biopharmaceutics

Question 1

Where do tumours usually result from?

Answer 1

Activation of immune system and inflammation. The tumour microenvironment is important.

Question 2

What are the two aspects to cancer causes?

Answer 2

Nature – genetics.

Nurture – environment leading to epigenetics.

Question 3

Why are humans so susceptible to cancer?

Answer 3

They are hyper mutable.

We have bad genetics – somatic defects and epigenetic changes.

Humans and viruses – transposable elements and proto-oncogenes.

Hypermutable genome – good and bad outcomes, viral driven cancers occur because we are primed to interact with viruses when they come into the body.

Question 4

What is cancer?

Answer 4

Cells have the ability to divide. The rate of that division is controlled by external cues. Cancer results when mechanisms that regulate division in cells lose control.

Question 5

Are two cancers the same?

Answer 5

No. There are a wide range of cancers which are defined by a similar phenotype and there are many sub-categories. The genotype associations are inconsistent; not even identical twins are truly identical – epigenetics. There are variations in outcome and course between patients and differences in therapy responses.

Question 6

How many types of cancers are there?

Answer 6

There are too many to count. Rare cancers are common and common cancers have large clinical trial information to support therapy approach. Anecdotal information often drives rare cancer therapy algorithms. Rare cancers are where personalised medicines are most needed. There are no set algorithms.

Question 7

What are the four stages of cancer?

Answer 7

Stage one – early stage where there is a small, invasive mass or tumour.
Stage two – localised where the cancer has started to affect nearby tissue.
Stage three – regional spread where the cancer affects more surrounding tissue.
Stage four – distant speed where the cancer has spread to other tissues or organs beyond the region where it originated.

Question 8

How do cancers kill?

Answer 8

Mainly by metastasis. The primary sites can often be resected. Most cancer deaths are due to metastatic burden and many times the primary site is never identified. Each cancer has hallmarks of original site or cell type and the cell type origin defines the likely metastatic behavior. These markers identify where the cell grows best.

Question 9

Why do cancer types change with age?

Answer 9

Children have higher replication rates and so cancer cells replicate faster and it is difficult to separate normal vs cancer cells.

There are many cancers which are more common in children. This raise many ethical questions with regard to clinical trial strategies as well as treatment decisions.

Need to be able to understand how drugs work and how they cause side effects to understand the ethics of clinical trials.

Question 10

How do cancer cell types differ between ethnic groups?

Answer 10

Patients can be profiled based on ethnicity. Certain populations have genetic drives which push them into certain categories.
Epidemiologists try to find connections between ethnic and regional trends and environmental differences eg diet, cultural habits and behaviours.

Question 11

What is the link between cell division and cancer?

Answer 11

Receptors under chronic inflammatory states become more activated. There are lots of inhibitors which can treat cancers but they are also there in normal conditions. The normal cells use the same systems as cancer cells when they need to divide and needs to be selective.

Question 12

How can kinases inhibitors treat cancer?

Answer 12

The inhibitor inhibits all of the kinases because we don’t know which kinase causes the problem of cancer.

Question 13

What are endogenous cancer suppressors?

Answer 13

Tumour suppressors eg p53 which has cellular roles in genome stability, DNA repair, apoptosis/ cell death and cell metabolism. Oncogenic suppressors can be passed along and people survive. P53 is a regulator of growth which happens in cells. Too much or too little p53 can cause cancer.

Question 14

What roles does tumour suppressor p53 have in the body?

Answer 14

Cellular roles in genome stability, DNA repair, apoptosis / cell death and cell metabolism.

Question 15

What are strategies to treat cancer?

Answer 15

Intracellular targets: Suppress kinase function and suppress cell division.
Extracellular targets: Antibodies, aptamers and delivery effectors.

Question 16

What happens when genomic alterations of kinases are activated?

Answer 16

Activating point mutations in genes coding for kinases can lead to the expression of constitutively attached kinase. Chromosomal amplification leads to increased kinase transcription and downstream pathways become over activated. Chromosomal alterations can localise a kinase gene in proximity to another gene and lead to a constitutively activated chimeric or truncated kinase.

Question 17

What are the potential therapeutic combinations to overcome resistance to BARF inhibitors?

Answer 17

Dual blockade within MAKP pathway or between the MAPK and parallel PI3K pathways and improves clinical outcome by reducing compensatory signaling and delaying the onset of resistance.

Question 18

What are the chemotherapy drug categories of small molecules used in the suppression of cell division?

Answer 18

Alkylating agents – bind DNA and stop replication.
Antimetabolites – block the use of nutrients.
Anti-microtubule agents – interfere with cell division.
Antibiotics – inhibit RNA synthesis to slow or block mitosis.

Question 19

What are the pros of antibody therapy to treat cancer?

Answer 19

Antibodies alone were easy to make and validate.

There is direct genetic or chemical coupling to make chimeras possible.

Question 20

What are the cons of antibody therapy to treat cancer?

Answer 20

There are complicated multi dosing ideas brought to the clinic.
There are multiple elements required have very challenging manufacturing and regulatory issues.
Toxins have issues.

Question 21

What are the extracellular actions of monoclonal antibodies?

Answer 21

Because of their physiochemical nature monoclonal antibodies do not access the cell cytoplasm but they have many extracellular actions:
Antibody directed cell killing.
Solid tumour growth requires angiogenesis.
T-lymphocytes function to kill intruding cells that do not have protective surface markers.
Radiation is mutagenic.
Toxins can be directed.
Effector cells can be brought to close proximity to cancer cells.
CAR T technology has an outgrowth of how biopharmaceuticals can be used to target and kill cancer cells.

Question 22

What are the pros for directed to cancer cells for tumour killing?

Answer 22

Tremendous selectivity.
Flexible nature for coupling of toxic and other agents. 
Can select different affinity.
Long systemic residence.
Relatively stable.

Question 23

What are the cons for directed to cancer cells for tumour killing?

Answer 23

Doses are very high due to massive volume of distribution.
Hard to find a truly tumour resistant antigen.
Can have off target outcomes.

Question 24

What are the pros of Vascular and stromal ablation?

Answer 24

Tremendous selectivity 
Flexible nature for coupling of toxic and other agents
Can select different affinity 
Long systemic residence 
Relatively stable

Question 25

What are the cons of vascular and stromal ablation?

Answer 25

Doses are very high due to massive volume of distribution
Hard to find a truly tumour restricted antigen
Can have off target outcomes.

Question 26

What are the pros of immune-mediated cell killing?

Answer 26

Tremendous selectivity
Flexible nature for coupling of toxic and other agents
Can select different affinity
Long systemic residence
Relatively stable

Question 27

What are the cons of immune-mediated cell killing?

Answer 27

Doses are very high due to massive volume of distribution
Hard to find a truly tumour restricted antigen
Can have off-target outcomes.