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Cancer Mechanisms and Therapeutics > Apoptosis and Targeted Cancer Therpeutics > Flashcards

Apoptosis and Targeted Cancer Therpeutics Flashcards

1
Q

What cancer was bcl-2 antisense therapy tried in

A

Metastatic melanoma

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2
Q

What cancer was siRNA for bcl2 used in

A

breast tumours –> caused robust repression in mice with xenograft
Showed apoptosis and autophagic death in cells in combination with doxorubicin

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3
Q

What is doxorubicin

A

A drug that induces functionally active CD95

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4
Q

What is usually overexpressed in c-myc tumours

A

Bcl-2 –> enables c-myc tumours to evade oncogene induced sensecence!

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5
Q

WHat mouse model is used eto show c-myc and bcl-2 coverexpressoin

A

Burkitt’s lymphoma in mice

Howvever c-myc overexpression without bcl-2 just causes masive apoptssi and tumour regression

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6
Q

Name the 3 BH3 mimetics

A

Navitoclax

Ventoclax

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7
Q

What are the differences between Naviotclax and ventoclax

A

Navitoclax inhibits BCL-XL and bcl-2

Ventoclax only inhibits BCL-2

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8
Q

Which anto-apoptotic protein can most BH3 mimetics not target

A

MCL-1 –> howver a specified MCL-1 antagonist has been developed

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9
Q

Where have bim peptides been shown to be effacious

A

in mouse models of AML

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10
Q

What helix blocks the BH3 groove in Bax

A

alpha 9 –> confirmational shape change allows its exposure before it can oligomerise and nsert into the membrane

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11
Q

Where is the additional BH3 binding site on Bax

A

between alpha helices 1 and 6

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12
Q

What molecules aim to bind to the BH3 additional binding site

A

Bax Activating Molecules (BAM) –> bind to the rear BH3 binding pocket and can killl cells

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13
Q

Why is TRAIL overexpressed many cancer cells

A

As TRAIL can enhance PI3K Signalling and enhance migration and invasion

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14
Q

What occurs when FADD Is releaed from the TRAIL complex

A

forms Complex 2 –> recruits TRADD which leads to the potent aftivation of NF-kB
Also recruity TRAF2 which activates the MAPkK pathway

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15
Q

What decoy trail receptor is upregulated in AML

A

Trail 3 esp. in CSCs

Agonistic Ab binding targeted to Trail 2 is the most successful!!

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16
Q

What is the function of Trail 4

A

It is a decoy TRAIL recepor
It has an intracellular domain that can also interfere with TRAIL 2 to impair caspase activation
Can also potentiate AKt activity

17
Q

Nae two Trail antibodeies

A

Maptumumab

Lexatumumab

18
Q

What happens in necroptosis

A

Instead of FADD recruiting caspase 8 it insteads recruits RIP-1, which then recruitys RIP-3 which phosphorylates MKLK which desitubas the m embrane integrity and causes necroptosis.

19
Q

What are the 4 peptides smac needs

A

alanine, proline, valine, isoleucine1

20
Q

Where have smac agonists seen the most success

A

Glioblastomas !! In combination with TRAIL caused the complete eradication of up to 50% of glioblastomas in mice

21
Q

Name a monovalent smac-mimetic

A

LCL-161 –> also induces an inflammatory response leading to phagocytosis of cancer cells

22
Q

What happens to embryonic mice lacking Bax or Back

A

fail t have complete embryonic development

These mice are resistant to a large array of apoptotic stimuli

23
Q

WHAT IS OCCURRING IN MICE THAT OR BOTH BAK OR BAX NULL BUT MANAGE TO SURVIVE FOR A FEW MOTNHS

A

Indicates a third multidomain pro-apoptotic protein termed Bok potentially exists!

24
Q

What are the 2 different models for how the BH3 only proteins work

A

1) Direct activation

2) Indirect activation

25
Q

What defines the IAP Family

A

Have BIR Repeats

Baculoviral IAP Repeats

26
Q

How do IAPs act to prevent apoptosis

A

they bind caspases and can label them for degradation by ubiquination or neddylation via the RING domain
XIAP also directly inhibits the enzymatic activity of caspases
IAPS can also prevent the assembly of caspase 8 or 10 platforms!

27
Q

Do IAPS also regulate the RIP family?

A

YES

as can also catalyse the ubqitination of RIP1

28
Q

How do IAPS increase NFkB signalling

A

Promotes the degradation of the IKB complex that sequesters NF-kB in the cytoplasm

29
Q

How can ew target IAPS in cancer

A

1) Antisense olignougleotides to XIAP

2) Synthetic IAP Antagonists e.g smac mimetics

30
Q

How does smac inhibit IAPs

A

binds and inhibits BIR2 and BIR3

Cancer Mechanisms and Therapeutics (10 decks)

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