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Genomic signatures to guide the use of chemotherapeutics. Authors: Anil Potti et. al Presenter: Jong Cheol Jeong. Motivation. What will be happened if ineffective chemotherapy is used?. Increasing the probability of side effects. Decreasing the quality of life. Purpose.

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genomic signatures to guide the use of chemotherapeutics

Genomic signatures to guide the use of chemotherapeutics

Authors: Anil Potti et. al

Presenter: Jong Cheol Jeong

motivation
Motivation
  • What will be happened if ineffective chemotherapy is used?

Increasing the probability of side effects

Decreasing the quality of life

purpose
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.
outline
Outline
  • Method
  • Results
  • Conclusion
method
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

method6
Method
  • Using the cell line in the NCI-60 Panel- 60 cancer cell line: sensitivity of 5084 compounds
  • Identifying cell line: most resistant or sensitive to docetaxel
  • Identifying genes: their expression correlated most highly with drug sensitivity
  • Bayesian binary regression analysis with LOOCV
results

The concentration of compound requiring 50% growth inhibition

or

The concentration of compound requiring 50% cytotoxic

Results

Cell lines from NCI-60

Blue: lowest expression

Red : highest expression

results8
Results

Validation of docetaxel response prediction model

30 lung and ovarian cancer cell lines

29 lung cancer cell lines

Significant correlation between predicted probability of docetaxel sensitive and IC50

results9
Results

Applying

a Mann-Whitney

U-test

showing the capacity of the predictor

result predicting response of combinations of drugs
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

result predicting response of combinations of drugs16
Result (predicting response of combinations of drugs)

Statistically significant distinction between the responders and nonresponders

result predicting response of combinations of drugs17
Result (predicting response of combinations of drugs)

Breast cancer with 45 cell lines

38 responders

11 nonresponders

result predicting response of combinations of drugs18
Result (predicting response of combinations of drugs)

Kaplan-Meier survival analysis

FAC adjuvant chemotherapy

Blue: sensitive

Red: resistant

PPV: Positive Predicted Value

NPV: Negative Predicted Value

result patterns of predicted chemotherapy response
Result (patterns of predicted chemotherapy response)

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

Respond to 5-FU are resistant to Adriamycin and Docetaxel:suggesting possibility of alternate treatments

Red: high probability of sensitivity of response

Blue: low probability of resistance

result linking chemotherapy sensitivity to oncogenic pathway status
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

result linking chemotherapy sensitivity to oncogenic pathway status21
Result (linking chemotherapy sensitivity to oncogenic pathway status)

17 lung cancer cell lines

Red: high probability of sensitivity of response or activation

Blue: low probability of resistance or deregulation

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

conclusion
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
references
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