Federico Manuel Giorgi

MSc Thesis Project in Bioinformatics

Tumor progression from a tractable form (e.g., pre-neoplastic lesions or in situ carcinoma) to an intractable, drug-resistant form represents perhaps the most formidable challenge both in terms of basic elucidation of tumor biology mechanisms and in terms of its translational and clinical implications.

A first issue is that not all tumors will spontaneously progress to a metastatic drug-resistant stage. Yet, our ability to identify the patients at greater risk of progression is still extremely limited {Irshad, 2013 #1}. This failure is reflected in significant overtreatment of breast, lung, and prostate cancers, among others {Esserman, 2014 #8}. For tumors destined to progress, however, the challenge is further decomposed into distinct, yet highly complementary perspectives. Macroscopically, progression occurs because either pharmacologically actionable mechanisms do not yet exist for a specific malignancy or because drug resistance ensues, due to genetic and epigenetic mechanisms. For instance, while 70% of HER2+ breast adenocarcinomas initially respond to trastuzumab, 70% of these will eventually relapse to trastuzumab-resistant tumors {Davoli, 2010 #3}. The same dismal outcome is reflected across most targeted therapeutics, from erlotinib in lung adenocarcinoma with activating EGFR alterations {Lin, 2014 #4}, to vemurafenib in BRAFV600E melanomas {Jang, 2013 #5}, to tamoxifen and enzalutamide in high-grade hormone dependent breast {Shien, 2014 #6} and prostate {Patel, 2014 #7} cancer, respectively. Microscopically, however, emergence of drug resistance is rooted in the exceedingly heterogeneous nature of cancer, both across individuals (inter-tumor) and individual tumor cells (intra-tumor).

In order to understand cancer heterogeneity one must first analyze and understand the different forms cancer can take in different patients. Pioneer studies based on the vast collection of tumors (pan-cancer) collected by The Cancer Genome Atlas (TCGA) {Weinstein, 2013 #9} have elucidated a higher than expected molecular heterogeneity within histologically identical tumors, while, on the other hand, previously undetected similarities were found between tumor subtypes arising from different tissues {Ciriello, 2013 #10}. Heterogeneity is present even within a single tumor, which can be composed by a different population of cells {Shalek, 2013 #41}, originating from a single clone {Aparicio, 2013 #11} or from individual different progenitors that co-evolve in a complex microenvironment {Feig, 2012 #12}.

Published on: July 28 2018