BIOMARKERS............................................................................................................................1
BIOINFORMATICS......................................................................................................................9
MASS SPECTROMETRY............................................................................................................16
NEXT GENERATION SEQUENCING...........................................................................................25
BIOMARKERS
1. Biomarkers in the pharmaceutical industry
Personalized medicine in melanoma. The first event that occurs in the benign nevus stage is
a BRAF mutation. Other tumor suppressive events can be arrest of the cell cycle, break or
inactivation. Some proteases are then increased or lost. BRAF is a kinase.
- Phosphorylation is not needed, kinase always active and always phosphorylates MEK
and ERK cell constantly grows
- B-RAFV600E (mutation in valine) cells always grow and become cancer cells
- RAF inhibitors will block pathway, block cell growth and inhibit cancers (in mice) that
have a B-RAFV600E mutation
- 60% of melanoma patients have B-RAFV600E mutation
- Basis for a personalized medicine!
B-RAF identified as a human oncogene, marker for melanoma Development of
Vemurafenib.
Biomarkers: a characteristic (gene, protein, compound in blood etc.) that is objectively
measured and evaluated as an indicator of normal biological processes, pathogenic
processes, or pharmacologic responses to a therapeutic intervention.
Pharmaceutical developments target discovery, lead discovery, lead optimization,
exploratory development.
, 2. Biomarkers in academic research and healthcare
Case study:
- Healthy parents two deceased children
- No mutations in the OXPHOS complex I-V
- Whole exome sequencing mutation in WARS2 gene
- WARS2 is mtDNA-coded tryptophanyl-tRNA synthases
- Novel mutation causes instability of WARS2 protein
- Less charging of Trp-tRNATrp
- New prenatal genetic test!
Lessons
- 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.
21000 genes 1000000-2000000 protein forms.
Glycosylation: addition of a sugar molecule usually on asparagine that has an effect on
structure, stability, interactions, transport and activity. Proteins can have multiple
glycosylations. Each glycosylation site can have multiple glycans. High number of
combinations. Proteins can be differential expressed.
Power of omics: rather tha referring to a single biomarker you refer to a panel with
standardized platforms higher diagnostic yield, contextualization of change.
, 3. Biomarkers in personalized (health)care
A molecule in a cell has an effect on another
molecule in another cell. People are more than
linear pathways. Different genetic make-ups and
lifestyles, environments, risk factors and
preferences.
Digital biomarkers
Definition: ‘Digital biomarkers are objective, quantifiable, physiological, and
behavioral measures that are collected by means of digital devices that are portable,
wearable, implantable, or digestible’
Definition: ‘Non-invasive, sensitive digital biomarkers offers the opportunity to
support monitoring of disease progression through capturing dynamic fluctuating
symptoms at home in the patient’s lived environment. Digital health technologies
may also reduce patient and site burden and enable engagement of more diverse
populations including rural environmental settings’.
Advantages digital biomarkers
- Continuous monitoring versus 1 snapshot observation
- Real world data versus data from clinically controlled circumstances
- More comprehensive and rich data sets
- Truely personalized
- Strong potential in molecular + clinical + digital + environmental biomarkers for
optimal insight in complex biological systems
- Better basis to drive Personalized health(care)
- Better support for phase 1, 2, 3, 4 clinical trials
4. Biomarker innovation gaps
Elevated levels of IL-8 in melanoma patients study that confirms these levels develop
IL-8 assays for clinical use.
- IL-8 appears to be sensitive to freeze-thawing.
- Tumor load might have been too low.
- There is tumor heterogeneity.
Vemurafenib shows strong initial effects but there is emerging drug resistance.
Biomarker levels I tissue vary. Also in body fluids.
3 translational innovation gaps.
- research to research
- research to diagnosis
BIOINFORMATICS......................................................................................................................9
MASS SPECTROMETRY............................................................................................................16
NEXT GENERATION SEQUENCING...........................................................................................25
BIOMARKERS
1. Biomarkers in the pharmaceutical industry
Personalized medicine in melanoma. The first event that occurs in the benign nevus stage is
a BRAF mutation. Other tumor suppressive events can be arrest of the cell cycle, break or
inactivation. Some proteases are then increased or lost. BRAF is a kinase.
- Phosphorylation is not needed, kinase always active and always phosphorylates MEK
and ERK cell constantly grows
- B-RAFV600E (mutation in valine) cells always grow and become cancer cells
- RAF inhibitors will block pathway, block cell growth and inhibit cancers (in mice) that
have a B-RAFV600E mutation
- 60% of melanoma patients have B-RAFV600E mutation
- Basis for a personalized medicine!
B-RAF identified as a human oncogene, marker for melanoma Development of
Vemurafenib.
Biomarkers: a characteristic (gene, protein, compound in blood etc.) that is objectively
measured and evaluated as an indicator of normal biological processes, pathogenic
processes, or pharmacologic responses to a therapeutic intervention.
Pharmaceutical developments target discovery, lead discovery, lead optimization,
exploratory development.
, 2. Biomarkers in academic research and healthcare
Case study:
- Healthy parents two deceased children
- No mutations in the OXPHOS complex I-V
- Whole exome sequencing mutation in WARS2 gene
- WARS2 is mtDNA-coded tryptophanyl-tRNA synthases
- Novel mutation causes instability of WARS2 protein
- Less charging of Trp-tRNATrp
- New prenatal genetic test!
Lessons
- 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.
21000 genes 1000000-2000000 protein forms.
Glycosylation: addition of a sugar molecule usually on asparagine that has an effect on
structure, stability, interactions, transport and activity. Proteins can have multiple
glycosylations. Each glycosylation site can have multiple glycans. High number of
combinations. Proteins can be differential expressed.
Power of omics: rather tha referring to a single biomarker you refer to a panel with
standardized platforms higher diagnostic yield, contextualization of change.
, 3. Biomarkers in personalized (health)care
A molecule in a cell has an effect on another
molecule in another cell. People are more than
linear pathways. Different genetic make-ups and
lifestyles, environments, risk factors and
preferences.
Digital biomarkers
Definition: ‘Digital biomarkers are objective, quantifiable, physiological, and
behavioral measures that are collected by means of digital devices that are portable,
wearable, implantable, or digestible’
Definition: ‘Non-invasive, sensitive digital biomarkers offers the opportunity to
support monitoring of disease progression through capturing dynamic fluctuating
symptoms at home in the patient’s lived environment. Digital health technologies
may also reduce patient and site burden and enable engagement of more diverse
populations including rural environmental settings’.
Advantages digital biomarkers
- Continuous monitoring versus 1 snapshot observation
- Real world data versus data from clinically controlled circumstances
- More comprehensive and rich data sets
- Truely personalized
- Strong potential in molecular + clinical + digital + environmental biomarkers for
optimal insight in complex biological systems
- Better basis to drive Personalized health(care)
- Better support for phase 1, 2, 3, 4 clinical trials
4. Biomarker innovation gaps
Elevated levels of IL-8 in melanoma patients study that confirms these levels develop
IL-8 assays for clinical use.
- IL-8 appears to be sensitive to freeze-thawing.
- Tumor load might have been too low.
- There is tumor heterogeneity.
Vemurafenib shows strong initial effects but there is emerging drug resistance.
Biomarker levels I tissue vary. Also in body fluids.
3 translational innovation gaps.
- research to research
- research to diagnosis
