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Cancer Bioinformatics for Biomarker Discovery

  • Author(s): Webber, James Trubek
  • Advisor(s): Bandyopadhyay, Sourav
  • Krogan, Nevan J
  • et al.
Abstract

Cancer is a complex and multifaceted disease, and a vast amount of time and effort has been spent on characterizing its behaviors, identifying its weaknesses, and discovering effective treatments. Two major obstacles stand in the way of progress toward effective precision treatment for the majority of patients.

First, cancer's extraordinary heterogeneity—both between and even within patients—means that most patients present with a disease slightly different from every previously recorded case. New methods are necessary to analyze the growing body of patient data so that we can classify each new patient with as much accuracy and precision as possible. In chapter 2 I present a method that integrates data from multiple genomics platforms to identify axes of variation across breast cancer patients, and to connect these gene modules to potential therapeutic options. In this work we find modules describing variation in the tumor microenvironment and activation of different cellular processes. We also illustrate the challenges and pitfalls of translating between model systems and patients, as many gene modules are poorly conserved when moving between datasets.

A second problem is that cancer cells are constantly evolving, and many treatments inevitably lead to resistance as new mutations arise or compensatory systems are activated. To overcome this we must find rational combinations that will prevent resistant adaptation before it can start. Starting in chapter 3 I present a series of projects in which we used a high-throughput proteomics approach to characterize the activity of a large proportion of protein kinases, ending with the discovery of a promising drug combination for the treatment of breast cancer in chapter 8.

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