Cancer biology
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Cancer biology

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Cancer biology Cancer biology Presentation Transcript

  • Principles of Cancer Biology and Therapy Gunjan Mehta, M.Sc., (PhD) Dept. of Biotechnology, VSC, Rajkot
  • Cancer and Age Breast ColonALL Testicular CNS NCCC 1988 - 2004
  • US Mortality, 2003 No. of % of allRank Cause of Death deaths deaths 1. Heart Diseases 685,089 28.0 2. Cancer 556,902 22.7 3. Cerebrovascular diseases 157,689 6.44. Chronic lower respiratory diseases 126,382 5.25. Accidents (Unintentional injuries) 109,277 4.5 6. Diabetes mellitus 74,219 3.0 7. Influenza and pneumonia 65,163 2.7 8. Alzheimer disease 63,457 2.6 1. Nephritis 42,453 1.7 10. Septicemia 34,069 1.4
  • Nomenclature• Benign – “Polyp”• Malignant – Epithelial • „Carcinoma‟ – Mesenchyme • „Sarcoma‟ – Hematopoietic • Leukemia, lymphoma, myeloma
  • 2006 Estimated US Cancer Cases* Men Women 720,280 679,510 Prostate 33% 31% Breast Lung & bronchus 13% 12% Lung & bronchus Colon & rectum 10% 11% Colon & rectum Urinary bladder 6% 6%Uterine corpus Melanoma of skin 5% 4% Non-Hodgkin lymphomaNon-Hodgkin 4% lymphoma 4%Melanoma of skin Kidney 3% 3% ThyroidOral cavity 3% 3% Ovary Leukemia 3% 2%Urinary bladder Pancreas 2% 2%Pancreas All Other Sites 18% 22% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2006.
  • 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
  • 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
  • Cytogenetic abnormalities• Translocations – Balanced – Reciprocal• Aneuploidy – Pseudodiploid – Hyperdiploid – Complex – Random loss or gain
  • 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
  • Support• Slideshare account:http://www.slideshare.net/gunjan_rjt• E mail:gunjan.rjt@gmail.com