Cancer as a Multistage Process (Herschman)

Question 1

BRCA1 and BRCA2

Answer 1

BRCA1 associated with hereditary breast cancer

BRCA2 associated with hereditary breast and/or ovarian cancer

Question 2

Normal AKT/PKB and mTOR signaling pathway

Answer 2

Ligand binds receptor –> cross phosphorylation on receptors –> PI3 kinase binds phosphorylated receptors –> PI3 kinase phosphorylates PIP2 to PIP3 –> PIP3 phosphorylates AKT/PKB –> AKT/PKB phosphorylates mTOR –> mTOR phosphorylates other substrates and promotes cell survival, proliferation, migration

Question 3

PTEN in AKT/PKB and mTOR pathway

Answer 3

PTEN dephosphorylates PIP3 to PIP2 so AKT/PKB signaling stops (turns pathway off)

Question 4

What are the consequences of not having a functional PTEN?

Answer 4

AKT/PKB activity is greater, so cells proliferate more and undergo apoptosis less

Question 5

Rapamycin

Answer 5

Rapamycin turns off mTOR inhibiting its kinase activity, which results in less cell survival, proliferation and migration

In clinical trials as targeted therapy for cancers in which PTEN is deleted

Question 6

c-Kit

Answer 6

Transmembrane tyrosine kinase receptor

Some patients with gastrointestinal stromal tumor (GIST) have c-Kit mutation (others don’t)

Gleevac can be used to treat GIST if caused by c-Kit mutation

Question 7

PET

Answer 7

18F-FDG probe is injected and absorbed by tissues. If hexokinase activity (metabolism) is high, 18F-FDG converted to 18F-FDG-P and trapped inside cells. Positrons are emitted by probe, and resulting 2 photons emitted are detected by PET scanner.

Question 8

PET vs. MRI or CT

Answer 8

PET measures metabolism, so in recently dead person will see no activity. Also, with PET, can see metabolic resopnse of tumor to drug within days.

MRI and CT measure structure, so in recently dead person, will still see image. Cannot see response of tumor to drug for weeks, until tumor has shrunk in size.

Question 9

PLX4032

Answer 9

aka Vemurafenib, Zelboraf

Inhibits mutated, constitutively active RAF gene (BRAF-V600E in melanoma)

Problems: joint pain, skin rash, fatigue, squamous cell carcinoma/keratoacanthomas, acquired resistance

Question 10

How many genes necessary to cause cancer? How do we know?

Answer 10

Probably 5 or 6 genes needed to cause cancer.

We know because cancer is not linear with age. Incidence shoots up quickly after age ~55, suggesting accumulation of mutations needed.

Question 11

How do we know multiple genes are involved in cancer?

Answer 11

Example: HL60 cells have Ras and c-myc mutations

Ras and myc mutation required to transform normal fibroblasts

Shown in mice that ras and myc cooperate to induce cancer more rapidly and extensively

Question 12

TPA

Answer 12

PKC agonist (takes the place of DAG) that is constitutively active and leads to tumor formation

“Promoter”

Question 13

DMBA

Answer 13

Initiator that leads to Ras mutation, works with the promoter TPA

DMBA can also be complete carcinogen if given at high enough doses