8215 results for "canc*"

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• Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

  Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor in adolescent and young adult patients. Currently, there is no standard-of-care treatment for these patients. Reliable models that represent this disease and can be used for translational research are scarce. To model SCCOHTs, we have established eight patient-derived tumoroid lines from tumor lesions of three patients with SCCOHT. The tumoroids recapitulate genomic and transcriptomic characteristics of the corresponding patient tumors and capture intrapatient tumor heterogeneity. Organoid drug profiling using a library of 153 clinical compounds identified methotrexate as an effective and selective drug against SCCOHTs with a clinically relevant IC50 of 35 nmol/L. RNA sequencing demonstrated that methotrexate induced TP53 pathway activation and apoptosis. These data underscore that organoid technology can support the design of therapeutic strategies for rare cancers.

  Study EGAS00001007911

• Drug screening reveals new insight for chemoresistant hepatoblastoma

  Hepatoblastoma (HB) is the most prevalent form of pediatric liver cancer. Although the standard treatment, primarily based on cisplatin, is effective in 80% of patients, it falls short in high-risk cases due to the development of chemoresistance. To identify new therapies overcoming this resistance, we screened 101 individual therapeutic compounds and 58 combinations, across 8 pediatric liver cancer cell lines. We identified ATR as a critical target to reverse cisplatin resistance. The ATR inhibitor elimusertib demonstrated the greatest synergy with cisplatin in 2D and 3D cultures and in subcutaneous xenograft models of cisplatin-resistant HB. This combination was found to enhance DNA damage and induces apoptosis through strong p53 activation. In conclusion, our study underscores the crucial role of ATR in cisplatin resistance and highlights the promising anti-proliferative effects of the Elimusertib/Cisplatin combination in cisplatin-resistant HB models, offering a potential new therapeutic option for treating high-risk and refractory HB.

  Study EGAS00001007916

• Stratton__WGS___Identification_of_Early_Life_Exposures_in_Paediatric_Colonic_Crypts_of_Healthy_Individuals

  The Stratton team uses DNA sequencing for somatic mutations to advance understanding of the causes of cancer. In particular, the investigation of “mutational signatures”, which report the mutational processes operative over the lifetime of each individual, to understand whether they are generated by endogenous or exogenous exposures and the extent to which these vary between human populations. Our work brings together global cancer epidemiology and genomics and is particularly characterised by large-scale multinational studies. Whole genome sequencing of colon crypts from healthy paediatric individuals for identification of early life exposure to carcinogens.

  Study EGAS00001007921

• Multi-Layered Molecular Profiling Informs the Diagnosis and Targeted Therapy of Desmoplastic Small Round Cell Tumor

  Desmoplastic small round cell tumor (DSRCT) is an ultra-rare soft tissue sarcoma with dismal prognosis and limited therapeutic options. Here, we identified individual therapeutic targets in a cohort of 30 DSRCT patients by use of multilayered molecular profiling (genomic, transcriptomic, and (phospho-)proteomic analyses) within the DKFZ NCT DKTK MASTER program. 28 of the 30 patients received at least one personalized treatment recommendation. In line with the observation that DSRCTs are an entity with a low mutational load, most of the treatment recommendations were based on target gene or -protein expression. 13 patients received a recommended therapy, resulting in four partial responses, four stable diseases, and five progressive diseases. Eight of 13 patients received the multi tyrosine kinase inhibitor pazopanib, with mixed response. Based on high ERBB2 expression levels, two patients received the antibody drug conjugate trastuzumab deruxtecan (T-DXd), showed exceptional, long-lasting responses and are currently (8/2024) still on treatment and progression-free. We detected high ERBB2 protein expression in all DSRCT samples with proteome data (n = 9), which suggests that ERBB2 may be a particularly useful therapeutic target for DSRCT patients. For one of the two exceptional responders we did not detect a substantial ERBB2/HER2 overexpression, which may indicate that T-DXd could also be efficacious in DSRCT patients with low levels of HER2, as also described for breast cancer patients. In conclusion, multi-omic molecular profiling revealed personalized therapeutic targets in patients with DSRCT with HER2 targeting, with T-DXd as a promising therapeutic option for this ultra-rare and difficult-to-treat tumor entity.

  Study EGAS00001007934

• Ewing and Ewing-like-sarcoma tumoroid biobank reveals distinct drug sensitivities: translocation makes the difference

  Ewing sarcoma (ES) and Ewing-like sarcomas (ELS) are highly aggressive tumors found in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Currently, there is a lack of preclinical cell models that can predict drug response of these entities in vitro. Here, we describe a pediatric ES and ELS tumor organoid (tumoroid) biobank containing tumoroids with different translocations, including EWSR1::FLI1, EWSR1::ERG, CIC::DUX4, and BCOR-rearrangements. Using histology, whole genome sequencing and RNA sequencing, we demonstrate that these tumoroids retain key properties of their matching patient tumors. In addition, we traced tumor subclones in the tumoroids across patient-matched longitudinal samples, which showed that cellular heterogeneity was maintained. We subsequently performed drug screening on the tumoroid models, which unveiled entity-specific drug sensitivity to various cytotoxic compounds and targeted compounds, including MCL-1 inhibitors for CIC::DUX4 sarcomas. Taken together, this newly established ES and ELS patient-derived tumoroid biobank generates a unique source of material for future basic cancer research and drug-screening.

