Molecular therapy
1st year master- Medical Biology
Week 1
Lecture: Personalized healthcare – a bird eye’s view and future directions
Consider individual differences in life science research
Separate patient group in different smaller groups for personalized healthcare
We want drugs that are not toxic, but beneficial
- The right therapy for right patient at right intensity at right time
- molecular biomarkers as key drivers of patient selection
= personalized medicine, precision medicine
Melanoma = multistage tumour development
Multiple events happen before a metastatic melanoma is there.
- BRAF mutation is one of the first mutations taking place in almost all patients with
melanoma (60%)
BRAF and personalized medicine in
melanoma
- BRAFV600E cells always grow and
become cancer cells
- RAF inhibitors will block pathways,
block cell growth and inhibit
cancers (in mice) that have a BRAF
mutation
- Basis for a personalized medicine
- BRAF is part of the ERK pathway
(growth pathway)
- Growth pathway: kinase domain
with 2 different phosphorylation
sites, ATP binds to it. Serin and
threonine both phosphorylated
MEK will get activated and
phosphorylates ERK in the same
way.
When patients with melanoma are tested and a BRAF mutation is found, you treat them
with BRAF inhibitor (Zelboraf)
- Tumours started to disappear
- Cells stop growing
- Patients live longer
- Unfortunately, tumours become drug resistant after 6-10 months combinations
of therapy e.g. Zelboraf with chemotherapy
Biomarkers:
- Definition: a characteristic that is objectively measured and evaluated as an indicator
of normal biological processes, pathogenic processes, or pharmacologic resposes to
a therapeutic intervention
1
, Molecular therapy
1st year master- Medical Biology
- Molecular biomarkers provide a molecular impression of a biological system (cell,
animal, human)
- Biomarkers can be various sorts of data, or combinations thereof
Pharma strategy on personalized medicine
The 5R’s assessment:
- Right target
- Right tissue
- Right safety
- Right patients
- Right commercial potential
During clinical tests, phase II is the most killing phase. (Testing of drug on participants to
assess efficacy and side effects.
Personalized healthcare in rare metabolic disease:
- Lab tests
- Whole exome sequencing allowed to discover a very rare genetic mutation
Role of molecular (omics) biomarker data in personalized healthcare
Personalized diagnosis + personalized therapy + patient-doctor interaction = personalized
healthcare
With the power of
genomics, we can
sequence a 3.000.000.000
DNA bases in 1 assay.
With omics we increase
the diagnostic yield and
we can see it in context
with other. Integration of
clinical omics data will give
better big picture and will
drive personalized
healthcare.
3 translational innovation gaps
- Research to research
- Research to diagnostics
- Research to society
We are not paying attention to confirming
what somebody else has been doing.
- Irreproducibility of data half of
published data cannot be reproduced.
2
, Molecular therapy
1st year master- Medical Biology
There should be a journal of irreproducible results.
Always look at:
- Known sample history
o Il-8 protein appeared sensitive to freeze/thawing
- Know all relevant information from the source (patient)
o Tumour load may be too low for our patients
- Do these type of expensive validation studies together.
o Share burden, increase power, ensure better data
In personalized
healthcare: always focus
on the end user: the
patient/ citizen
3 aspects of personalized
health(care)
- What to measure?
- How much can it
change?
- What should be
the follow-up for
me?
Take the right
action/intervention at the
pre-disease state to prevent entering the “full disease” state.
Tutorial: Pharmacology and drug disposition
The dose defines whether a drug/substance can be effective or a poison.
Pharmacology is the science that is concerned with the use, effects and modes of action of
chemicals on the function of living system.
Pharmacology is an ancient and multidisciplinary field
- Therapeutics
- Chemistry
- Commerce
- Biomedical sciences
Pharmacology focuses on many different levels: molecule, cell, organ, organism, family and
population.
Pharmacotherapy: pharmacology that focuses on patients driven by pathophysiology
Questions in pharmacotherapy:
- What does the patient with the drug? = Pharmacokinetics
- What does the drug with the patient? = Pharmacodynamics
3
, Molecular therapy
1st year master- Medical Biology
Rational vs. evidence-based pharmacotherapy:
- Rational pharmacotherapy: “mechanism-based pharmacotherapy”
- Evidence-based pharmacotherapy: It does not matter how it works, as long as it
works.
Pharmacological phases in pharmacotherapy:
- Exposition phase: Behaviour of a substance in the environment, changes in the
application form, available for uptake. E.g. what about the stability, how long can
you keep it, in which form should we applicate it? Dose
- Toxicokinetic phase: Absorption, Distribution, Metabolism (toxification,
detoxification), Excretion. (ADME). Dose/Effect
- Toxicodynamic phase: Interactions with receptors or other (macro) molecules at the
site of the operation. Effect
2 types of interactions of a drug:
- Agonist: activates a receptor leading to signal transduction
- Antagonist: blocks function of receptor
Classical drug-receptor-interactions
G-protein coupled: most targeted class nowadays
Note the time scale Protein synthesis takes time.
