Cancer Biology Targeting Pathways Flashcards
What is the most common type of estrogen receptors for breast cancer
Estrogen receptor alpha
What is triple negative breast cancer
negative for ER, PR and Her2
Which one are the hardest to treat
Triple negative, they are treated with chemo and radiation
Know the mechanism of actions of estrogen
Estrogen goes through the cell membrane, binds to the receptor, the receptor homodimerizes and then binds to the DNA and regulates transcription. C-MYC, Cyclin D and E are unregulated which causes the cell to proliferate
How do you treat estrogen positive breast cancer
- Block the production of estrogen 2. Block the estrogen receptors
Explain the detail of estrogen receptor
It has 6 domains, one of them is the ligand binding domain. Estrogen binds to the ligand binding domain, anti estrogen chemicals also bind to this domain
What is the difference in the mechanism of hormonal therapies of estrogen when comparing aromatase inhibitors and anti estrogens
Aromatase inhibitors inhibit estrogen by inhibiting its conversion to its active form (aromatase inhibitors inhibit aromatase enzyme that converts the estrogen to its active form) whereas anti estrogens bind to the ER (in the ligand binding domain) and inhibit the effect of estrogen.
Examples of aromatase inhibitors
Anastrozole
Examples of antiestrogens
Tamoxifen
When is aromatase inhibitors used?
They are used to treat cancer in post menopausal women
Why are aromatase inhibitors used to treat post menopausal women when they already have low estrogen production due to their old age
Risk of developing breast cancer is determined by the lifetime exposure to estrogen. Main source of estrogen in post menopausal women is not the ovaries but the fat tissue.
What is the difference of action between tamoxifen and fulvestrant
Tamoxifen inhibits estrogen, when estrogen binds to its receptors, Tamoxifen stops the ER from binding to the nucleus and regulating transcription. Whereas on the other hand Fulvestrant inhibits estrogen from binding to its receptor. Fulvestrant binds to the receptors of the estrogen AND also causes degradation of the receptor.
What is the difference in treatment of premenopausal women and post menopausal women
In premenopausal women, the main source of estrogen is not the androgens but it is from the ovaries. So giving tamoxifen or fulvestrant will not be effective and usually they are treated by giving aromatase inhibitors as well as some EGFR inhibitors. In post menopausal women the main source of estrogen is the androgens. They are treated usually just by giving them aromatase inhibitors.
What are the classes of 3rd generation aromatase inhibitors.
There are 2 kinds: 1. Steroidal inhbitors - exemestane 2. Nonsteroidal inhibitors - anastrazole and letrozole
How do these enzymes work
They work by selectively blocking the heme moiety of the enzyme. Active sites of steroidogenic enzymes remain free.
Explain in detail what does Tamoxifen do to the estrogen receptor
It causes a conformation change in the receptor such that it doesn’t enhance gene activation, estrogen also causes a conformational change in the receptor such that gene transcription is increased. Also it is important to know that Tamoxifen does not induce cell death, instead it induced G1 cell cycle arrest - hence tamoxifen is a cytostatic inhibitor.
What is the active form of Tamoxifen and how does it get there?
It is metabolized to its active form by CYP2D6 enzyme in the liver, forming 4OHT and ENDOX which are its active forms
Difference between Tamoxifen and AIs
They’re saying here is that Tamoxifen or fulvestrant are not AIs
What does it means when we say Tamoxifen is SERM
SERM: selective estrogen receptor modulator
In some tissue it will work as one way and it another tissue it work in a different way.
In stimulates the uterus to increase cell proliferation. It can also modify bone, it usually preserves bone so people who are at risk for osteoporosis will also benefit from taking Tamoxifen.
What does Fulvestrant do
It is purely an antagonist. it is a second line therapy since it degrades the estrogen receptors.
Compare the different therapies in women of different age
What does trastuzumab do to the HER2 receptor
It inhibits dimerization
What does herceptin do
It also acts as a HER2 inhibitor
What are the limitations of targeted therapy
Patients develop resistance to the therapy. There are some pathways these cancer cells use to minimize the effect of these drugs, there are 3 major mechanisms:
Pathway redundancy
Escape pathways
Pathway reactivation
What is she trying to explain here
She is trying to explain the point that over time in a tumor transformation happens and tumor cells become resistant to drugs like tamoxifen. This is done by introducing mutations in the ER which causes the recepotor to become ligand independent, where they can acitvate themselves and cause continuous tumor proliferation.
All of these mutations are in the ligand binding domain.
How does cancer cells get resistant to trastuzumab
PTEN is mutated, cells continue to proliferate
How does Her2/neu pathway lead to excessive cell proliferation
It increase the activity of the mTOR pathway. Cell progresses quickly from G1 to S phase.
What can you do in HER2/neu positive tumors that have become resistant to trastuzumab
You can inhibit the CDKs 4 and 6
