9 - Molecular targeted cancer drugs ‐ breast cancer and prostate cancer

Question 1

Why is breast cancer a heterogeneous disease

Answer 1

Encompasses multiple subgroups with differing molecular signatures, prognoses and responses to therapies

Question 2

What are three major subtypes of breast cancer

Answer 2

1) Hormone receptor positive tumours that express estrogen or progesterone receptors
2) HER2 - amplified breast cancer
3) Triple negative breast cancers that lack ER, PR and HER2 expression

Question 3

Where is estrogen produced in premenopausal vs postmenopausal women

Answer 3

Ovaries

Peripheral aromatase

Question 4

What do estrogens activate

Answer 4

ERa and ERb

Question 5

What is an ER antagonist

Answer 5

Tamoxifen

Question 6

What does partial agonism of ER in the uterus and vascular system cause

Answer 6

Increased risk of endometrial cancer and thromboembolism

Question 7

What is a steroidal PR antagonist

Answer 7

Onapristone

Question 8

What does tamoxifen require for activation

Answer 8

CYP2D6

Question 9

What are some mechanisms of tamoxifen resistance (3)

Answer 9

ERa mutations
Overactivity of ER-independent proliferative pathways
Overactivity of PI3K/Akt survival cascade

Question 10

What do inhibitors of aromatase do

Answer 10

Block conversion of testosterone to estradiol

Question 11

What are AIs in clinical use

Answer 11

Anastrozole
Letrozole
Exemestane

Question 12

What is HER2 a subtype of

Answer 12

EGF

Question 13

What does trastuzumab (herceptin) do

Answer 13

Prevent HER2 dimerisation

Monoclonal antibody

Question 14

2 Mechanisms of resistance to trastuzumab

Answer 14

1) Alternate proliferative pathways used by tumours
2) Increased survival signalling e.g. presence of activating PI3-kinase mutations or loss of function of the phosphatase PTEN
3) HER2 overexpression in tumours

Question 15

Why is TNBC an aggressive disease

Answer 15

No clear therapeutic target

Question 16

Do women with TNBC benefit from either endocrine therapy or trastuzumab

Answer 16

No

Question 17

What is the breast cancer susceptibility gene

Answer 17

BRCA1

Question 18

What does BRCA1 usually do

Answer 18

Co-regulate ERa-regulated gene

Question 19

What does BRCA1 inhibit

Answer 19

1) Proliferation by the ER

2) DNA repair and genome stability rebulation

Question 20

Are BRCA-1 positive tumours likely to be ER and HER-2 negative

Answer 20

Yes

Question 21

What is the current mainstay of TNBC treatment

Answer 21

Combination chemotherapy

Question 22

What is effective against TNBC

Answer 22

Anthracycline

Newer cytototxic agents ixabepilone

Question 23

What is an emerging treatment for TNBC

Answer 23

DNA repair enzyme PARP

PARP inhibitors as PARP is higher in TNBC

Question 24

What is a PARP inhibitor

Answer 24

olaparib

Question 25

What occurs in patients with advanced prostate cancer

Answer 25

Bone metastases that form osteoblastic lesions

Question 26

Are there subtypes of prostate cancer

Answer 26

No

Question 27

How is localised prostate cancer treated

Answer 27

Surgically or with radiation | Or monitored if low risk

Question 28

How is recurrent prostate cancer treated

Answer 28

Androgen deprivation therapy | Bilateral orchietomy

Question 29

How does luteinising hormone releasing hormone work

Answer 29

Act on pituitary to release LH which activates steridogenesis

Question 30

What is an LHRH agonist

Answer 30

Leuprolide

Question 31

What is a LHRH antagonist

Answer 31

Degarelix

Question 32

What is an AR antagonist

Answer 32

Bicalutamide

Question 33

WHat is a CYP17 inhibitor

Answer 33

Abiraterone

Question 34

What is a 5a-reductase inhibitor

Answer 34

Finasterise

Question 35

What are adverse effects of ADT

Answer 35

Osteoporosis and fractures Obesity and insulin resistance Increased serum cholesterol and triglycerides Increased diabetes and CV disease risk

Question 36

What are mechanisms of CRPC

Answer 36

1) AR overexpression 2) Ligand-independent AR activation 3) Androgens produced within the tumour, stimulating AR 4) Loss of signalling control

Question 37

How do cytokines and chemokines affect prostate cancer

Answer 37

Enhanced proliferation of progenitor cells

Question 38

What can IL-4 do to prostate cancer cells

Answer 38

Render them resistant to apoptosis and activate AR in absence of androgen

Question 39

What is treatment for CRPC

Answer 39

Chemo Biological therapies Radiopharmaceuticals Anti-hormonal agents

Question 40

What are some biological therapies in CRPC (3)

Answer 40

Bevacizumab Aflibercept Sipuleucel-T

Question 41

What is bevacizumab

Answer 41

Humanised anti-VEGF receptor antibody

Question 42

What is aflibercept

Answer 42

Soluble fusion protein corresponding to the VEGF-receptor extracellular domain

Question 43

What is sipuleucel-T

Answer 43

A vaccine derived from dendritic cells activated by antigen prostatic acid phosphatase

Question 44

Where are breast metastases found

Answer 44

Bones Brain Lungs Liver

Question 45

Where are prostate metastases found

Answer 45

Bone | Lungs

Question 46

Which receptor is overexpressed in prostate cancers that have metastasised to bone

Answer 46

MET receptor (KI)

Question 47

How is MET activated

Answer 47

Hepatocyte growth factor

Question 48

What is MET involved in

Answer 48

Proliferation Differentiation Migration of osteoblasts and osteoclasts

Question 49

What is a MET receptor inhibitor

Answer 49

Cabozantinib

Question 50

Which tyrosine kinase has a central role in growth, invasion and metastasis of prostate carcinomas

Answer 50

SRC

Question 51

What is a SRC inhibitor

Answer 51

Dasatinib

Question 52

What is a biological therapy in metastatic breast and prostate cancer

Answer 52

RANK-ligand

Question 53

What is an anti-RANK-ligand monoclonal antibody

Answer 53

Denosumab

Question 54

What does denosumab do

Answer 54

Supress bone resorption by RANK

Question 55

What does zoledronic acid do

Answer 55

1) Reduce number of skeletal events in patients with bone metastases 2) Increase bone mineral density 3) Inhibit osteoclast-mediated bone resorption