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An extensive summary of Molecular Therapy
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Molecular Therapy – lecturesLecture 1 – Personalized healthcare
Nowadays the research is more focused on the differences between individuals.
You want the group in the green circle.
So there is principle of personalized healthcare: the
right therapy for right patient at right
intensity/dose at right time. Molecular biomarkers
are key drivers of patient selection. This is also
called personalized medicine or precision medicine
Personalized medicine in melanoma → BRAF mutation happens at first (it is a spontaneous
mutation), there are breaks to stop, but when the break is broken more mutations can happen. ERK
is the transcription factor that goes to the nucleus and stimulates the cell to grow (after it is
phosphorylated), this happens when there is BRAF mutation because normally the cell does not grow
consistently. RAF inhibitors will block the pathway, block cell growth and inhibit cancers (in mice)
that have the BRAF mutation. It is known that 60% of melanoma patients have a BRAF mutation. This
is the basis for personalized medicine.
- Vemurafenib is the RAF inhibitor, this is used when it becomes clear that a patient has the
BRAF mutation.
- There is a lot of brown, this means that ERK is phosphorylated. By using the RAF inhibitor,
ERK will not be phosphorylated (no brown) anymore so not active to go to the nucleus.
- It happened that the tumor became resistant to the drug, so when they figured this out they
gave the patient the RAF inhibitor with chemotherapy or in combination with another
targeting drug.
Biomarkers → a characteristic that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic or pharmacologic responses to a therapeutic intervention.
Biomarkers can be anything, as long as it can be objectively measured (SNIP, protein, etc). So
biomarkers can be various sorts of data, or combinations hereof.
Molecular biomarkers proved a molecular impression of a biological system (cell, animal, human).
Phase II in the drug process → to make sure that the drug is working in humans
The 5R’s strategy:
1. Right target
2. Right tissue
3. Right safety
4. Right patients
5. Right commercial potential
By using this strategy more drugs got to the market, astrazeneca was the company that developed
the 5R strategy.
Personalized healthcare; Two sons died with the same clinical phenotypes (epilepsy, low blood
sugar…) both died. There was a suspicion of mitochondrial disease, the doctors could not find any
other cause. The mitochondria needs to be tested in cells, so the researchers got fibroblast as well as
blood. It showed that there was a low ATP production and creatine phosphate production. But after
this research there was no sign of mitochondrial disease. However, in 2010 WES was possible, and
,this showed a WARS2 mutation. WARS2 is mtDNA-coded tryptophanyl-tRNA synthases. They create a
test, when it is positive there is WARS2 mutation, negative means not. This family got again
pregnant, and test was negative.
Lessons learned:
- Technology innovation is driving impact in personalized healthcare
- Crucial to combine different molecular views to understand human health and disease (X-
omics)
- Fast translational of biomarker research to implementation needed
Molecular biomarkers are getting more important in personalized healthcare. So these omics
(molecular biomarkers) are important. When you have the omics platform the researcher uses this to
monitor the therapy (like the BRAF therapy), so is the dosing correct, is the biomarker effective, are
there any side effects?
- It is now possible to test the whole genome below the cost of €1000
At patient 1 you can see that the ‘specific
cytokine (like Il 6) is a factor 2 increased.
This is different in patient 2 where Il6 is
increased but all the other cytokines are
increased and decreased as well.
So with the omics panel there is a higher
diagnostic yield, because you test a lot
more biomarkers. But you can also make
the change into context, which is
important.
Integration of clinical omics data will give better big picture and it will drive personalized healthcare.
There are now digital biomarkers → small digital devices which can measure multiple biomarker
entities in smart ways. Patient can test at home her oncology biomarkers, and send this to the
hospital so that she does not have to visit the hospital.
- There are more cool apps, and it is not always clear why they detect something but they
work. → like the app that can detect a heart attack a week before you have it. Because the
app listen to your tone of voice, and one week before the heart attack your tone (amplitude)
changes.
- Another app → you have a substrate and you put blood on it, then the substrate will change
colour. Then you scan the substrate with your smartphone and it will give an analysis.
**Warning → there is a lot of data, but not all data is useful. So it is time for quality not quantity.
,However, there are 3 translational innovation gaps;
1. Research to research
2. Research to diagnostics
3. Research to society
There are a lot of biomarkers created per day, like 5 per day. There was a study and it showed that
half of the published data cannot be reproduced, the work from other researchers.
In the same study they showed that the US is
throwing away 29 B dollars, because not all
biomarkers are reproducible.
➔ The outcome of this
experiment was not the same as
what was published before. So
this shows that not all research
can be reproduced.
Lessons learned from this?
1. Know sample history → IL-8 protein appeared sensitive to freeze-thawing
2. Know all relevant information from the source (patient) → tumor load may be too low for
our patients
3. Do these type of expensive validation studies together! → share burden, increase power,
ensure better data
➔ If we want to innovate clinical molecular biomarkers, we need to increase quality, not
quantity of our research.
, Scientist nowadays can choose → do you want to discover new things, or confirm the research from
others?
In personalized healthcare: always focus on the end user: the patient / citizen
3 aspects of personalized health(care):
1. What to measure?
2. How much can it change?
3. What should be the follow-up for me?
Personal profile data → knowledge → understanding → decision → action
We need a personalized data-driven GPS for health;
- Monitor on background
- Alert when you are at risk
- Advice what to do
- Doctor as coach? → together decide what to do
Prevention is health promotion.
There is a personalize choice, because do you what to know everything what is going to happen in
the future? → do you want to know that maybe later on you will develop diabetes?
Afterthought: there is no single one reflection of health. Your health is like a funhouse mirror effect.
There are multiple sources of your data:
- multiple omics
- clinical chemistry
- electronic patient dossier
- wearables
- digital biomarkers
- commercial health tests
- social media
- surrounding
➔ each are a skewed image of you
Tutorial 1 – Pharmacology and drug disposition - 6-09-21
The dose depends if a drug or substance can be effective or it causes harm. So the dose defines the
poison.
Pharmacology is the science that is concerned with the use, effects and modes of action of chemicals
on the function of living system.
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