EMIR T PASARIBU

BLOCK ONKOLOGY
 PERSPECTIVE

 Cancer is not modern disease

 Hippocrates (± 400 bc): Cancer as
imbalance between black humor
(spleen) and three bodily humor
(blood, plegm, bile)
Sir Percival Pott (1775):
one of the first scientific inquiries
in to the cause of the cancer
→ observed chimney soot
as carcinogen for cancer of
the scrotal.
Virchow, 19 th century, pathologist
“every cell is born from another cell”
Cancer as a cellular disease,
where was loss of normal
control of the cell
prolifration
Fisher:
Breast cancer is
systemic disease
as its inception
Mormons in Utah
 Many type of cancer depend on relatedness
– that is, on the sharing of genes
 Cancer, as a genetic disease
 Basic molecules of life

All life depends on three critical molecules:

1. DNAs
 Hold information on how cell works
2. RNAs
 Act to transfer short pieces of information to different
parts of cell
 Provide templates to synthesize into protein
3. Proteins
 Form enzymes that send signals to other cells and
regulate gene activity
 Form body’s major components (e.g. hair, skin, etc.)
 Central Dogma of Molecular Biology

DNA
Translation

RNA
Transcription

Protein
A gene is expressed in 3 steps:
1) Transcription: RNA synthesis
2) Splicing: removal of intron sequence from RNA
3) Translation: Protein synthesis
 Genetic alteration may arise direct or
indirect from:
1. Inherited gen mutations
2.Chemical or radiation induced DNA
damage and genetic instability
3.Incorporation of virus into the cell
4.Random error during DNA synthesis
Cause of cancer?
Multiple genetic abnormalities
Internal factors : defect genetic/inherited
External factors :
 X RAYS
 Viral infections
 Carcinogenic compounds : food, working
area, lifestyle
KARSINOGENESIS
 Merupakan proses perubahan menjadi kanker
 Melalui tahapan multi step karsinogenesis
1. TAHAP INISIASI

2. TAHAP PROMOSI

3. TAHAP PROGRESI (Transformasi maligna)

 Inisiasi dan Promosi akibat akumulasi mutasi

DNA → reversibel eg. displasia
 PROGRESI → irreversibel
INTERAKSI INISIATOR DAN PROMOTOR
 Proto-Oncogene Oncogene

1.Mutation 2. Abnormal 3.Gene Translocation 4. Amplification

Activity

Abnormal Activity

How does a Proto-oncogene

become an Oncogene?
Functions of oncogene
1. Growth Factor (ex: Epithelium growth
factor EGF , and platelet derived
growth factor PDGF)
2. Growth Factor Receptor (Ex: PDGFR)
3. Signal transudation (example; Ras,
Raf, & MEK)
4. Transcription Factor (example; Jun,
Fos, Elk-1 & myc)
 Oncogenes
 Oncogene causes cancer by affecting:
1. Cell Proliferation: (ex: Ras, Raf, EGF)
2. Cell differentiation (ex: PML/RAR that
inhibits the differentiation of
promyelocyte to granulocyte which
will maintain the cell in its active
proliferate state)
3. Cell Survival (ex: PIK-3/AKT will
activate BCL-2 inhibit
Apoptosis & maintain cell survival.
Tumour Suppressor Genes
Tumour Suppressor genes: are genes that
act to inhibit cell proliferation and
tumour development.
If Tumor Suppresor Gene was

Mutated OR Inactivated

It will lead to cell transformation

Function of Tumour Suppressor gene
1. Antagonize the action of oncogene. (ex.PTEN which
converts PIPIII to PIPII because PIPIII will activate Pl-
3/AKT which will activate BCL-2 that will inhibit apoptosis
and induce cell transformation)

PTEN
PIPII PIPIII
PI-3
AKT

BCL-2

Inhibit apoptosis & induce

cell transformation
Function of Tumour Suppressor gene
2. Transcription factors
 Repressor transcription factors: exa, WT1
is a repressor that appears to suppress
transcription factor ( Insulin like growth
factor) which will contribute in the
development of tumour
 Activator transcription factors: exa,SMAD
family that are activated by TGF-β,
leading to inhibition of cell proliferation
Function of Tumour Suppressor gene
3. Regulate cell cycle :
 Rb gene: that inhibits the cell cycle in the
G1 phase decrease cell proliferation
 INK-4 gene: that produces P16 that
inhibits cdk4/cyclin D action ( to
phosphorylate Rb gene to inactivate it’s
action)
 P53: that produces P21 that has the same
action of P16 in inhibiting the action of
cdk4/cyclin D
Function of Tumour Suppressor gene

4. Induce apoptosis:
 P53 release will increase Bax
form holes in the mitochondria
release cytochrom c
activate apoptosis
 number of
cancer cells
Tumor Growth
10 12

10 9 diagnostic
threshold
(1cm)

time

undetectable detectable
cancer cancer

limit of host
clinical death
detection
Gompertzian Growth
• Growth rates are exponential at early stages of
development and slower at later stages of development.

