Top-down systems biology in
oncology
Group
Top-down vs bottom-up
Clinical applications
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Diagnosis, prognosis
Treatment
Therapeutics
Various fields
– Oncology
– Pathology
• Will use prostate cancer as example
Diagnostic techniques
• Measurement of prostate specific antigen
(PSA)
– High sensitivity (90%), low specificity (10-31%)
– Also elevated in non-cancerous conditions, such
as benign prostatic hyperplasia (BPP).
– Lots of people receive unnecessary procedures
and some have undetected cancer
– In prostate cancer, early detection improves
prognosis significantly (x% vs y%)
Diagnostic techniques
• Want to add to the PSA test
– Use of systems biology to identify new biomarkers
– Might also have a less invasive test
• Metabolomics
– Measurement of metabolites (small molecules)
• Epigenomics
– Methylation of DNA
• Other -omics
Epigenomics
• Methylation of DNA backbone changes
binding specificities
– Hypermethylation of tumor suppression
promoters in early stages of cancer progression
– Genome-wide hypomethylation in later stages
– Measured using inexpensive, sensitive techniques
such as methylation-specific PCR
Methylation
• Figure 1 from methylation paper
Methylated genes
• Table showing methylated promoters
Epigenomics
• Could provide better sensitivity and specificity
than PSA
– Various promising biomarkers
– Differences in methylation patterns useful for
cancer progression determination
– No marker for stage I & II identified yet
– Also lack of specificity for prostate cancer versus
other cancers
Metabolomics
• Tumor cells show different metabolic profiles
• Mass spectrometry
– Very sensitive, in the order of picograms
– Requires extensive sample preparation
– Exposure to environment degrades samples
– Replication of results can be problematic
(temperature, humidity, storage conditions, etc
etc)
Metabolomics
• Nuclear magnetic resonance
– Not as sensitive as mass spectrometry
– In general less sample preparation required
– Non-invasive tests possible
• Different types
– MRSI for in vivo metabolite detection
– HR-MAS for detection in small volume samples
Metabolomics
• Metabolites measured in prostate cancer and
normal samples
– Determined by gas chromatography mass
spectrometry
– Elevated sarcosine levels indicative of prostate
cancer
Comparison
• Metabolomics
– In vivo measurement possible
– More!
• Epigenomics
– Stable samples (DNA half life 541 years)
– Very sensitive
– More!
Conclusion
• Top-down systems biology promising for
diagnosis and prognosis of prostate cancer
– Methods can be applied to other cancers
– Other –omics which haven’t been studied
– Clinical application would require biomarkers from
different -omics
– From biomarker to diagnostic tool is still far off
Discussion
• Also useful in therapeutics and research
– NMR-based techniques can be used for ablative
therapy targeting
– Can measure tumor response to treatment
– Identifying therapeutic targets by mapping
biomarkers to pathways -> systems biology
– More!
Discussion
• Critique of sarcosine paper here!