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. 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

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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’

    • Hematopoietic

      • Leukemia, lymphoma, myeloma


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

  • Oncogenes

    • myc, ras, src, abl, bcl2

  • Tumor suppressor genes

    • p53, Rb, APC, MEN1, NF1

  • MicroRNA

    • Transcriptome control


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”

  • 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


“I always thought that record would stand until it was broken.”

Yogi Berra


Tissue and tumor architecture

Dingli & Pacheco, 2008


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

  • 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


Translocations

Balanced

Reciprocal

Aneuploidy

Pseudodiploid

Hyperdiploid

Complex

Random loss or gain

Cytogenetic abnormalities


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

  • Autocrine loops

  • Over-expression of receptor

  • Receptor is always ‘on’

  • Downstream signals

Scaltriti et al, 2006


Insensitivity to antigrowth signals

Hanahan & Weinberg, 2000


Evading apoptosis

  • External triggers

  • Intracellular triggers

  • Death receptors

  • Caspases

    • Sensors (8, 9)

    • Executioners (3)


Sustained angiogenesis

  • VEGF

  • FGF1/2

  • Thrombospondin

  • Thalidomide

  • Avastin


Tissue invasion and metastases


Tumor burden - Staging

  • Tumor

    • Size, capsule invasion

  • Nodes

    • Involved, how many?

  • Metastases

    • Present/absent

    • “Unknown primary”


Imaging

  • CT scan

  • PET/CT

  • SPECT/CT

  • MRI

  • Staging

  • Response


Prognostic scoring systems

  • Host vs Disease

  • Disease burden

  • Disease biology

  • Co-morbid conditions

  • Performance status


Therapy

  • Surgery

  • Radiation

  • Chemotherapy

  • Antibodies

  • Small molecules

  • Adjunctive


Surgery

  • Diagnosis

  • Therapy

    • Curative

    • Palliative

      • Debulking

      • Symptoms control

      • Prevent complications


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

  • 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


Radiation

  • Consolidation

    • “Mantle radiation”

    • “Axillary radiation”

  • Palliation

    • Spinal cord compression

    • Pain relief


Radio(immuno)conjugates or -emitters


Free isotopes


Chemotherapy

  • Antimetabolites

    • Antifolates, Purine nucleosides, nucleoside synthesis inhibitors

  • Alkylators

    • Direct DNA damage (Many), platinum

  • Spindle poisons

    • Vinca alkaloids, taxanes

  • Topoisomerase inhibitors

    • Anthracyclines, Etoposide


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

  • 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


Antibodies


Small molecules

  • Target oncogene product

    • Bcr-Abl, PML-RARA,

  • Inhibit signaling at key steps

  • Safer than chemotherapy

  • Specific side effects

  • Specificity is often relative


Small molecules


Adjuncts

  • Glucocorticosteroids

  • Estrogens/anti-androgens/SERMs

  • Bisphosphonates


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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