4
1st year master- Medical Biology
Week 1
Lecture: Personalized healthcare – a bird eye’s view and future directions
Consider individual differences in life science research
Separate patient group in different smaller groups for personalized healthcare
We want drugs that are not toxic, but beneficial
- The right therapy for right patient at right intensity at right time
- molecular biomarkers as key drivers of patient selection
= personalized medicine, precision medicine
Melanoma = multistage tumour development
Multiple events happen before a metastatic melanoma is there.
- BRAF mutation is one of the first mutations taking place in almost all patients with
melanoma (60%)
BRAF and personalized medicine in
melanoma
- BRAFV600E cells always grow and
become cancer cells
- RAF inhibitors will block pathways,
block cell growth and inhibit
cancers (in mice) that have a BRAF
mutation
- Basis for a personalized medicine
- BRAF is part of the ERK pathway
(growth pathway)
- Growth pathway: kinase domain
with 2 different phosphorylation
sites, ATP binds to it. Serin and
threonine both phosphorylated
MEK will get activated and
phosphorylates ERK in the same
way.
When patients with melanoma are tested and a BRAF mutation is found, you treat them
with BRAF inhibitor (Zelboraf)
- Tumours started to disappear
- Cells stop growing
- Patients live longer
- Unfortunately, tumours become drug resistant after 6-10 months combinations
of therapy e.g. Zelboraf with chemotherapy
Biomarkers:
- Definition: a characteristic that is objectively measured and evaluated as an indicator
of normal biological processes, pathogenic processes, or pharmacologic resposes to
a therapeutic intervention
1
, Molecular therapy
1st year master- Medical Biology
- Molecular biomarkers provide a molecular impression of a biological system (cell,
animal, human)
- Biomarkers can be various sorts of data, or combinations thereof
Pharma strategy on personalized medicine
The 5R’s assessment:
- Right target
- Right tissue
- Right safety
- Right patients
- Right commercial potential
During clinical tests, phase II is the most killing phase. (Testing of drug on participants to
assess efficacy and side effects.
Personalized healthcare in rare metabolic disease:
- Lab tests
- Whole exome sequencing allowed to discover a very rare genetic mutation
Role of molecular (omics) biomarker data in personalized healthcare
Personalized diagnosis + personalized therapy + patient-doctor interaction = personalized
healthcare
With the power of
genomics, we can
sequence a 3.000.000.000
DNA bases in 1 assay.
With omics we increase
the diagnostic yield and
we can see it in context
with other. Integration of
clinical omics data will give
better big picture and will
drive personalized
healthcare.
3 translational innovation gaps
- Research to research
- Research to diagnostics
- Research to society
We are not paying attention to confirming
what somebody else has been doing.
- Irreproducibility of data half of
published data cannot be reproduced.
2
, Molecular therapy
1st year master- Medical Biology
There should be a journal of irreproducible results.
Always look at:
- Known sample history
o Il-8 protein appeared sensitive to freeze/thawing
- Know all relevant information from the source (patient)
o Tumour load may be too low for our patients
- Do these type of expensive validation studies together.
o Share burden, increase power, ensure better data
In personalized
healthcare: always focus
on the end user: the
patient/ citizen
3 aspects of personalized
health(care)
- What to measure?
- How much can it
change?
- What should be
the follow-up for
me?
Take the right
action/intervention at the
pre-disease state to prevent entering the “full disease” state.
Tutorial: Pharmacology and drug disposition
The dose defines whether a drug/substance can be effective or a poison.
Pharmacology is the science that is concerned with the use, effects and modes of action of
chemicals on the function of living system.
Pharmacology is an ancient and multidisciplinary field
- Therapeutics
- Chemistry
- Commerce
- Biomedical sciences
Pharmacology focuses on many different levels: molecule, cell, organ, organism, family and
population.
Pharmacotherapy: pharmacology that focuses on patients driven by pathophysiology
Questions in pharmacotherapy:
- What does the patient with the drug? = Pharmacokinetics
- What does the drug with the patient? = Pharmacodynamics
3
, Molecular therapy
1st year master- Medical Biology
Rational vs. evidence-based pharmacotherapy:
- Rational pharmacotherapy: “mechanism-based pharmacotherapy”
- Evidence-based pharmacotherapy: It does not matter how it works, as long as it
works.
Pharmacological phases in pharmacotherapy:
- Exposition phase: Behaviour of a substance in the environment, changes in the
application form, available for uptake. E.g. what about the stability, how long can
you keep it, in which form should we applicate it? Dose
- Toxicokinetic phase: Absorption, Distribution, Metabolism (toxification,
detoxification), Excretion. (ADME). Dose/Effect
- Toxicodynamic phase: Interactions with receptors or other (macro) molecules at the
site of the operation. Effect
2 types of interactions of a drug:
- Agonist: activates a receptor leading to signal transduction
- Antagonist: blocks function of receptor
Classical drug-receptor-interactions
G-protein coupled: most targeted class nowadays
Note the time scale Protein synthesis takes time.
4
