Cancer as a Multistage Process (Herschman) Flashcards Preview

Block 1 lectures > Cancer as a Multistage Process (Herschman) > Flashcards

Flashcards in Cancer as a Multistage Process (Herschman) Deck (13):
1

BRCA1 and BRCA2

BRCA1 associated with hereditary breast cancer

BRCA2 associated with hereditary breast and/or ovarian cancer

2


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

3


PTEN in AKT/PKB and mTOR pathway


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

4


What are the consequences of not having a functional PTEN?


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

5


Rapamycin


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

6


c-Kit


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

7


PET


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.

8

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.

9


PLX4032


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

 

10

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.

11


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

12


TPA

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

"Promoter"

13


DMBA


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

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