DD2

What are the 3 main points of intervention for cancer?

Viral elements

Stop activation of growth factors

Stem cells vs differentiated cells

What does p53 have cellular roles in?

genome stability, DNA repair, apoptosis/cell death, and cell metabolism

What happens if growth and suppressor factors are against each other?

Cell apoptosis

Why can SNP cause issues?

Mutation can cause a change in amino acid

Why does screening of SNPs happen?

To allow for cataloguing of hotspots which could be pharmalogical targets

What are the two strategies to treat cancers?

Small molecules , intracellular cellular

Biopharmaceuticals, extracellular targets

Describe some of the targets for small molecules?

• Suppress kinase function

• Suppress cell division

Describe some of the targets for biopharmaceuticals?

• Antibodies

• Aptamers

• Delivery of effectors

What do most kinase suppressing drugs do?

hit a couple of steps in the kinase function pathway → do need a specific target

What are the main features that tumours need to survive?

Motility, evading anti tumour immunity, DNA damage check points, proliferation, angiogenesis, metabolism

Describe ways that kinases can become mutated?

Point mutations causing kinase to be constitutively active

Chromosomal amplification leads to increase kinase transcription and overactivation

Deletions or translocations can move the kinase gene close to another gene that leads to a constitutively active kinase

Describe the potential combinations of therapeutics to overcome resistance to the BRAF inhibitors?

Dual blockade within MAPK pathway or MAPK and PI3K pathways improves clinical outcomes by reducing compensatory signalling and delaying onset of resistance

Why is small molecules hitting allosteric elements beneficial?

can hit multiple receptors, can have more targets

Define chemo Alkylating agents?

bind DNA stop replication

Define chemo Antimetabolites?

block use of nutrients

Define chemo Anti-microtubule agents?

interfere with cell division

Define chemo Antibiotics?

inhibit RNA synthesis to slow or block mitosis

What do traditional cancer therapies usually target?

Part of the cell cycle, either something in the replication pathway or the mitosis pathway, microtubule components

How to biopharmaceuticals affect inside the cell?

they have to use modulators on the outside the cell

What is the average amount of antibodies needed for a doe?

1g

Describe the hybridoma method?

• inject a mouse with the human target

• It raises immune responses against that non-self human protein

• Take the b cells from the mouse that recognise different parts of that protein,

• Hybridise those cells into a cancer cell line

  • Lymphoma cancer cell line that will immortalise each of those B cells

• Each b cell is producing an individual clone of antibody that will recognise one particular thing on the original target

• Called monoclonal antibodies, because each of them are derived from a single clone of hybrid donor B cell fusion

• Grow all the cells up and they produce antibodies

• Collect the antibodies and see which one works best for the profile you want

• Produce those antibodies in large fermenters

Why can antibodies circulate for 3-4 weeks?

• Binds to FC receptors on vascular bed

• Spends most time outside the vascular bed

  • By going in to the endothelial cells

  • Last so long due to time spent outside vascular bed

What are the 2 types of antibody target strategies?

Peak target

Durable response

Describe the peak target response?

• Hit something on the surface/ a target

• This causes the activation of something

Describe the durable response?

• Continuous dosing

• Sustain suppression of a growth factor or growth response mechanism

Why are pre-clinical studies unrealistic?

Mouse models the % of the body that is the tumour is much larger than humans

What happens when small molecules enter the body?

The majority of the drug doe not get to the tumour, whereas antibodies can targeted

What is the best strategy for addressing drivers and suppressors?

Suppress the overactivity rather than trying to bring up the non activity

What do most antibodies do in terms of suppressors and drivers?

• blocks stress response or growth cycle

• have capacity for immune system to role in do some damage

What are the pros of antibodies?

• Antibodies alone were easy to make and validate

• Direct genetic or chemical coupling to make chimeras was possible

What were the cons of antibodies?

• Complicated multi-dosing ideas were brought to the clinic

• Multiple elements required very challenging manufacturing and regulatory issues.

• Toxins have issues.

What are some of the extracellular actions of antibodies?

Antibody-directed cell killing

Blocking angiogenesis

Blocking immune suppressor receptors

Radiation cargo

Toxins can be directed

effector cells can be brought close to cancer cells

CAR T cells

What are the pros of antibodies be used to direct things towards the tumour?

• Tremendous selectivity

• Flexible nature for coupling of toxic and other agents

• Can select different affinity

• Long systemic residence

• Relatively stable

What are the cons of antibodies be used to direct things towards the tumour?

• Doses are very high due to massive volume of distribution

• Hard to find a truly tumour-restricted antigen

• Can have off-target outcomes

Describe the difference between the uses of agonists and antagonists?

• Agonist → only need to spike it and let the cell carry out its function → Peak

• Antagonist → need to keep the antibody there for a long period of time as you are blocking receptor function

What are the pros of stromal and vascular ablation?

Multiple new targets

What are the cons of stromal and vascular ablation?

Unexpected outcomes

What are pros and cons of immune-mediated killing?

Engaging the immune system

Why are high affinity antibodies not always the best?

As the cells on the surface are more superficial so mop up a lot of the antibodies so they do not reach the tumour, moderate affinity will bind and come off and work their way to tumour core

Why can catastrophic infections lead to tumour shrinkage?

Immune response revved up get factors such as tumour necrosis factor, gets the immune system to engage and recognise the tumour that is suppressing immune system

What does ATCC stand for?

Antibody-dependent cell-mediated cytotoxicity

What does ADPC stand for?

Antibody-dependent cellular phagocytosis

What can PD do?

Check point that says do not kill

Why is mixing up therapy good?

Mabs can target cell surfaces while while small molecules can affect intracellular targets.

Can reduce doses

Reduce side effects

Reduce stress of systems

Increase safety

How do most clinical trials happen?

Due to a combination of an improved drug and the new drug to make it ethical and to see if new drug has any added benefit