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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 l.jpg

Principles of Cancer Biology and Therapy

David Dingli, MD, PhD

Hematology and Molecular Medicine

Mayo Clinic Rochester


Cancer and age l.jpg
Cancer and Age

Breast

Colon

Testicular

CNS

ALL

NCCC 1988 - 2004


Nomenclature l.jpg
Nomenclature

  • Benign

    • “Polyp”

  • Malignant

    • Epithelial

      • ‘Carcinoma’

    • Mesenchyme

      • ‘Sarcoma’

    • Hematopoietic

      • Leukemia, lymphoma, myeloma


Etiology l.jpg
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 l.jpg
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



Tissue and tumor architecture l.jpg
Tissue and tumor architecture broken.”

Dingli & Pacheco, 2008


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Cancer stem cells broken.”

  • 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 l.jpg
Genomic instability broken.”

  • 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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Translocations broken.”

Balanced

Reciprocal

Aneuploidy

Pseudodiploid

Hyperdiploid

Complex

Random loss or gain

Cytogenetic abnormalities


Limitless reproductive potential l.jpg
Limitless reproductive potential broken.”

  • 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 broken.”

  • Autocrine loops

  • Over-expression of receptor

  • Receptor is always ‘on’

  • Downstream signals

Scaltriti et al, 2006


Insensitivity to antigrowth signals l.jpg
Insensitivity to antigrowth signals broken.”

Hanahan & Weinberg, 2000


Evading apoptosis l.jpg
Evading apoptosis broken.”

  • External triggers

  • Intracellular triggers

  • Death receptors

  • Caspases

    • Sensors (8, 9)

    • Executioners (3)


Sustained angiogenesis l.jpg
Sustained angiogenesis broken.”

  • VEGF

  • FGF1/2

  • Thrombospondin

  • Thalidomide

  • Avastin



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Tumor burden - Staging broken.”

  • Tumor

    • Size, capsule invasion

  • Nodes

    • Involved, how many?

  • Metastases

    • Present/absent

    • “Unknown primary”


Imaging l.jpg
Imaging broken.”

  • CT scan

  • PET/CT

  • SPECT/CT

  • MRI

  • Staging

  • Response


Prognostic scoring systems l.jpg
Prognostic scoring systems broken.”

  • Host vs Disease

  • Disease burden

  • Disease biology

  • Co-morbid conditions

  • Performance status


Therapy l.jpg
Therapy broken.”

  • Surgery

  • Radiation

  • Chemotherapy

  • Antibodies

  • Small molecules

  • Adjunctive


Surgery l.jpg
Surgery broken.”

  • Diagnosis

  • Therapy

    • Curative

    • Palliative

      • Debulking

      • Symptoms control

      • Prevent complications


Radiation l.jpg
Radiation broken.”

  • External beam radiation

    • Gamma photons

    • Neutron beams

  • Radioimmunoconjugates

    • Antibody targeted radiation

  • Radioconjugates

    • Isotope tagged to bone seeking material

  • Free isotopes

    • 131I, Gallium


Radiation targets l.jpg
Radiation targets broken.”

  • 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 broken.”

  • Consolidation

    • “Mantle radiation”

    • “Axillary radiation”

  • Palliation

    • Spinal cord compression

    • Pain relief


Radio immuno conjugates or emitters l.jpg
Radio(immuno)conjugates broken.” or -emitters


Free isotopes l.jpg
Free isotopes broken.”


Chemotherapy l.jpg
Chemotherapy broken.”

  • Antimetabolites

    • Antifolates, Purine nucleosides, nucleoside synthesis inhibitors

  • Alkylators

    • Direct DNA damage (Many), platinum

  • Spindle poisons

    • Vinca alkaloids, taxanes

  • Topoisomerase inhibitors

    • Anthracyclines, Etoposide


Chemotherapy32 l.jpg
Chemotherapy broken.”

  • 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 l.jpg
Antibodies broken.”

  • 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


Antibodies34 l.jpg
Antibodies broken.”


Small molecules l.jpg
Small molecules broken.”

  • Target oncogene product

    • Bcr-Abl, PML-RARA,

  • Inhibit signaling at key steps

  • Safer than chemotherapy

  • Specific side effects

  • Specificity is often relative


Small molecules36 l.jpg
Small molecules broken.”


Adjuncts l.jpg
Adjuncts broken.”

  • Glucocorticosteroids

  • Estrogens/anti-androgens/SERMs

  • Bisphosphonates


The target l.jpg
The target broken.”

  • 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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