Block C Lecture 3 - Targeted Cancer Therapies Flashcards

Question

What is the mechanism of action of pertuzumab?

Answer 1

It prevents HER2 from dimerising with other HER family receptors, blocking downstream signalling and enhancing the antibody-dependent cellular cytotoxicity (ADCC) response, recruiting immune cells to kill HER2-overexpressing cancer cells (Slide 12)

Answer 2

A combination of trastuzumab with emtansine (DM1) (Slide 12)

Answer 3

Emtansine (DM1) is a cytotoxic agent (also a spindle poison) which inhibits microtubule formation, which delivers targeted chemotherapy directly to HER2-positive tumour cells, leading to cell cycle arrest and apoptosis, while the trastuzumab component maintains a HER2 blockage by inhibiting downstream pathways (Slide 12)

Answer 4

In early and metastatic (spread) breast cancer (Slide 12)

Answer 5

Trastuzumab - as it complements it by targeting HER2 receptor dimerization, enhancing trastuzumab's effect (Slide 12)

Answer 6

Neratinib Lapatinub (Slide 13)

Answer 7

It is an irreversible inhibitor of the HER family which blocks downstream signalling cascades, which prevents tumour cell proliferation and survival (Slide 13)

Answer 8

As an extended adjuvant (helps increase efficiency or potency of a drug) post-trastuzumab (Slide 13)

Answer 9

It blocks HER2 and EGFR activity, blocking intracellular signalling and preventing tumour cells from surviving and proliferating (Slide 13)

Answer 10

When ATP binds to the active site of the kinase domain of the receptor, the kinase domain then catalyzes the transfer of a phosphate group from ATP to a tyrosine residue on the receptor itself (autophosphorylation) or on downstream effector proteins. This phosphorylation activates signaling pathways inside the cell. (Slide 14)

Answer 11

They impair the ability of tyrosine kinases to bind and utilise ATP by binding to the ATP binding site, reducing the receptor's activity (Slide 14)

Answer 12

Selective Oestrogen Receptor Modulators (SERMs) Aromatase Inhibitors (AIs) Selective Oestrogen Receptor Degraders (SERDs) (Slide 15)

Answer 13

Selective Oestrogen Receptor Modulator (SERM): Tamoxifen Aromatase Inhibitor (AI): Letrozole, Anastrozole, Exemestane Selective Oestrogen Receptor Degraders (SERDs): Fulvestrant (Slide 15)

Answer 14

They block oestrogen receptors in the breast tissue by binding to them and changing their shape which increases recruitment of co-repressors, which blocks activating of the ER pathway, which results in the inhibition of transcription, cancer cell growth and prevention of tumour progression. (Slides 15 and 16)

Answer 15

They reduce oestrogen production by inhibiting the aromatase enzyme, which is responsible for converting androgens into oestrogens, reducing activation of the ER pathway, inhibiting cancer cell growth and tumour progression (Slide 15)

Answer 16

Postmenopausal women (Slide 15)

Answer 17

They degrade and inactive oestrogen receptors by binding to ERα and inducing a conformational change which prevents co-activator recruitment while also targeting ERα for proteasomal degradation. This reduces ER levels in the cell, which reduces the activation of the ER pathway, resulting in the inhibition of cancer cell growth and tumour progression (Slides 15 and 18)

Answer 18

In advanced or metastatic ER-positive breast cancer (Slide 15)

Answer 19

They determine if a gene is activated or repressed (Slide 16)

Answer 20

It changes conformation when oestrogen binds, and the receptor binds to the oestrogen response element (ERE) on DNA, which recruits co-activators that alter gene expression (Slide 16)

Answer 21

In breast cancer cells, high levels of SRC-3 can lead to excessive ER signalling, which can drive tumour growth (Slide 16)

Answer 22

They can activate or block oestrogen signalling based on the tissue type (Slide 17)

Answer 23

1. Tissues expressing different levels of ERα and ERβ 2. Tissue specific co-activators or co-repressors 3. Gene expression patterns in each tissue (Slide 17)

