BRCA1 and BRCA2
BRCA1 associated with hereditary breast cancer
BRCA2 associated with hereditary breast and/or ovarian cancer
Normal AKT/PKB and mTOR signaling pathway
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
PTEN in AKT/PKB and mTOR pathway
PTEN dephosphorylates PIP3 to PIP2 so AKT/PKB signaling stops (turns pathway off)
What are the consequences of not having a functional PTEN?
AKT/PKB activity is greater, so cells proliferate more and undergo apoptosis less
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
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
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.
PET vs. MRI or CT
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.
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
How many genes necessary to cause cancer? How do we know?
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.
How do we know multiple genes are involved in cancer?
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
PKC agonist (takes the place of DAG) that is constitutively active and leads to tumor formation
Initiator that leads to Ras mutation, works with the promoter TPA
DMBA can also be complete carcinogen if given at high enough doses