Top-down systems biology in oncology

1. Top-down systems biology in oncology Group

2. Top-down vs bottom-up

3. Clinical applications • Diagnosis, prognosis • Treatment • Therapeutics • Various fields • Oncology • Pathology • Will use prostate cancer as example

4. 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%)

5. 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

6. 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

7. Methylation • Figure 1 from methylation paper

8. Methylated genes • Table showing methylated promoters

9. 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

10. 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)

11. 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

12. Metabolomics • Metabolites measured in prostate cancer and normal samples • Determined by gas chromatography mass spectrometry • Elevated sarcosine levels indicative of prostate cancer

13. Comparison • Metabolomics • In vivo measurement possible • More! • Epigenomics • Stable samples (DNA half life 541 years) • Very sensitive • More!

14. 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

15. 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!

16. Discussion • Critique of sarcosine paper here!