Genomic signatures to guide the use of chemotherapeutics Authors: Anil Potti et. al Presenter: Jong...
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Genomic signatures to guide the use of chemotherapeutics
Authors: Anil Potti et. al
Presenter: Jong Cheol Jeong
![Page 2: Genomic signatures to guide the use of chemotherapeutics Authors: Anil Potti et. al Presenter: Jong Cheol Jeong.](https://reader036.fdocuments.net/reader036/viewer/2022062308/56649d6b5503460f94a4b173/html5/thumbnails/2.jpg)
Motivation
What will be happened if ineffective chemotherapy is used?
Increasing the probability of side effects
Decreasing the quality of life
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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.
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Outline
Method
Results
Conclusion
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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
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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
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Results
50GI 50ICor The concentration of compound requiring 50% growth inhibition
50LC The concentration of compound requiring 50% cytotoxic
Cell lines from NCI-60
Red : highest expressionBlue: lowest expression
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Results
Validation of docetaxel response prediction model
30 lung and ovarian cancer cell lines
Significant correlation between predicted probability of docetaxel sensitive and IC50
29 lung cancer cell lines
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Results
showing the capacity of the
predictor
Applying a Mann-Whitney
U-test
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Results
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Results(developing series of expression profile from NCI-60)
![Page 12: Genomic signatures to guide the use of chemotherapeutics Authors: Anil Potti et. al Presenter: Jong Cheol Jeong.](https://reader036.fdocuments.net/reader036/viewer/2022062308/56649d6b5503460f94a4b173/html5/thumbnails/12.jpg)
Results(developing series of expression profile from NCI-60)
![Page 13: Genomic signatures to guide the use of chemotherapeutics Authors: Anil Potti et. al Presenter: Jong Cheol Jeong.](https://reader036.fdocuments.net/reader036/viewer/2022062308/56649d6b5503460f94a4b173/html5/thumbnails/13.jpg)
Results(developing series of expression profile from NCI-60)
![Page 14: Genomic signatures to guide the use of chemotherapeutics Authors: Anil Potti et. al Presenter: Jong Cheol Jeong.](https://reader036.fdocuments.net/reader036/viewer/2022062308/56649d6b5503460f94a4b173/html5/thumbnails/14.jpg)
Results(developing series of expression profile from NCI-60)
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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
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Result (predicting response of combinations of drugs)
Statistically significant distinction between the responders and nonresponders
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Result (predicting response of combinations of drugs)
Breast cancer with 45 cell lines
38 responders11 nonresponders
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Result (predicting response of combinations of drugs)
PPV: Positive Predicted ValueNPV: Negative Predicted Value
Blue: sensitiveRed: resistant
FAC adjuvant chemotherapy
Kaplan-Meier survival analysis
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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 samplesEx) 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 responseBlue: low probability of resistance
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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
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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 activationBlue: low probability of resistance or deregulation
17 lung cancer cell lines
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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
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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