- Biological growth follows this characteristic curve.

22
The Future of Onccology
 Prevention
 Early detection
 Treatment
Biomarkers and Prevention…?
 Folate and vit B12 – decreased breast Ca risk
(Canc Epid Biomarkers Prev 2006;15(3):443-448)
 Genetic variation of Nucleotide excission repair
(NER) and cancer risk ( Canc Epid Biomarkers
Prev 2006;15:536-542)
 Lipid profile :Monosaturates lipid elevated and
low ratio w6/w3 fatty acid – decreased breast ca
risk ( Canc Epid Biomarkers Prev 2006;15:416-
421)
Cancer Detection
 Cancer detection :
 Clinical detection by mammogram,
coloscopy… etc
 Molecular detection Serotype
 Restriction fragment length
polymorphism (RFLP)
 PCR
 Western Blot
CANCER TREATMENT
 SURGERY
 RADIATION THERAPY
 CHEMOTHERAPY
 HORMONAL THERAPY
 TARGETED THERAPY
Cancer Treatment
 Chemotherapy:
 Deals with DNA damage, & has affinity to all
proliferating cells not specifying if it was a cancer
cell or not.
 Inhibiting Angiogenesis
 Inhibit blood flow/supply to the tumour cells
 Decrease franesylation of Ras
 Decrease activation of Ras, because Ras mutation
causes most cancers.
 Monoclonal Antibody
What is Targeted Therapy?
 If we use the analogy of pesticides: empiric
therapy would be “Raid” while targeted therapy
is the “Roach Hotel.”
Dr. David Gandara

 A “smart” bomb versus a “cluster” bomb.

Dr. Nevin Murray
How to hit the target

 If you know the target, and there is only one

target you can be very specific.
 If you don’t really know or it’s a really big target,
a larger weapon may be needed.
Six Essential Alterations
in Cell Physiology in Malignancy
Self-sufficiency in
Hanahan & Weinberg,
growth signals
Cell 100:57 (2000)
Evading Insensitivity to
apoptosis anti-growth signals

Targets for classical drugs?

Targets for novel drugs?

Sustained Tissue invasion

angiogenesis & metastasis

Limitless replicative
potential
Targeted Therapy: The Future
 Modern biology has identified a host of new
potential targets for cancer therapy
 Drugs interacting with these targets are available.
 The benefit of these agents is dependant upon the
criticality of the target. More than one target may
need to be inhibited.
 New agents may “tip the balance” when combined
with chemotherapy, radiation.
Molecular target in cancer therapy
 Anti tyrosine kinase: Gleevec, Iressa
 Anti VEGF
 EGFR inhibitor etc

Need to enhance translational research into early

IRT-MTA (Interdiscilinary Research Teams) for
Molecular Target assesment
 Development of Technical
Operation of Breast Cancer

Ancient →→ CRM/MRM → → BCT → → NSP+TRAM

 Key words
Oncogenesis: Pathogenesis of neoplasm (b/m)
Carcinogenesis: Pathogenesis of cancer (m)
Carcinogen - agent causing cancer.
Oncogen - agent causing neoplasm.
Mutagen - agent causing mutation.
Tumour Suppressor genes: are genes that act
to inhibit cell proliferation and tumour
development.
1. Tannock IF. Introduction to Cancer Biology. In :
The Basic Science of Oncology, Mc Graw-Hill
Inc, Boston, 2005.
2. Devita VT, Hellman S, Rosenberg SA. Penyunting.
Cancer Principlels & practice of Oncology. Edisi
ke-8. Philadelphia. Lippincott William & Wilkins.
2008.
3. Sofia MH. Mutagenesis dan Transformasi, Basic
Science of Oncology, Ilmu Onkologi Dasar. POI.BP
FKUI, Jakarta 2010
4. Cornain S. Perangai Biologik Sel Kanker dan
Onkogenesis, Basic Science of Oncology, Ilmu
Onkologi Dasar, POI,BP FKUI,Jakarta 2010
TERIMAKASIH