Democratizing clinical-genomic data: How federated platforms can promote benefits sharing in genomics.

Since the first sequencing of the human genome, associated sequencing costs have dramatically lowered, leading to an explosion of genomic data. This valuable data should in theory be of huge benefit to the global community, although unfortunately the benefits of these advances have not been widely distributed. Much of today's clinical-genomic data is siloed and inaccessible in adherence with strict governance and privacy policies, with more than 97% of hospital data going unused, according to one reference. Despite these challenges, there are promising efforts to make clinical-genomic data accessible and useful without compromising security. Specifically, federated data platforms are emerging as key resources to facilitate secure data sharing without having to physically move the data from outside of its organizational or jurisdictional boundaries. In this perspective, we summarize the overarching progress in establishing federated data platforms, and highlight critical considerations on how they should be managed to ensure patient and public trust. These platforms are enabling global collaboration and improving representation of underrepresented groups, since sequencing efforts have not prioritized diverse population representation until recently. Federated data platforms, when combined with advances in no-code technology, can be accessible to the diverse end-users that make up the genomics workforce, and we discuss potential strategies to develop sustainable business models so that the platforms can continue to enable research long term. Although these platforms must be carefully managed to ensure appropriate and ethical use, they are democratizing access and insights to clinical-genomic data that will progress research and enable impactful therapeutic findings.

Computational Drug Repositioning Identifies Potentially Active Therapies for Chordoma.

BACKGROUND: Chordomas are aggressive bone tumors that often recur despite maximal resection and adjuvant radiation. To date there are no Food and Drug Administration (FDA)-approved chemotherapies. Computational drug repositioning is an expanding approach to identify pharmacotherapies for clinical trials. OBJECTIVE: To identify FDA-approved compounds for repurposing in chordoma. METHODS: Previously identified highly differentially expressed genes from chordoma tissue samples at our institution were compared with pharmacogenomic interactions in the Comparative Toxicogenomics Database (CTD) using ksRepo, a drug-repositioning platform. Compounds selected by ksRepo were then validated in CH22 and UM-Chor1 human chordoma cells in Vitro. RESULTS: A total of 13 chemical compounds were identified in silico from the CTD, and 6 were selected for preclinical validation in human chordoma cell lines based on their clinical relevance. Of these, 3 identified drugs are FDA-approved chemotherapies for other malignancies (cisplatin, cytarabine, and lucanthone). Cytarabine, a deoxyribonucleic acid polymerase inhibitor approved for the treatment of various leukemias, exhibited a significant concentration-dependent effect against CH22 and UM-Chor1 cells when compared to positive (THZ1) and negative (venetoclax) controls. Tretinoin exhibited a significant concentration-dependent cytotoxic effect in CH22, sacral chordoma-derived cell lines but to a much lesser extent in UM-Chor1, a cell line derived from skull base chordoma. CONCLUSION: Cytarabine administration reduces the viability of human chordoma cells. The equally effective reduction in viability seen with tretinoin seems to be cell line dependent. Based on our findings, we recommend the evaluation of cytarabine and tretinoin in an expanded set of human chordoma cell lines and animal models.

Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity.

Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition, leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape and autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition, which globally downregulates transcription, leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.

IRF2 is a master regulator of human keratinocyte stem cell fate.

Resident adult epithelial stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. The stem cell potential of human epidermal keratinocytes is retained in vitro but lost over time suggesting extrinsic and intrinsic regulation. Transcription factor-controlled regulatory circuitries govern cell identity, are sufficient to induce pluripotency and transdifferentiate cells. We investigate whether transcriptional circuitry also governs phenotypic changes within a given cell type by comparing human primary keratinocytes with intrinsically high versus low stem cell potential. Using integrated chromatin and transcriptional profiling, we implicate IRF2 as antagonistic to stemness and show that it binds and regulates active cis-regulatory elements at interferon response and antigen presentation genes. CRISPR-KD of IRF2 in keratinocytes with low stem cell potential increases self-renewal, migration and epidermis formation. These data demonstrate that transcription factor regulatory circuitries, in addition to maintaining cell identity, control plasticity within cell types and offer potential for therapeutic modulation of cell function.

Small-molecule targeting of brachyury transcription factor addiction in chordoma.

Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.