GN 3.1.3

Question 1

What is the role of ESR1 in development of resistance?

Answer 1

Mutation in this receptor can make it ligand independent thus becoming resistant to drug therapies

Question 2

What is the estrogen/estradiol receptor pathway?

Answer 2

Conversion to estradiol by aromatase which then binds with ER. ER then dimerizes and translocates into the nucleus. This then increases transcription of cell proliferative signals.

Question 3

What is pathway reactivation?

Answer 3

Mutation in a downstream element can turn it constitutively

Question 4

What is lapatinib?

Answer 4

Drug that inhibits tyrosine kinase activity of HER2/neu receptors

Question 5

What does Fulvestrant do?

Answer 5

It binds to ER and doesn’t allow them to dimerize; high affinity for ER. The large side chain makes ER unstable and targets it for degradation.

Question 6

What are some ways cancer cells can develop resistance?

Answer 6

Pathway redundancy, Escape pathways, pathway reactivation

Question 7

What is a SERM?

Answer 7

Selective Estrogen Receptor Modulator

Question 8

What is over-expression in regards to HER2/neu receptors?

Answer 8

Increased expression of proteins on the surface of the cell

Question 9

What are some possible targets for overcoming resistance?

Answer 9

mTOR pathway and CDK4/6. These can also be used in conjunction with other therapies.

Question 10

What is pertuzumab?

Answer 10

It inhibits heterodimerization of HER2/neu receptors

Question 11

What are some criteria for targeted therapy?

Answer 11

Specific molecules that present as molecular targets Molecules can be more abundant in cancer cells than normal cells Determination if the protein should be turned on or off Chromosomal abnormalities that can create different protein (fusion protein)

Question 12

What is the role in IHC and FISH in determining a HER2/neu cause for breast cancer?

Answer 12

IHC will stain for HER2/neu receptors on the cell surface and will have deeper staining in the presence of increased receptors (oxer-expression) FISH will show chromosomal areas on increased amount of gene copies of HER2/neu (amplification)

Question 13

What is amplification in regards to HER2/neu?

Answer 13

Increase in the number of HER2/neu gene copies inthe nucleus?

Question 14

What is the steroidal ER drug?

Answer 14

Exemestane

Question 15

What does an aromatase inhibitor do?

Answer 15

It blocks aromatase, preventing the conversion of androgens to estradiol.

Question 16

What is the role of Trastuzumab (herceptin)?

Answer 16

Antibody that disrupts the dimerization of HER2/neu receptors

Question 17

What are the non-steroidal ER drugs?

Answer 17

Letrozole and anastrozole

Question 18

What does Tamoxifen do?

Answer 18

It blocks dimerized ERs from binding to DNA. Competitive binding results in decreased transcription of estrogen regulated genes. Blocks cells from going through cell cycle and arrests them in G1 stage (cytostatic drug)

Question 19

How can Tamoxifen act as an agonist?

Answer 19

It can have proliferative effects leading to endometrial cancer

Question 20

What is an escape pathway?

Answer 20

A cell that recruits alternate signaling pathway to achieve a similar outcome as before

Question 21

What are some obstacles for trastuzumab?

Answer 21

Question 22

What is pathway redundancy?

Answer 22

The ability of a pathway to stay activated even in the presence of an inhibitor