Principles of Cancer Biology and Therapy

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Principles of Cancer Biology and Therapy

• David Dingli, MD, PhD
• Hematology and Molecular Medicine
• Mayo Clinic Rochester

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Cancer and Age
Breast
Colon
Testicular
CNS
ALL
NCCC 1988 - 2004
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Nomenclature

• Benign
• Polyp
• Malignant
• Epithelial
• Carcinoma
• Mesenchyme
• Sarcoma
• Hematopoietic
• Leukemia, lymphoma, myeloma

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Etiology

• Nature
• Inherited cancer syndromes
• p53, BRCA1 and 2, MMR
• Immune deficiency syndromes
• Inherited/Congenital or acquired
• Nurture
• Radiation (cosmic, fallout, radon)
• Chemotherapy (MDS)
• Viruses and bacteria
• EBV, HTLV-I/II, H. pylori
• Repeated injury (Acid reflux, hepatitis)

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Cancer pathogenesis

• Oncogenes
• myc, ras, src, abl, bcl2
• Tumor suppressor genes
• p53, Rb, APC, MEN1, NF1
• MicroRNA
• Transcriptome control

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The path to cancer

• Clonal proliferation
• Starts from a single cell
• Expansion in steps
• Pre-malignant states
• Polyp, MDS, MGUS
• Serial accumulation of mutations
• Clonal evolution
• Resistance

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Hallmarks of cancer

• Self-sufficiency in growth signals
• Insensitivity to anti-growth signals
• Evading apoptosis
• Limitless reproductive potential
• Sustained angiogenesis
• Tissue invasion and metastases
• Genomic instability

Hanahan Weinberg, 2000
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I always thought that record would stand until
it was broken.

• Yogi Berra

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Tissue and tumor architecture
Dingli Pacheco, 2008
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Cancer stem cells

• Present in most (all) tumors
• Small fraction of population
• No universal marker
• Often resistant to therapy
• May be important target of therapy
• Cancer initiating cells in mice

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Genomic instability

• Is it necessary?
• Normal vs abnormal mutation rate
• 2 current views
• Chromosomal instability
• Gross translocations, loss and gain of chromosome
  parts
• Mutator phenotype
• Repair genes
• Xeroderma pigmentosum
• MMR etc

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Cytogenetic abnormalities

• Translocations
• Balanced
• Reciprocal
• Aneuploidy
• Pseudodiploid
• Hyperdiploid
• Complex
• Random loss or gain

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Limitless reproductive potential

• Hayflick hypothesis
• Limited number of doublings
• Telomere maintenance
• Telomerase
• Not all tumor cells have this potential
• Tumor stem cells

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Self-sufficiency in growth signals

• Autocrine loops
• Over-expression of receptor
• Receptor is always on
• Downstream signals

Scaltriti et al, 2006
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Insensitivity to antigrowth signals
Hanahan Weinberg, 2000
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Evading apoptosis

• External triggers
• Intracellular triggers
• Death receptors
• Caspases
• Sensors (8, 9)
• Executioners (3)

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Sustained angiogenesis

• VEGF
• FGF1/2
• Thrombospondin
• Thalidomide
• Avastin

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Tissue invasion and metastases
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Tumor burden - Staging

• Tumor
• Size, capsule invasion
• Nodes
• Involved, how many?
• Metastases
• Present/absent
• Unknown primary

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Imaging

• CT scan
• PET/CT
• SPECT/CT
• MRI
• Staging
• Response

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Prognostic scoring systems

• Host vs Disease
• Disease burden
• Disease biology
• Co-morbid conditions
• Performance status

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Therapy

• Surgery
• Radiation
• Chemotherapy
• Antibodies
• Small molecules
• Adjunctive

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Surgery

• Diagnosis
• Therapy
• Curative
• Palliative
• Debulking
• Symptoms control
• Prevent complications

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Radiation

• External beam radiation
• Gamma photons
• Neutron beams
• Radioimmunoconjugates
• Antibody targeted radiation
• Radioconjugates
• Isotope tagged to bone seeking material
• Free isotopes
• 131I, Gallium

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Radiation targets

• DNA
• Water
• Free radical generation
• Oxygen is required
• Anti-oxidants are not helpful
• Direct and indirect effects
• Not all cells are created equal
• Geometry important

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Radiation

• Consolidation
• Mantle radiation
• Axillary radiation
• Palliation
• Spinal cord compression
• Pain relief

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Radio(immuno)conjugates? or ?-emitters
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Free isotopes
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Chemotherapy

• Antimetabolites
• Antifolates, Purine nucleosides, nucleoside
  synthesis inhibitors
• Alkylators
• Direct DNA damage (Many), platinum
• Spindle poisons
• Vinca alkaloids, taxanes
• Topoisomerase inhibitors
• Anthracyclines, Etoposide

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Chemotherapy

• Often used in combinations
• CHOP, ABVD, AC, Taxol/Carbo
• Minimizes resistance
• Reduces toxicity
• Different side effects
• Can be curative in specific cases
• AML, ALL, HD, NHL, Testicular cancer

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Antibodies

• Target specific antigen
• Specificity is relative
• Various mechanisms of action
• Complement activation
• ADCC
• Calcium entry
• May synergize with chemotherapy
• R-CHOP and CHOP
• Expected or unexpected toxicities

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Antibodies
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Small molecules

• Target oncogene product
• Bcr-Abl, PML-RARA,
• Inhibit signaling at key steps
• Safer than chemotherapy
• Specific side effects
• Specificity is often relative

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Small molecules
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Adjuncts

• Glucocorticosteroids
• Estrogens/anti-androgens/SERMs
• Bisphosphonates

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The target

• Tumor cells do not live in isolation
• Stroma
• Adhesion resistance
• Blood vessels
• Angiogenesis inhibitors
• Antibodies (Avastin)
• Small molecules (Thalidomide, other IMiDs)
• Immune system
• Transplantation
• Vaccines