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Principles of Cancer Biology and Therapy. David Dingli, MD, PhD Hematology and Molecular Medicine Mayo Clinic Rochester. Cancer and Age. Breast. Colon. Testicular. CNS. ALL. NCCC 1988 - 2004. Nomenclature. Benign “ Polyp ” Malignant Epithelial ‘Carcinoma’ Mesenchyme ‘Sarcoma’

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principles of cancer biology and therapy

Principles of Cancer Biology and Therapy

David Dingli, MD, PhD

Hematology and Molecular Medicine

Mayo Clinic Rochester

cancer and age
Cancer and Age

Breast

Colon

Testicular

CNS

ALL

NCCC 1988 - 2004

nomenclature
Nomenclature
  • Benign
    • “Polyp”
  • Malignant
    • Epithelial
      • ‘Carcinoma’
    • Mesenchyme
      • ‘Sarcoma’
    • Hematopoietic
      • Leukemia, lymphoma, myeloma
etiology
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)
cancer pathogenesis
Cancer pathogenesis
  • Oncogenes
    • myc, ras, src, abl, bcl2
  • Tumor suppressor genes
    • p53, Rb, APC, MEN1, NF1
  • MicroRNA
    • Transcriptome control
the path to cancer
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
hallmarks of cancer
“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

tissue and tumor architecture
Tissue and tumor architecture

Dingli & Pacheco, 2008

cancer stem cells
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
genomic instability
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
cytogenetic abnormalities
Translocations

Balanced

Reciprocal

Aneuploidy

Pseudodiploid

Hyperdiploid

Complex

Random loss or gain

Cytogenetic abnormalities
limitless reproductive potential
Limitless reproductive potential
  • Hayflick hypothesis
  • Limited number of doublings
  • Telomere maintenance
  • Telomerase
  • Not all tumor cells have this potential
    • Tumor stem cells
self sufficiency in growth signals
Self-sufficiency in growth signals
  • Autocrine loops
  • Over-expression of receptor
  • Receptor is always ‘on’
  • Downstream signals

Scaltriti et al, 2006

insensitivity to antigrowth signals
Insensitivity to antigrowth signals

Hanahan & Weinberg, 2000

evading apoptosis
Evading apoptosis
  • External triggers
  • Intracellular triggers
  • Death receptors
  • Caspases
    • Sensors (8, 9)
    • Executioners (3)
sustained angiogenesis
Sustained angiogenesis
  • VEGF
  • FGF1/2
  • Thrombospondin
  • Thalidomide
  • Avastin
tumor burden staging
Tumor burden - Staging
  • Tumor
    • Size, capsule invasion
  • Nodes
    • Involved, how many?
  • Metastases
    • Present/absent
    • “Unknown primary”
imaging
Imaging
  • CT scan
  • PET/CT
  • SPECT/CT
  • MRI
  • Staging
  • Response
prognostic scoring systems
Prognostic scoring systems
  • Host vs Disease
  • Disease burden
  • Disease biology
  • Co-morbid conditions
  • Performance status
therapy
Therapy
  • Surgery
  • Radiation
  • Chemotherapy
  • Antibodies
  • Small molecules
  • Adjunctive
surgery
Surgery
  • Diagnosis
  • Therapy
    • Curative
    • Palliative
      • Debulking
      • Symptoms control
      • Prevent complications
radiation
Radiation
  • External beam radiation
    • Gamma photons
    • Neutron beams
  • Radioimmunoconjugates
    • Antibody targeted radiation
  • Radioconjugates
    • Isotope tagged to bone seeking material
  • Free isotopes
    • 131I, Gallium
radiation targets
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
radiation1
Radiation
  • Consolidation
    • “Mantle radiation”
    • “Axillary radiation”
  • Palliation
    • Spinal cord compression
    • Pain relief
chemotherapy
Chemotherapy
  • Antimetabolites
    • Antifolates, Purine nucleosides, nucleoside synthesis inhibitors
  • Alkylators
    • Direct DNA damage (Many), platinum
  • Spindle poisons
    • Vinca alkaloids, taxanes
  • Topoisomerase inhibitors
    • Anthracyclines, Etoposide
chemotherapy1
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
antibodies
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
small molecules
Small molecules
  • Target oncogene product
    • Bcr-Abl, PML-RARA,
  • Inhibit signaling at key steps
  • Safer than chemotherapy
  • Specific side effects
  • Specificity is often relative
adjuncts
Adjuncts
  • Glucocorticosteroids
  • Estrogens/anti-androgens/SERMs
  • Bisphosphonates
the target
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
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