Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

phar 301 > 2: Lecture 9 > Flashcards

2: Lecture 9 Flashcards

1
Q

Main targeted agents of Cancer

A

HER-2–>targeted in breast cancer
BCR/ABL–>targeted in Chronic myeloid leukemia (CML)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Cause of Chronic Myeloid Leukemia (CML)

A

Philadelphia chromosome translocation–>juxtaposition of ABL gene from chromosome 9 and BCR from chromosome 22–>BCR/ABL fusion gene–>activates transcription of genes without need of external signaling

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What can target Chronic Myeloid Leukemia (CML)

A

Imatinib
Imatinib targets and inhibits the BCR/ABL tyrosine kinase through competitive binding at ATP-binding site

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Main action of Epidermal Growth Factor Receptor (EGFR)

A

EGFR is structurally similar to HER (human growth factor receptors)
Regulates cell cycle progression and metastasis
Many oncogenes are in the EGFR family

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What can target Epidermal Growth Factor Receptor (EGFR)

A

Cetuximab (monoclonal antibody)–> Inhibits the EGFR by preventing ligand binding
Also tyrosine kinase inhibitors (gefitinib, erlotinib, or afatinib, lapatinib, neratinib)–>binds to ATP binding site–>prevent kinase activity–>interrupt downstream signaling

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What can target Human Epidermal Growth Factor Receptor 2 (HER2)

A

HER2 is a part of the EGFR family
Trastuzumab, Pertuzumab, Lapatinib AND neratinib, Trastuzumab emtansine, trastuzumab deruxtecan, ZW2S
All inhibit downstream PI3-kinase signaling to promote cell cycle arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Mechanism of Trastuzumab (against HER2) (antibody)

A

Binds domain IV of HER2–>inhibits dimerization of other EGFRs–>promotes internalization and degradation–>engagement of antibody-dependent cellular cytotoxicity
Inhibit downstream PI3-kinase signaling to promote cell cycle arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Mechanism of Pertuzumab (against HER2) (antibody)

A

Binds domain II of HER2–>inhibits dimerization of HER2–>promotes receptor internalization and degradation
Inhibit downstream PI3-kinase signaling to promote cell cycle arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Drugs that can be used in combination against HER2

A

Synergistic effect (act on different domains)
Lapatinib and neratinib–>direct inhibition of downstream tyrosine kinase domain
Neratinib is an irreversible covalent inhibitor
Inhibit downstream PI3-kinase signaling to promote cell cycle arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Antibodies conjugated with cytotoxic agents against HER2

A

Trastuzumab emtansine and trastuzumab deruztecan–>specifically deliver cytotoxic agents to cancer cells
Inhibit downstream PI3-kinase signaling to promote cell cycle arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Mechanism of ZW2S (against HER2) (antibody)

A

Targets BOTH domain IV (trastuzumab) and domain II (pertuzumab)
Inhibit downstream PI3-kinase signaling to promote cell cycle arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Possible mechanism for antibodies to kill cancer cells

A

CDC–>complement-dependent cytotoxicity
ADCC–>antibody-dependent cellular cytotoxicity
ADCP–>antibody-dependent cellular phagocytosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Mechanism of CDC, ADCC, ADCP

A

CDC (complement-dependent cytotoxicity)–>antibody recruits complement to promote tumor cell lysis
ADCC (antibody-dependent cell cytotoxicity)–>antibody recruits Natural killer cells (NK) which release granzyme and perforin (cytotoxic to tumor cell)
ADCP (antibody-dependent cellular phagocytosis)–>antibody recruits macrophages that remove tumor cells by phagocytosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Components of Antibody drug conjugates (ADCs)

A

Antigen, antibody, cytotoxic payload, and linker

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Requirements of Antigen in Antibody conjugate (ADC)

A

Must have HIGH homogenous expression (all tumor cells must produce antigen to be recognized by antibody)
Must be LOW or NO expression of antigen on healthy tissues (prevent antibody targeting healthy tissues)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Requirements of Antibody in Antibody drug conjugate (ADC)

A

Must have HIGH affinity and avidity for tumour antigen
Chimeric or humanized to decrease immunogenicity
Must have LONG half life

17
Q

Requirements of Cytotoxic payload in antibody-drug conjugate (ADC)

A

Must be a highly potent agent with an IC50 range (to have effect at minimal concentration)

18
Q

Requirements of Linker in antibody-drug conjugate (ADC)

A

Must be STABLE in circulation with efficient release of payload at target sites
Prevents premature release of payload at non-target tissues
Can be cleavable or non-cleavable

19
Q

What does Antibody engagement lead to in Antibody-drug conjugates (ADC)

A

Leads to payload -independent antitumour activity such as
FC-mediated stimulation of immune cell effectors (antibodies recruit natural killer cell which release granzymes and perforins to induce cytotoxic effect)
Disruption of receptor dimerization and/or function (inhibiting downstream signaling

