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Principles of Cancer Biology and Therapy

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... Resistance Hallmarks of cancer Self-sufficiency in growth signals Insensitivity to anti-growth signals Evading apoptosis Limitless reproductive ... – PowerPoint PPT presentation

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Title: Principles of Cancer Biology and Therapy


1
Principles of Cancer Biology and Therapy
  • David Dingli, MD, PhD
  • Hematology and Molecular Medicine
  • Mayo Clinic Rochester

2
Cancer and Age
Breast
Colon
Testicular
CNS
ALL
NCCC 1988 - 2004
3
Nomenclature
  • Benign
  • Polyp
  • Malignant
  • Epithelial
  • Carcinoma
  • Mesenchyme
  • Sarcoma
  • Hematopoietic
  • Leukemia, lymphoma, myeloma

4
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5
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6
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)

7
Cancer pathogenesis
  • Oncogenes
  • myc, ras, src, abl, bcl2
  • Tumor suppressor genes
  • p53, Rb, APC, MEN1, NF1
  • MicroRNA
  • Transcriptome control

8
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

9
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
10
I always thought that record would stand until
it was broken.
  • Yogi Berra

11
Tissue and tumor architecture
Dingli Pacheco, 2008
12
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

13
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

14
Cytogenetic abnormalities
  • Translocations
  • Balanced
  • Reciprocal
  • Aneuploidy
  • Pseudodiploid
  • Hyperdiploid
  • Complex
  • Random loss or gain

15
Limitless reproductive potential
  • Hayflick hypothesis
  • Limited number of doublings
  • Telomere maintenance
  • Telomerase
  • Not all tumor cells have this potential
  • Tumor stem cells

16
Self-sufficiency in growth signals
  • Autocrine loops
  • Over-expression of receptor
  • Receptor is always on
  • Downstream signals

Scaltriti et al, 2006
17
Insensitivity to antigrowth signals
Hanahan Weinberg, 2000
18
Evading apoptosis
  • External triggers
  • Intracellular triggers
  • Death receptors
  • Caspases
  • Sensors (8, 9)
  • Executioners (3)

19
Sustained angiogenesis
  • VEGF
  • FGF1/2
  • Thrombospondin
  • Thalidomide
  • Avastin

20
Tissue invasion and metastases
21
Tumor burden - Staging
  • Tumor
  • Size, capsule invasion
  • Nodes
  • Involved, how many?
  • Metastases
  • Present/absent
  • Unknown primary

22
Imaging
  • CT scan
  • PET/CT
  • SPECT/CT
  • MRI
  • Staging
  • Response

23
Prognostic scoring systems
  • Host vs Disease
  • Disease burden
  • Disease biology
  • Co-morbid conditions
  • Performance status

24
Therapy
  • Surgery
  • Radiation
  • Chemotherapy
  • Antibodies
  • Small molecules
  • Adjunctive

25
Surgery
  • Diagnosis
  • Therapy
  • Curative
  • Palliative
  • Debulking
  • Symptoms control
  • Prevent complications

26
Radiation
  • External beam radiation
  • Gamma photons
  • Neutron beams
  • Radioimmunoconjugates
  • Antibody targeted radiation
  • Radioconjugates
  • Isotope tagged to bone seeking material
  • Free isotopes
  • 131I, Gallium

27
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

28
Radiation
  • Consolidation
  • Mantle radiation
  • Axillary radiation
  • Palliation
  • Spinal cord compression
  • Pain relief

29
Radio(immuno)conjugates? or ?-emitters
30
Free isotopes
31
Chemotherapy
  • Antimetabolites
  • Antifolates, Purine nucleosides, nucleoside
    synthesis inhibitors
  • Alkylators
  • Direct DNA damage (Many), platinum
  • Spindle poisons
  • Vinca alkaloids, taxanes
  • Topoisomerase inhibitors
  • Anthracyclines, Etoposide

32
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

33
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

34
Antibodies
35
Small molecules
  • Target oncogene product
  • Bcr-Abl, PML-RARA,
  • Inhibit signaling at key steps
  • Safer than chemotherapy
  • Specific side effects
  • Specificity is often relative

36
Small molecules
37
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38
Adjuncts
  • Glucocorticosteroids
  • Estrogens/anti-androgens/SERMs
  • Bisphosphonates

39
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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