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

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


I always thought that record would stand until it was broken

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

Yogi Berra


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


Tissue invasion and metastases

Tissue invasion and metastases


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


Radio immuno conjugates or emitters

Radio(immuno)conjugates or -emitters


Free isotopes

Free isotopes


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


Antibodies1

Antibodies


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


Small molecules1

Small molecules


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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