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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 broken.”

Dingli & Pacheco, 2008


Cancer stem cells
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
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


Cytogenetic abnormalities

Translocations broken.”

Balanced

Reciprocal

Aneuploidy

Pseudodiploid

Hyperdiploid

Complex

Random loss or gain

Cytogenetic abnormalities


Limitless reproductive potential
Limitless reproductive potential broken.”

  • 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 broken.”

  • Autocrine loops

  • Over-expression of receptor

  • Receptor is always ‘on’

  • Downstream signals

Scaltriti et al, 2006


Insensitivity to antigrowth signals
Insensitivity to antigrowth signals broken.”

Hanahan & Weinberg, 2000


Evading apoptosis
Evading apoptosis broken.”

  • External triggers

  • Intracellular triggers

  • Death receptors

  • Caspases

    • Sensors (8, 9)

    • Executioners (3)


Sustained angiogenesis
Sustained angiogenesis broken.”

  • VEGF

  • FGF1/2

  • Thrombospondin

  • Thalidomide

  • Avastin



Tumor burden staging
Tumor burden - Staging broken.”

  • Tumor

    • Size, capsule invasion

  • Nodes

    • Involved, how many?

  • Metastases

    • Present/absent

    • “Unknown primary”


Imaging
Imaging broken.”

  • CT scan

  • PET/CT

  • SPECT/CT

  • MRI

  • Staging

  • Response


Prognostic scoring systems
Prognostic scoring systems broken.”

  • Host vs Disease

  • Disease burden

  • Disease biology

  • Co-morbid conditions

  • Performance status


Therapy
Therapy broken.”

  • Surgery

  • Radiation

  • Chemotherapy

  • Antibodies

  • Small molecules

  • Adjunctive


Surgery
Surgery broken.”

  • Diagnosis

  • Therapy

    • Curative

    • Palliative

      • Debulking

      • Symptoms control

      • Prevent complications


Radiation
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
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


Radiation1
Radiation broken.”

  • Consolidation

    • “Mantle radiation”

    • “Axillary radiation”

  • Palliation

    • Spinal cord compression

    • Pain relief


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


Free isotopes
Free isotopes broken.”


Chemotherapy
Chemotherapy broken.”

  • Antimetabolites

    • Antifolates, Purine nucleosides, nucleoside synthesis inhibitors

  • Alkylators

    • Direct DNA damage (Many), platinum

  • Spindle poisons

    • Vinca alkaloids, taxanes

  • Topoisomerase inhibitors

    • Anthracyclines, Etoposide


Chemotherapy1
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
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


Antibodies1
Antibodies broken.”


Small molecules
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 molecules1
Small molecules broken.”


Adjuncts
Adjuncts broken.”

  • Glucocorticosteroids

  • Estrogens/anti-androgens/SERMs

  • Bisphosphonates


The target
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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