Answer 24

High (such as in the breast) - SERDs block ER signalling, leading to cancer cell death Moderate (such as in bones) - SERDs produce a minimal effect and don't cause osteoporosis like aromatase inhibitors Variable level (such as in the uterus) - SERDs don't stimulate ER and avoid uterine cancer risk as seen with tamoxifen Low to none (such as in the brain, liver or muscle) - SERDS produce a minimal effect and preserve normal function (Slide 18)

Answer 25

As in them, the main source of oestrogen is the ovaries. These have a negative feedback loop; Low oestrogen increases Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), which increase oestrogen production by the ovaries, which can overcome aromatase inhibition (Slide 19)

Answer 26

The ovaries convert androgens into oestrogen using aromatase The peripheral tissues convert adrenal androgens into oestrogen (this is the main oestrogen source in postmenopausal women) (Slide 19)

Answer 27

They don't have any aromatase activity, HOWEVER, they can produce androgen precursors, but just can't convert them into oestrogen (Slide 19)

Answer 28

Steroidal (type I) and non-steroidal (type II) (Slide 20)

Answer 29

Type I structure is androgen-like whereas type II structure is non steroidal (triazole / imidazole) Type I is an irreversible inhibitor which permanently deactivates aromatase whereas type II is a reversible competitive inhibitor which only temporarily blocks enzyme activity Type I lasts long than type II due to enzyme degradation (Slide 20)

Answer 30

Steroidal: Exemestane (Aromasin) Non-steroidal: Letrozole (Femara) or Anastrozole (Arimidex) (Slide 20)

Answer 31

Due to their high potency (Slide 20)

Answer 32

Hot flashes Venous thromboembolism (blot clot in vein) Endometrial cancer (uterine) risk (due to agonist effect) (Slide 21)

Answer 33

Osteoporosis Joint pain Hot flashes (Slide 21)

Answer 34

Injection site reactions Fatigue Nausea (Slide 21)

Answer 35

SERMs and aromatase inhibitors are delivered as an oral tablet whereas SERDs are delivered via intramuscular injection (Slide 21)

Answer 36

Originally just EGFR mutations (such as in exons 19 and 21), but eventually went to T790M and EGFR mutations and then T790M-specific EGFR mutations and now scientists are currently working on an inhibitor which targets C797S mutations Note: These have also went from reversible to irreversible inhibitors (Slide 23)

Answer 37

1st generation EGFR tyrosine kinase inhibitors which were approved in the early 2000s and later withdrawn due to a lack of survival benefit but re-approved for first line treatment of EGFR mutant Non-small cell lung cancer (NSCLC) in the early 2010s. (Slide 24)

Answer 38

An acquired T790M point mutation (Slide 27)

Answer 39

Erlotinib and gefitinib bind to the ATP binding site of EGFR. Most common EGFR mutations structurally change the ATP-binding pocket, increasing drug affinity as the receptor has weaker ATP binding. For the T790 mutation, steric hindrance prevents erlotinib and gefitinib from binding effectively with the mutation, as a small threonine amino acid is replaced with a large methionine one. This increases the receptors affinity for ATP, making the receptor prefer ATP over the TKI drugs (Slide 28)

Answer 40

A third generation EGFR TKI, which was originally approved for use in treating Non-small cell lung cancer (NSCLC) whose disease has progressed on after another EGFR TKI was used but it is now the preferred first-line treatment over first generation (such as gefitinib and erlotinib) and second generation (such as afatinib or dacomitinib) EGFR TKIs for NSCLC (Slides 29 and 30)

Answer 41

As it has a structure which can still effectively bind to and inhibit the mutated EGFR, including the T790M form. (Slides 29 and 30)

Answer 42

A C797S mutation, as cysteine 797 (C797) is a key residue where osimertinib covalently binds to EGFR, with the change of cysteine to serine preventing irreversible binding of osimertinib (Slide 31)

Answer 43

Rash and diarrhoea (Slide 32)