Jan 18, 2016
Molecular Biology of Cancer
CANCER TAKES TIME
CANCER IS A DISEASE OF GENETIC MUTATIONS
ACCUMULATION OF MANY MUTATIONS CAUSES CANCER
YOU MUST REMEMBER THAT ALL MUTATIONS ARE
RANDOMYOU WILL MUTATE DRIVERS AND PASSENGERS
WHAT MAKES A CANCER CELL A CANCER CELL?
UNLIMITED GROWTHUNLIMITED MOVEMENT
Growth Factorsint-2sis
Growth Factor ReceptorserbB-1fmskitmeterbB-2
Cytoplasmic Kinasessrcbcr-ablfeslckyes
Nuclear Proteinsetsfosjunmyc
FGFPDGF
EGF-RCSF-1RStem Cell GF-RHepatic GF-RHeregulin R
FAMOUS ONCOGENES
The Cell Cycle
FAMILIAL CANCER SYNDROMES
Li-Fraumenip53
Deleted in PancreasSmad4
RetinoblastomaRb
Breast CancerBrca1,2
Wilms TumorWT1
Nonpolyposis ColonMSH2,MLH1
Neurofibromatosis 1,2NF1,NF2
von Hippel-LindauVHL
Adenomatous PolyposisAPC
MelanomaINK4a/ARF
Cowden DiseasePTEN
GorlinPTCH
Multiple Endocrine NeoplasiaMEN1
THE DEFINITION OF A TUMOR SUPPRESSOR
Classical Features:
1. Loss of function mutations2. Targeted allelic loss- Methylation or Deletion3. Inherited mutations that predispose to cancer4. Somatic mutation in spontaneous tumors5. Ability to inhibit transformed cells in vitro
ACTIVATING THE p53 RESPONSE
p53 Modifications
ACCESSING THE CELL CYCLE MACHINERY
The Ink4a/Arf Locus
1b 1a 32CpG CpG
DE-REPRESSION
ONCOGENES
RAS
PRC1PRC2
ARF INK4A
SELECTIVE PRESSURE THROUGH STRESS
From environment:
-Low oxygen-Low nutrients-Radiation-Ligands
From self:
-Random mutant-ROS-Grow too fast
Dealing with it:
-Arrest/Senesce-Apoptosis
MUTATE
Not just division… But growth
Understanding what translation is really all about
Growth signals
PI-3k/mTOR PathwayAnd
Regulators ofRibosome biogenesis 60S 40S
5’
AA
AA
AA
AA
AA-3’
UTR
UTR
Active translationRibosome biogenesis
rRNA synthesisrRNA processingrRNA export
PI3K
GFR
Akt
Rheb
Ras
mTOR
Tuberin/Hamartin
PTEN
Neurofibromin
Tuberous sclerosis complex
Neurofibromatosis type 1 (NF1)
Cowden Syndrome Lhermitte-Duclos
disease
S6KeIF4E
NPMARF p68
THINKING ABOUT TRANSLATION
THE NUCLEOLUS
NPMARF
MAKING RIBOSOMAL RNA
Micro RNA
PUTTING IT ALL TOGETHER
1. IDENTIFY THE MUTATIONS 2. SEPARATE DRIVERS FROM PASSENGERS
3. FIND DRUGGABLE TARGETS 4. TEST IT ON THE RIGHT PATIENTS