X
Fibrosis X X
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
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
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
Staging Principles
TNM Classification
Round 4
Staging Principles
• Stage I– Organ confinement
• Stage II– Organ plus regional lymph nodes
• Stage III– Locally advanced
• Stage IV– Metastatic
Common Chemotherapeutic Agents
Round 5
Drug Classification
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
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
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
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
Antimicrotubule Mechanism of Action
Inhibition of Polymerization:
Inhibition of Depolymerization:
MicrotubuleTubulin
• docetaxel• paclitaxel
• vinblastine• vinorelbine
Vinca alkaloids
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
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
Taxanes
• Mechanism:– Interfere with structure and function
of the microtubules
• Indication:– Breast– Lung– Ovarian
• Analogues:– Taxol (TAC)– Taxotere
• Toxicity:– myelosuppression– neuropathy
SummaryCommon Agents
• Agents may be:– cell cycle dependent or independent– oral or intravenous– bolus or continuous infusion
• Specific toxicities:– nonoverlapping/overlapping– facilitate combination chemotherapy
Targeted Therapies
Round 6
Receptors HER-2 proteins
Antiangiogenesis
Treatment Options for Women with HER2 Positive Breast Cancer
“The Herceptin Story”
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
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
• 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
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
HER2 Receptor Transmembrane Signal Transduction Pathway
Signaltransductionto nucleus
Nucleus
Binding site
Tyrosinekinase activity
Cytoplasm
Plasmamembrane
Growth factor
Gene activationCELL
DIVISION
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
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
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
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
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
VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X
X(1)
X(2)
X(3)
Inhibiting Angiogenesis
• Deplete VEGF
• Block VEGF receptor:– Extracellular = monoclonal antibodies
– Intracellular = tyrosine kinase inhibitor
• Target immature endothelial cells
VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X(1)
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
Colorectal Cancer
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
VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X(2)
• 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
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
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
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?
VEGF
VEGFR - 2
Cell membrane
Tyrosine Kinase
Signal Transduction
X(3)
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
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
Putting it all Together
…welcome to my world!!
Knockout
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
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
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
