L16. Anticancer II

Question 1

EGFR

Answer 1

1. stimulation by ligands
2. receptor dimerization
3. activating tyrosine kinase activity
4. downstream signalling
5. increase proliferation, metastasis ..

Question 2

drugs used to target EGFR:

Answer 2

• prevent ligand binding to EHGR thus inhibiting receptor dimerization
• tyrosine kinase inhibitors bind ATP binding site inhibiting EGFR

Question 3

HER2

Answer 3

• tyrosine kinase receptor
• member of human epidermal growth receptor family
• has to dimerize upon binding to have downstream effects

Question 4

lapatinib and neratinib

Answer 4

• kinase inhibitors
• cause direct inhibition of downstream tyrosine kinase domain

Question 5

trastuzumab

Answer 5

• mab
• binds to the dimerization domain outside the receptor
• inhibits HER2 dimerization
• leading to no downstream signaling
• leads to ADCC: immune cells recognize cancer and promote the killing of the cancer by releasing cytotoxic substances

Question 6

pertuzumab

Answer 6

• mab
• binds to the dimerization domain outside the receptor
• inhibits HER2 dimerization
• leading to no downstream signaling
• leads to ADCC: immune cells recognize cancer and promote the killing of the cancer by releasing cytotoxic substances

> can be used with trastuzumab since they both binds to a diff portion leading to a synergistic effect

Question 7

HR+/HER2-

Answer 7

• most common type of breast cancer
• easy to treat
• treat it with endocrine therapy: aromatase inhibitors of SERDs ++ CDK4/6 inhibitors
  > in pre-menopausal women, ovarian suppression/ablation is necessary

Question 8

HR-/HER2-

Answer 8

• worst prognosis
• no tx found so we treat with chemotherapy

Question 9

HR+/HER2+

Answer 9

• treat with combination therapy: trastuzumab (with or without pertuzumab) + endocrine therapy/anti-hormone tx

Question 10

HR-/HER2+

Answer 10

least common type of breast cancer
- treat with trastuzumab (with or without pertuzumab) + chemotherapy

Question 11

tamoxifen

Answer 11

• SERM that blocks estrogen receptors in breasts
• estrogen receptor
  recognizes tamoxifen -> ER dimerizes -> ER binds to recognition elements on DNA -> altered gene transcription
• tamoxifen acts as an antagonist in breast tissue
• it is metabolized into 4-hydroxytamoxifen and endoxifen by CYP2D6 and CYP3A4/5

Question 12

aromatase inhibitors

Answer 12

• in post-menopausal women, they continue to produce low levels of estrogen
• testosterone and androstenedione are converted to estradiol and estrogen via enzyme aromatase
• aromatase inhibitors will inhibit the enzyme aromatase which will reduce estrogen levels inhibiting the growth of cancer cells

Question 13

fulvestrant

Answer 13

• selective estrogen receptor downregulation
• pure ER antagonist with no agonist activity
• downregulates and destroys ER receptors
• fulvestrant has a long side chain that will cause the ER dimerization to be sterically hindered which will destroy ER receptor

Question 14

CDK6 and CDK4 inhibitors

Answer 14

CDK4/6 usually promote cell cycle entry by blocking repressor retinoblastoma and cell progression from G1 phase to S phase

Question 15

synthetic lethality

Answer 15

combination of two non-lethal mutations resulting in cell death while each mutation alone is not lethal

Question 16

cancer immunotherapy

Answer 16

principle of activating and enhancing the body’s immune system to recognize and destroy cancer cells

Question 17

CTLA4 and PD1

Answer 17

both expressed on tumour cells that will help cancer evade the immune system

Question 18

checkpoint inhibitors

Answer 18

antibodies against CTLA4 and PD1 will inhibit them and will make the immune cells recognize the cancer cells to attack them
–> targeting them will enhance the immune system’s ability to recognize and attack cancer cells