20
Q

What is the bystander effect

A

When Antibody-drug conjugates are internalized and processed–>cytotoxic payload released–>cell death in tumour AND neighbouring cells (regardless of target expression)

21
Q

Hormone therapy for tumours

A

Tumours from organs can have same dependence for hormones as the organs they originate from (can inhibit hormone secretion to tumor to prevent growth)
Prostate cancer–>androgen deprivation therapy
Breast cancer–>endocrine therapy

22
Q

Antihormonal drug treatment strategies for breast cancer

A

Block estrogen receptors with selective estrogen receptor modulators (SERMs like tamoxifen)
Inhibition of estrogen production (aromatase inhibits (AIs))
Selective estrogen receptor down-regulators (SERDs like Fulvestrant)

23
Q

What is HR+ in breast cancer

A

Hormone receptor positive
Tumor cells have receptors for estrogen and progesterone–>can promote growth of HR+ tumors

24
Q

What is HER2+ mean in breast cancer

A

Tumor cells overexpress HER2+–>associated with aggressive types of breast cancer

25
Q

Luminal A breast cancer (HR+/HER2-)

A

73% of all breast cancer (most common)
Responds well to endocrine therapy as tumor cells have receptors for estrogen and progesterone and not aggressive type of cancer (no overexpression of HER2)

26
Q

Triple negative breast cancer (TNBC) (HR-/HER2-)

A

13% of all breast cancers
Worst prognosis
Tumor cell lacks expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2)
Main therapy–>chemotherapy
Up to 20% of patients with TNBC have a BRCA mutation which can be treated with PARP inhibitors like Olaparib

27
Q

Luminal B breast cancer (HR+/HER2+)

A

10% of all cases
Tumor is aggressive and has receptors for estrogen and progesterone (can be targeted)

28
Q

HER2 enriched breast cancer (HR-/HER2+)

A

5% of all breast cancer
Tumor lacks receptors for estrogen and progesterone and is aggressive due to overexpression of HER2

29
Q

Main action of Aromatase inhibitors (AIs)

A

ex. Anastrozole and Letrozole
Decrease aromatase activity to prevent synthesis of estrone and estradiol (inhibiting conversion from testosterone and androstenedione)–>inhibits estrogen receptor activation–>inhibits cell proliferation

30
Q

Endocrine therapy for HR+/HER- breast cancer

A

Aromatase inhibitors (AIs) or Selective estrogen down-regulators (SERDs) with CDK4/6 inhibitors (palbociclib)
In premenopausal women–>additional ovarian suppression or ablation is necessary

30
Q

Main action of Selective Estrogen Receptor Modulators (SERMs)

A

May increase of decrease activity of estrogen receptors depending on tissue
In breast cancer–> SERMs act as ER antagonists in breast tissue preventing cell proliferation and estrogen signaling
ex Tamoxifen (but need to be metabolized by CYP450s and CYP2D6 into 4-hydroytamoxifen and endoxifen)

30
Q

Main action of Selective estrogen down-regulators (SERDs)

A

ex. Fulvestrant
Pure ER antagonist (no agonistic activity like in SERMS)
Has long side chain–>hindered receptor dimerization–>rapid proteasome dependent ER degradation
Fulvestrant has low bioavailability unlike tamoxifen (SERM) or AIs)

31
Q

Treatment of HER2+

A

Chemotherapy and trastuzumab with or without pertuzumab (Anti-HER2 antibodies)

32
Q

Mechanism of Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6)

A

Promote cell cycle entry by
Inactivating tumor suppressor Rb (retinoblastoma protein) by phosphorylation–> initiated transition from G2 phase to S phase

33
Q

Consequence of BRCA1and BRCA2 mutation

A

Dysfunctional homologous recombination–>makes cells inhibit PARP activity (repair in single strand DNA breaks)–>chromosomal instability, cell-cycle arrest, apoptosis

34
Q

Immune checkpoint inhibitor for first immune checkpoint CTLA-4

A

CTLA4 is a receptor on T cell that Deactivates the T cell when antigen presenting cell binds to it in the lymph node
Stimulation of CTLA-4 can be blocked with Ipilimumab (anti CTLA-4 antibodies)
Blockage of CTLA-4 and PD-1/PD-L1 interaction induces antitumor responses (synergistic effect)

35
Q

Immune checkpoint inhibitor for second immune checkpoint PD-1

A

When T cell finds antigen on tumor cell, tumor cell can express PD-L1 which binds to PD-1 on T-cell and inactivates T cell response
Stimulation of PD-1 can be inactivated by PD1 or PD-L1 antibodies like Pembrolizumab
Blockage of CTLA-4 and PD-1/PD-L1 interaction induces antitumor responses (synergistic effect)

phar 301 (23 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions