L15 - Anti-cancer 3: Targeting hormone-sensitive cancers, transcription factors & signal transduction

Question 1

What are hormone responsive cancers?

Answer 1

cancer regresses on hormone treatment

Question 2

What are hormone dependent cancers?

Answer 2

cancer regresses on hormone removal

Question 3

What hormone is involved in breast cancer?

Answer 3

estrogen

Question 4

What hormone is involved in prostate cancer

Answer 4

androgen

Question 5

What is the mechanism of steroid hormone action?

Answer 5

steroid taken up into nucleus

interact with hormone receptor

becomes active when binds to receptor

steroid-receptor complex binds to chromatin - activating transcription of specific genes

express genes in cellular growth & proliferation

Question 6

What is Tamoxifen?

Answer 6

Selective estrogen receptor modulator (SERM)

Question 7

Why is tamoxifen limited to 5 years of use?

Answer 7

weak estrogen so possible stimulates pre-cancerous lesions

Question 8

How does Tamoxifen work?

Answer 8

competes with estrogen for binding to estrogen receptor

when tamoxifen binds - not active as transcription factor - does not stimulate expression of genes involved in cell growth and proliferation

Question 9

What is tamoxifen used in conjunction with?

Answer 9

leuprolide

Question 10

How is tamoxifen administered and what is the fate?

Answer 10

oral

excreted by bile into faces

Question 11

What are aromatase inhibitors?

Answer 11

Anastrozole
Letrozole

inhibit peripheral synthesis of estrogen in menopausal women

Question 12

Where can peripheral estrogen be found?

Answer 12

liver
adipose tissue (obesity?)
breast

Question 13

How are aromatase inhibitors administered and what is the fate?

Answer 13

oral

metabolised by liver

Question 14

3 anti-androgens for prostate cancer?

Answer 14

Flutamide
Nilutamide
Bicalutimide

compete with androgen to bind to receptor

Question 15

Is EGFR often mutated in cancer?

Answer 15

YES

activity increased
overexpression on cell surface

Question 16

What is the ligand of ErB, an EGFR?

Answer 16

epidermal growth factor

Question 17

What happens when EGF binds to receptor?

Answer 17

phosphorylation in the cytoplasmic domain

Question 18

What is that intracellular domain of ErB

Answer 18

Intracellular tyrosine kinase domain

Question 19

What happens when tyrosine is phosphorylated?

Answer 19

attract and bind other proteins in the cytoplasm - signal transduction cascade

activates nuclear genes involved in cell proliferation and cell cycle

Question 20

What happens if there are deletion mutations in EGFR?

Answer 20

lose binding site for EGF - is turned on ALL THE TIME WITHOUT EGF - constant phosphorylation of cytoplasmic tyrosine

Question 21

What are the 2 inhibitors of tyrosine kinase (EGFR)?

Answer 21

Iressa
Tarceva

target cells in which is kinase is only active

Question 22

Why does the BCR-ABL fusion protein occur?

Answer 22

chromosomal translocation in CML

Question 23

What activity does the BCR-ABL fusion protein have?

Answer 23

tyrosine kinase activity

Question 24

Is BCR-ABL fusion protein present in normal cells?

Answer 24

No

Question 25

Inhibitor of BCR-ABL?

Answer 25

Gleevec (Imatinib)

Question 26

How viruses inactive tumour suppressor gene products?

Answer 26

DNA viruses (HPV) bind to the products and inactivate them

mimic proteins that bind to tumour suppressor products in protein:protein complexes

Question 27

What do tumour suppressors frequently form?

Answer 27

protein:protein complexes

Question 28

What does p53 tumour suppressor often form a complex with?

Answer 28

MDM2 (oncogene)

degrades p53

Question 29

What molecules can bind to MDM2 to release p53 so it can apoptose cancer cells?

Answer 29

Nutlins

Question 30

How can p53 be supplied to the body if mutations are too severe?

Answer 30

adenovirus vector - express p53

restore growth control in p53-negative cancer

Question 31

What mutation is in 50% of melanoma cancers?

Answer 31

B-Raf

Question 32

Inhibitors of B-Raf

Answer 32

a-serine/threonine protein kinase

Question 33

What is the B-Raf inhibitor in renal cancer?

Answer 33

Nexavar

Question 34

What is the GTP-bound Ras and B-Raf interaction?

Answer 34

GTP-bound Ras = active

GDP-bound ras = inactive

Mutant Ras is locked in GTP-boudn for - mutation from proto-oncogene to oncogene

Constantly activates B-Raf causing pathway to always be activated - transcribing genes involved in suppressing apoptosis

Question 35

What is the usual cell equilibrium of GTP-bound to GDP-bound Ras?

Answer 35

usually more GDP-bound Ras, not always activating the pathways

Question 36

What is the racial variation of Iressa treatment?

Answer 36

Japanese 3x more likely to respond than Americans

drug binds more effetively to EGFR in Japanese?

Question 37

What is personalised medicine?

Answer 37

tailor drug therapies to person’s genome sequence

Question 38

What causes drug resistance?

Answer 38

amplification of P-glycoprotein channel
ATP, pumps drug out

cross resistance - diff drugs but same transporter pumps out

combo of drugs can be used at lower conc.

Question 39

What is the inhibitor of P-glycoprotein?

Answer 39

Verapamil

Question 40

What is myelosuppression?

Answer 40

effects pre-cursors of blood cells

suppress bone marrow

effect pre cursor cells that differentiate into WBCs and platelets

Question 41

How can myelosuppression be mitigated?

Answer 41

leucovorin with MTX

remove bone marrow, have high dose chemotherpay, then return bone marrow & repopulate