Principles of Cancer Biology and Therapy

Gunjan Mehta, M.Sc., (PhD)Dept. of Biotechnology,

VSC, Rajkot

Cancer and Age

Breast Colon

ALL Testicular CNS

NCCC 1988 - 2004

1. Heart Diseases 685,089 28.0

2. Cancer 556,902 22.7

3. Cerebrovascular diseases 157,689 6.4

4. Chronic lower respiratory diseases 126,382 5.2

5. 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

Rank Cause of DeathNo. of deaths

% of all deaths

US Mortality, 2003

Nomenclature

• Benign– “Polyp”

• Malignant – Epithelial

• ‘Carcinoma’

– Mesenchyme• ‘Sarcoma’

– Hematopoietic• Leukemia, lymphoma, myeloma

2006 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2006.

Men720,280

Women679,510

31% Breast

12% Lung & bronchus

11% Colon & rectum

6% Uterine corpus

4% Non-Hodgkin lymphoma

4% Melanoma of skin

3% Thyroid

3% Ovary

2% Urinary bladder

2% Pancreas

22% All Other Sites

Prostate 33%

Lung & bronchus 13%

Colon & rectum 10%

Urinary bladder 6%

Melanoma of skin 5%

Non-Hodgkin 4% lymphoma

Kidney 3%

Oral cavity 3%

Leukemia 3%

Pancreas 2%

All Other Sites 18%

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

Scaltriti et al, 2006

• Autocrine loops

• Over-expression of receptor

• Receptor is always ‘on’

• Downstream signals

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

• Consolidation– “Mantle radiation”– “Axillary radiation”

• Palliation– Spinal cord compression– Pain relief

Radiation

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

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http://www.slideshare.net/gunjan_rjt

• E mail:

gunjan.rjt@gmail.com