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