Robustness and reproducibility of simple and complex synthetic logic circuit designs using a DBTL loop.

Computational tools addressing various components of design-build-test-learn (DBTL) loops for the construction of synthetic genetic networks exist but do not generally cover the entire DBTL loop. This manuscript introduces an end-to-end sequence of tools that together form a DBTL loop called Design Assemble Round Trip (DART). DART provides rational selection and refinement of genetic parts to construct and test a circuit.

A toolkit for enhanced reproducibility of RNASeq analysis for synthetic biologists.

Sequencing technologies, in particular RNASeq, have become critical tools in the design, build, test and learn cycle of synthetic biology. They provide a better understanding of synthetic designs, and they help identify ways to improve and select designs. While these data are beneficial to design, their collection and analysis is a complex, multistep process that has implications on both discovery and reproducibility of experiments.

Prediction of whole-cell transcriptional response with machine learning.

Motivation: Applications in synthetic and systems biology can benefit from measuring whole-cell response to biochemical perturbations. Execution of experiments to cover all possible combinations of perturbations is infeasible. In this paper, we present the host response model (HRM), a machine learning approach that maps response of single perturbations to transcriptional response of the combination of perturbations.

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program.

Purpose: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC.

Copy Number Loss of 17q22 Is Associated with Enzalutamide Resistance and Poor Prognosis in Metastatic Castration-Resistant Prostate Cancer.

Purpose: The purpose of this study was to measure genomic changes that emerge with enzalutamide treatment using analyses of whole-genome sequencing and RNA sequencing.

Experimental Design: One hundred and one tumors from men with metastatic castration-resistant prostate cancer (mCRPC) who had not been treated with enzalutamide ( = 64) or who had enzalutamide-resistant mCRPC ( = 37) underwent whole genome sequencing. Ninety-nine of these tumors also underwent RNA sequencing.

Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance.

Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4.

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program.

BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer.

BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown.

Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer.

The BET bromodomain protein BRD4 is a chromatin reader that regulates transcription, including in cancer. In prostate cancer, specifically, the anti-tumor activity of BET bromodomain inhibition has been principally linked to suppression of androgen receptor (AR) function. MYC is a well-described BRD4 target gene in multiple cancer types, and prior work demonstrates that MYC plays an important role in promoting prostate cancer cell survival.

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer.

Integrative molecular network analysis identifies emergent enzalutamide resistance mechanisms in prostate cancer.

Recent work demonstrates that castration-resistant prostate cancer (CRPC) tumors harbor countless genomic aberrations that control many hallmarks of cancer. While some specific mutations in CRPC may be actionable, many others are not. We hypothesized that genomic aberrations in cancer may operate in concert to promote drug resistance and tumor progression, and that organization of these genomic aberrations into therapeutically targetable pathways may improve our ability to treat CRPC.

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor.

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) - the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR.