Colin Collins

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). It can develop de novo from prostate neuroendocrine cells, yet primarily is a treatment-induced phenotype arising from transdifferentiated prostate adenocarcinoma (AD) cells (NEtD). Currently there is an unmet clinical need for predictive biomarkers, therapeutic targets, and more reliable diagnostics. In this dissertation we use the first-in-field patient-derived xenograft model of NEtD, six in vitro CRPC/NEPC models, and ~30,000 PCa patient samples, including 344 NEPC or molecular analogous NEPC samples. We implement a state-of-the-art next-generation sequence analysis pipeline, capable of detecting transcripts at low expression levels to build a comprehensive lncRNA catalog (~N=40,000). Our xenograft model enabled identification of transcriptional changes during NEtD. Our in vitro models were used for functionalization and our patient samples were used to determine clinical relevancy and/or to test for patient survival. In Chapter I, we review lncRNA research in PCa over the last 30 years. We include known genomic structures, mechanisms of actions, roles in PCa progression, and their use in disease management. In Chapter II, we identify a 122-lncRNA signature capable of robustly classifying NEPC from AD, 25 with predictive ability to classify metastatic patients, and 2 (SSTR5-AS1 and LINC00514) capable of stratifying patients more probable to develop metastasis following androgen deprivation therapy (ADT). In Chapter III, we identify two NEPC molecular subtypes driven by lncRNAs FENDRR and GAS5. They also have a predictive ability to stratify ADT patients by clinical outcome. In Chapter IV, we investigate our top candidate NEPC lncRNA H19. We identify the active isoform, determine it is conserved, a dozen associated PCa risk single nucleotide polymorphisms (SNPs) nearby, and NEPC-related TFBS (MYC/MAX) embedded within. H19 was highly sensitive and relatively specific for NEPC. Functionally, we identified associations to invasion, proliferation, the NEPC phenotype, and physical interactions with EZH2. Most importantly H19 is predictive for ADT-patient outcome. Collectively, this thesis constitutes a step forward in understanding the complexity of the transcriptome for NEPC and the NEtD process. The results here will advance our knowledge of clinically relevant lncRNAs involved in cancer progression and treatment resistance.

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Advances in high-throughput sequencing technologies has drastically increased the efficiency to access different alterations in the genome, transcriptome, proteome, and epigenome of a cancer cell. This has increased the computational burden to analyze these “big data” making the translation of the knowledge into insightful and impactful patient outcomes extraordinarily challenging.Among these alterations, only a few “driver” alterations are expected to confer crucial growth advantage. These are greatly outnumbered by functionally inconsequential “passenger” alterations. This poses a significant challenge for the identification of driver alterations, requiring solutions to novel algorithmic problems. Although, the insight on driver alterations is critical to guide selection of appropriate drug therapies for the patient, no specific tools exist to help clinicians contextualize the enormous genomic information when making therapeutic decisions. In this thesis we describe novel algorithms for the identification and prioritization of cancer driver genes. First we describe, HIT’nDRIVE, a combinatorial algorithm measuring the impact of genomic aberration to global changes of gene expression pattern to prioritize cancer driver genes. We also demonstrate its application on large multi-omics cancer datasets to guide precision oncology. We further describe integrative multi-omics characterization of peritoneal mesothelioma, a rare cancer of abdomen. Here using HIT’nDRIVE, we identified peritoneal mesothelioma with BAP1 loss to form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. Finally, we describe, cd-CAP, a combinatorial algorithm to identify subnetworks with conserved molecular alteration pattern across a large subset of a tumor sample cohort. Notably, we demonstrate that many of the largest highly conserved subnetworks within a tumor type solely consist of genes that have been subject to copy number gain, typically located on the same chromosomal arm and thus likely a result of a single, large scale copy number amplification.

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