ClinicalOmicsDB: exploring molecular associations of oncology drug responses in clinical trials.

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established ontology for easier navigation. The web application provides users with three options to explore molecular associations of oncology drug responses, focusing on studies, treatments or genes, respectively. Gene set analysis further connects treatment response to pathway activity and tumor microenvironment attributes. The user-friendly web interface of ClinicalOmicsDB streamlines interactive analysis. A Rust-based backend speeds up response time, and application programming interfaces and an R package enable programmatic access. We use three case studies to demonstrate the utility of this resource in human cancer studies. ClinicalOmicsDB is freely available at http://trials.linkedomics.org/.

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1-/- tumor cells, using immortalized non-tumor NF1+/- cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

Chromosome 8 gain is associated with high-grade transformation in MPNST.

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.

Unmasking Intra-tumoral Heterogeneity and Clonal Evolution in NF1-MPNST.

Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%-13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1.

Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.

SDG8-Mediated Histone Methylation and RNA Processing Function in the Response to Nitrate Signaling.

Chromatin modification has gained increased attention for its role in the regulation of plant responses to environmental changes, but the specific mechanisms and molecular players remain elusive. Here, we show that the Arabidopsis (Arabidopsis thaliana) histone methyltransferase SET DOMAIN GROUP8 (SDG8) mediates genome-wide changes in H3K36 methylation at specific genomic loci functionally relevant to nitrate treatments. Moreover, we show that the specific H3K36 methyltransferase encoded by SDG8 is required for canonical RNA processing, and that RNA isoform switching is more prominent in the sdg8-5 deletion mutant than in the wild type. To demonstrate that SDG8-mediated regulation of RNA isoform expression is functionally relevant, we examined a putative regulatory gene, CONSTANS, CO-like, and TOC1 101 (CCT101), whose nitrogen-responsive isoform-specific RNA expression is mediated by SDG8. We show by functional expression in shoot cells that the different RNA isoforms of CCT101 encode distinct regulatory proteins with different effects on genome-wide transcription. We conclude that SDG8 is involved in plant responses to environmental nitrogen supply, affecting multiple gene regulatory processes including genome-wide histone modification, transcriptional regulation, and RNA processing, and thereby mediating developmental and metabolic processes related to nitrogen use.