PED1003/L26 Cancer Therapeutics Flashcards

1
Q

Describe the two methods of ATP synthesis in healthy cells.

A

Some by glycolysis in cytoplasm
More by oxidative phosphorylation in mithchondria

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2
Q

What is the Warburg effect?

A

Shift towards glycolysis associated with immune cell activation, cancer and age-related diseases

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3
Q

Why do cancer cells switch to favour glycolysis? (3)

A

Scarcity of oxygen
Faster ATP production (100x)
Intermediates used for DNA synthesis, proteins and lipids

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4
Q

How do cancer cells speed up their energy production?

A

Uptake more glucose through GLUT1-4
Elevate expression of glycolytic enzymes

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5
Q

Name 2 glycolysis enzymes.

A

HK2
PFK1
PK-M2
LDHA

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6
Q

Give 2 roles of lactate inside cancer cells.

A

Regeneration of NADH
Reduction of ROS production

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7
Q

Give a role of lactate outside cancer cells.

A

Lactate lower pH of microenvironment (pro-invasive)

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8
Q

What is the role of lactate in metabolic symbiosis? (3)

A

Lactate converted to pyruvate in normoxic cells
Enters TCA cycle
Energetic source for these cells

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9
Q

What is the role of lactate in immunosuppression? (3)

A

Promotes TME acidification
Lower pH within immune cells affecting signalling pathways
Inhibit CD4, CD8 T cells NK cells dendritic cells by lowering pH
Apoptosis of CD8 T cells and NK cells

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10
Q

Explain how immune destruction is avoided. (4)

A

When tumours arise, immune cells recognise and eliminate them
Variant tumour cells arise that are more resistant to being killed
Over time a variety of different cancer cells develop
One variant may escape killing mechanism or recruit regulatory cells to protect it so can spread unchallenged

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11
Q

Give the 5 main mechanisms by which immune destruction is avoided.

A

Low immunogenicity
Tumour treated as self antigen
Antigenic modulation
Tumour-induced immune suppression
Tumour-induced privileged site

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12
Q

Describe low immunogenicity. (3)

A

No peptide:MHC ligand
No adhesion molecules
No co-stimulatory molecules

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13
Q

Describe tumour treated as self antigen.

A

Tumour antigens taken up and presented by APCs in absence of co-stimulation tolerize T cells

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14
Q

Describe antigenic modulation.

A

T cells may eliminate tumours expressing immunogenic antigens but not tumours that have lost such antigens

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15
Q

Describe tumour-induced immune suppression. (2)

A

Factors secreted by tumour cells inhibit T cells directly
Expression of PD-L1 tumours

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16
Q

Describe tumour-induced privileged site.

A

Factors secreted by tumour cells create a physical barrier to the immune system

17
Q

How are monoclonal antibodies used in cancer immunotherapy? (2)

A

Tumour-specific antigen must be expressed on tumour cell surface
Trastuzumab targets HER2 receptor overexpressed in 25% breast cancers
Rituximab - anti-CD20 antibody trigger apoptosis of B cells used in non-Hodgkin B-cell lymphoma

18
Q

Give 2 problems with using monoclonal antibodies in cancer.

A

Inefficient killing of cancer cells
Inefficient penetration of antibody into tumour mass
Soluble target antigens mopping up antibody

19
Q

Give 2 solutions with using monoclonal antibodies in cancer.

A

Linking antibody to toxin
Coupling it to radiation or a drug
Use of small body fragments

20
Q

Give an example of a small body fragment.

A

Blinatumomab
ScFv targeting CD19/CD3 approved for Acute Lymphoblastic Leukemia

21
Q

Describe how Blinstumomab works. (3)

A

Enables patient’s T cells to recognise malignant B cells
Combines 2 binding sites for CD3 T cells and CD19 site for target B cells
Links 2 cell types and activates T cell to exert cytotoxic activity on target cell

22
Q

How are T cells used to express CARs in cancer? (4)

A

T cells harvested from blood of patient with B-cell tumour
Retrovirus encoding an anti-CD19 CAR infects T cells that are activated with antibodies to CD3 and CD28
Infected T cells express an anti-CD19 CAR
T cells infused into patient to mediate antitumour activity

23
Q

What is a Chimeric Antigen Receptor (CAR)?

A

A fusion receptor that contains extracellular antigen-specific domains fused to intracellular domains that provide signals for activation and stimulation
Allow target specificity to be almost any molecule recognisable by antibody rather than just peptide:MHC complexes

24
Q

Give 2 ways in which a vaccine can be prepared.

A

Mixing cell tumour extracts with killed bacteria
Antigen-loaded dendritic cells (or other APC cells) to stimulate cytotoxic T cells against tumours

25
Q

Describe Sipulelucel and how it works in prostate cancer treatment.

A

Monocytes extracted from patieents treated with prostatic antigen and GM-CSF to stimulate monocyte differentiation in dendritic cells

26
Q

Give a positive and negative checkpoint in the immune response.

A

T-cell response is modulated by B7 co-stimulatory receptors on APC
Inhibitory receptors such as CTLA-4 and PD-1 block activation of potentially autoreactive T cells

27
Q

Describe how iplimumab and pembrolizumab work. (3)

A

Monoclonal antibody-mediated blockade of CTLA-4 or PD-1 expressed by CD8 cytotoxic or CD4 helper cells
Blocks inhibitory signals and allows for untreated T-cell effector function and attack on cancer cells
CTLA-4 blockade affects Tregs which express CTLA-4