ls6003 mAb and TKIs (dr Modjthedi) - lecture 2

Question 1

name the 4 main drugs in cancer therapy (CT)

Answer 1

-alkylaitng agents
-antimetabolites
-cytotoxic antibioitcs
pant derivatives

Question 2

how do alkylaitng agents work, give 2 example drugs

Answer 2

forms covalent bonds with dna -> interfers with DNA replication
platinum compounds,q cispaltin, carboplatin

Question 3

how do antimetabolites work, give an example drug

Answer 3

block DNA/RNA synthesis
folate antagonists, methotrexate

Question 4

how do antimetabolites work, give an example drug

Question 5

how do cytotoxic antibioitcs work, give an example drug

Answer 5

multiple effects on DNA/RNA synthesis+enzyme topoisomerase
e.g. anthractclines (doxorubicin, epirubicin

Question 6

how do plant derivatives and similar compounds work, give an example drug

Answer 6

block microtubule assembly and spindle formation e.g. taxanes (docetaxel, paclitaxel)
inhibiting the enzyme topoisomerase e.g. camptothecins (Irinotecan, topotecan)

Question 7

what can be used to treat hormone sensitive breast cancers

Answer 7

anti-estrogen drugs (tamoxifen
aromatase inhibitors (anastrozole)

Question 8

what can be used to treat androgen-dependent prostate cancers

Answer 8

anti-androgen drugs (flutamide)

Question 9

targeted therapy of human cancers can be perfromed using what 2 products

Answer 9

mAb-based-products -> target outside of cell
TKIs -> target inside of cell

Question 10

Fc domain of human IgG1 subclass is responsible for inducing tumour killing via what 2 methods

Answer 10

-complementart dependent cytotoxicity (CDC)
-Ab dependent cellular cytotoxicity (ADCC)

Question 11

name 3 applications of mAb

Answer 11

-tols in basic research
diagnosis aents
therapeutic agents for treatment of many diseases

Question 12

mAb mechanisms induce anti-tumour activity, but this is dependent on what 3 factors

Answer 12

-subclass of Ab
-Ab format
-antigen recognised by Ab

Question 13

what are the 5 mAb mechanisms inducing anti-cancer activity, include examples

Answer 13

1)blocking growth factor-receptor interaction and thus signal transduction pathway e.g. cetuximb, trastuzumab
2) activating Ab-dependent cellular cytotoxicity (ADCC) e.g. herceptin, avastin, erbitux
3) inducing complement-dpeendent cytotoxicity (CDC) e.g. anti-cd20mAb Rituxan, Herceptin
4)delivering cytotoxic drug, toxin, enzymes readioisotopes to tumouir sites e.g. Kadcyla, zevalin
5) stimulating patients cytotoxic T lymphocytes e.g. anti-CTLA-4 blocking antibody (checkpoint inhibitors)

Question 14

name an anti-CD20 monoclonal antibody

Answer 14

Ritxuxan (Rituxamab)

Question 15

CD20 antigen is present where?

Answer 15

on the surface of more than 90% of B-cell NHL, on pre-lymphocytes, mature lymphocytes
but not stem cells, plasma cells, or other normal tissues

Question 16

what are the MoAs of rituxan (rituxamab)

Answer 16

-promotes apoptosis
-ADCC
-CDC

Question 17

name the anti-HER-2 mAb

Answer 17

Herceptin

Question 18

overexpression of HER-2 occurs in what group of patients?

Answer 18

breast cancer patients

Question 19

High levels of expression of HER-2 is associated with what 3 things?

Answer 19

-more aggressive disease
-resistance to various forms of therapy
-poor survival

Question 20

Herceptin is a recombinant-humanised form of what?

Answer 20

mouse anti-HER-2 mAb 4D5

Question 21

what are the cytostatic and cytotoxic MoA for anti-HER-2 Ab Herceptin (trastuzumab)

Answer 21

cytostatic:
-inhibits tumour cell proliferation
-inhibits angiogenesis
-induces G1 arrest and p27 cell cycle inhibitor
-reduces downstream pp13kAkt, MAPK -signalling
-reduces cyclin D1 levels
-blocks HER-2 cleavage/constitutive activation
cytotoxic:
-inititates Fc-receptor-mediated antibody-dependent cellular cytotoxicity (ADCC)
-induces CDC
increases chemo sensitivity (promotes apoptosis)

Question 22

define ADCC

Answer 22

antibody-dependent cellular cytotoxicity (ADCC)

Question 23

define CDC

Answer 23

complement-mediated-cytotoxicity

Question 24

what is the back up drug for Herceptin when HER-2 changes conformation?

Answer 24

Pertuzumab
This also targets HER-2 but at a different binding site

Question 25

name the HER2 targeted Ab-drug conjugate

Answer 25

Kadcycla (ado-trasuzumab emtansine)

Question 26

name the chimeric mAb against EGFR

Answer 26

Erbitux (Centuximab)

Question 27

what does cyclin D1 promote?

Answer 27

progression through G1-S phase

Question 28

what is cetuximab approved for?

Answer 28

first line treatment of metastatic carcinoma of colon and rectum
-head and neck cancer patients whose tumours overexpress EGFR

Question 29

what does EGFR stand for?

Answer 29

epidermal growth factor receptor

Question 30

Anti-checkpoint proteins therapuetic antibodies:
PD-L1 binds to PD-1 and inhibits T cell killing of tumour cells. By blocking PD-L1 or PD1, this allows for Tcell kiling of tumour cells. What does this prevent?

Answer 30

autoimmunity

Question 31

list 3 limitations of anti-cancer therapeutic Abs

Answer 31

high cost
adverse effects
resstance to Abs

Question 32

what are tyrosine kinases

Answer 32

a gorup of enzymes responsive gfor activation o fvarious proteins in cell wignal transduction pathways, by phosphorylation

Question 33

what are TKIs

Answer 33

drugs tht inhibit phosphorylation of tyrosine reside and subsequent cell signal transduction pathways