1. Genomic signatures to guide the use of chemotherapeutics Authors: Anil Potti et. al Presenter: Jong Cheol Jeong

2. Motivation  What will be happened if ineffective chemotherapy is used? Increasing the probability of side effects Decreasing the quality of life

3. Purpose  Developing gene expression signatures which predict responses to various cytotoxic chemotherapeutic drugs.  Giving us the direction for using cytotoxic agents which best matches the characteristics of the individual.

4. Outline  Method  Results  Conclusion

5. Method NCI-60: composed with 60 cell line and the sensitivity to 5084 compounds Sensitivity: exposing each cell line to each compound for 48hours, assessing the growth inhibition by sulforhodamine B

6. Method  Using the cell line in the NCI-60 Panel - 60 cancer cell line: sensitivity of 5084 compounds 1)Identifying cell line: most resistant or sensitive to docetaxel 2)Identifying genes: their expression correlated most highly with drug sensitivity 3)Bayesian binary regression analysis with LOOCV

7. Results or The concentration of compound requiring 50% growth inhibition The concentration of compound requiring 50% cytotoxic Cell lines from NCI-60 Red : highest expression Blue: lowest expression

8. Results Validation of docetaxel response prediction model 30 lung and ovarian cancer cell lines Significant correlation between predicted probability of docetaxel sensitive and IC 50 29 lung cancer cell lines

9. Results showing the capacity of the predictor Applying a Mann-Whitney U-test

10. Results

11. Results (developing series of expression profile from NCI-60)

15. Result (predicting response of combinations of drugs)  4 cytotoxic agents: paclitaxel, 5-FU, adriamycin, and cyclophosphamide  51 cell lines: 13 responders, 38 nonresponders Individual chemosensitivity predictions

16. Result (predicting response of combinations of drugs) Statistically significant distinction between the responders and nonresponders

17. Result (predicting response of combinations of drugs) Breast cancer with 45 cell lines 38 responders 11 nonresponders

18. Result (predicting response of combinations of drugs) PPV: Positive Predicted Value NPV: Negative Predicted Value Blue: sensitive Red: resistant FAC adjuvant chemotherapy Kaplan-Meier survival analysis

19. Result (patterns of predicted chemotherapy response) Respond to 5-FU are resistant to Adriamycin and Docetaxel: suggesting possibility of alternate treatments Step1. Chemotherapy response predictors calculates the likelihood of sensitivity to the seven agents in a large collection of samples Ex) breast, lung, and ovarian tumor Step2. Clustering the samples according to patterns of predicted sensitivity to the various chemotherapeutics and plotted a heatmap Red: high probability of sensitivity of response Blue: low probability of resistance

20. Result (linking chemotherapy sensitivity to oncogenic pathway status) Someone who initially responds to a given agent is likely to eventually suffer a relapse; therefore the development of gene expression signatures that reflect the activation of several oncogenic pathways are needed Step1: stratifying the NCI cell lines based on predicted docetaxel response Step2: examining the patterns of pathway deregulation associated with docetaxel sensitivity or resistance

21. Result (linking chemotherapy sensitivity to oncogenic pathway status) Significant relationship between phosphatidylinositol 3-OH (PI3)-kinase pathway deregulation and docetaxel resistance. - Giving an opportunity to use a PI3-kinase inhibitor in this group Red: high probability of sensitivity of response or activation Blue: low probability of resistance or deregulation 17 lung cancer cell lines

22. Conclusion  The signature of chemosensitivity generated from the NCI-60 panel have the capacity to predict therapeutic response in individuals receiving either single agent or combination chemotherapy

23. References  Staunton, et. Al. “Chemosensitivity prediction by transcriptional profiling”, PNAS, 98-19, 10787- 10792, 2001  Potti, A. “Genomic signatures to guide the use of chemotherapeutics”, Nature Medicine, 12-11, 2006