  Study EGAS00001007941

• Integrated genomic analysis for HCC

  Liver cancer is a common malignancy and is the third cause of cancer-related death in the world and hepatocellular carcinoma (HCC) is the major type of liver cancer, accounting for ~90% of cases. Only 20 ~ 30% of patients can benefit from combined immunotherapy and targeted therapy due to the high inter-tumor heterogeneity of HCC. This work aims to identify homogeneous and robust molecular subtypes in HCC based on a large, homogenous and well-annotated cohort. We performed whole genome/exome sequencing (WGS/WES) and/or RNA sequencing (RNA-seq) on 529 HCC from 461 patients collected mainly in France. Based on the great consistence between genomic and transcriptomic data, we identified 9 robust HCC subtypes mainly based on driver mutations. And we further characterized HCC subtypes using genomic, transcriptomic and clinicopathological features. Among 9 subtypes, 5 subtypes belonged to chromosome instable tumors, while 3 subtypes belonged to chromosome stable tumors. In addition, our subtypes were associated with prognosis and we also found different distributions of subtypes across various features, such as etiology and gender. Our study provided a robust molecular classification based on a large HCC dataset from Western country, it improves our understanding of the mechanisms of carcinogenesis and will facilitate development of genome-based precision medicine in HCC.

  Study EGAS00001007957

• MethylationEPIC BeadChip samples of pre- and post-5ZA-treated head and neck cancer patients refractory to anto-PD-1 therapy

  Background Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, most patients are refractory. Methods In a non-randomized, open-label phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5’azacytidine (5’aza) daily for either 5- or 10-days in combination with fixed doses of durvalumab and tremelimumab after progression on ICB therapy. The primary objective was to assess the biologically effective dose of 5’aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety. Results Thirty-eight percent (3/8) of participants with evaluable paired tissue samples had a greater than 2-fold increase from baseline in interferon-gamma (IFN-ɣ) signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA) and 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%) with 58% (7/12) of treated participants demonstrated prolonged OS of greater than 12 months. Conclusion Our findings suggest that low-dose 5’aza can reprogram systemic host immune responses and the local TME to increase IFN-ɣ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon re-challenge with ICB.

  Study EGAS00001007998

• Stratton__WGS___RCC___Japan

  The Stratton team uses DNA sequencing for somatic mutations to advance understanding of the causes of cancer. In particular, the investigation of “mutational signatures”, which report the mutational processes operative over the lifetime of each individual, to understand whether they are generated by endogenous or exogenous exposures and the extent to which these vary between human populations. Our work brings together global cancer epidemiology and genomics and is particularly characterised by large-scale multinational studies.

  Study EGAS00001008001

• Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)

  Purpose: Pediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Experimental Design: Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Results: In the preclinical match study, we identified one specific single agent response to LY3023414 in an osteosarcoma model with a TSC2 variant of unknown significance. Combinations of nano-liposomal irinotecan were effective in treating both Ewing sarcoma and rhabdomyosarcoma xenografts. Conclusion: Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations.

  Study EGAS00001008011

• Single_cell_RNA_sequencing_of_rhabdomyosarcoma_tumour_tissue

  The aim of this study is to investigate the genomic landscape of human cancer.

  Study EGAS00001008275

• Limited Association between HRR Gene Alterations and HRD in Molecular Tumor Board Cancer Samples: Who should be tested for HRD?

  Alterations in Homologous Recombination Repair (HRR) Pathway genes have been found to be associated with HR-Deficiency (HRD), which is an approved biomarker for PARP Inhibitor (PARPi) treatment. The aim of a Molecular Tumor Board (MTB) is to identify molecular alterations in cancer patients with advanced tumors that may suggest off-label treatment options. So far, few studies have analyzed the presence of HRR gene mutations and their association with HRD outside of clinical studies. Currently, no data on HRD testing in the setting of a MTB have been published. For the present study, a cohort of 237 patients encompassing 24 different tumor entities was collected from the MTB of the Comprehensive Cancer Center Erlangen-EMN. We show that an elevated Genomic Instability Score (GIS ≥ 42) can occur in samples with and without mutations in HRR-related genes. Overall, 38.1% of cancer samples with BRCA1/2 mutations, 10.9% of tumors with alterations in HRR genes other than BRCA1/2, and 4.3% of cancer samples without HRR gene mutations harbored an elevated GIS. Notably, our data show that various inactivating BRCA1/2 mutations are not associated with an elevated GIS. Taken together, panCancer assessment of HRD in addition to BRCA1/2 and other HRR gene mutational analysis is recommended to guide decisions regarding PARPi treatment. Further studies are needed to establish thresholds for GIS in non-ovarian cancer entities. Finally, HRD can be observed in 4.3% of BRCA1/2 and other HRR gene wildtype cancer samples, and may emerge as an independent biomarker for PARPi in the future.

  Study EGAS00001008063

• A standardised framework for robust fragmentomic feature extraction from cell-free DNA sequencing data

  Fragmentomic features of cell-free DNA represent promising non-invasive biomarkers for cancer diagnosis. However, a lack of systematic evaluation of biases in feature quantification has hindered the adoption of such applications. We compared features derived from whole-genome sequencing of ten healthy donors using nine library kits and ten data-processing routes, and validated them in 1,182 plasma samples from published studies. Our results clarify the variations resulting from library preparation and feature quantification methods. We designed the Trim Align Pipeline and the cfDNAPro R package as unified interfaces for data pre-processing, feature extraction, and visualisation, aiming to standardise multimodal feature engineering and integration for machine learning.

  Study EGAS00001008051

• Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma

  Homologous recombination DNA repair deficient (HRD) tumors account for about 50% of tubo-ovarian high-grade serous carcinomas (HGSC) and are associated with a high response to platinum-based chemotherapy. However, a subset of patients with HRD tumors have unexpected resistance to chemotherapy and experience short survival. Our study compared BRCA-deficient and proficient HGSC among patients with short (<3 years, the lowest quartile of overall survival (OS)) versus longer-term (>3 year OS) to identify prognostic markers and potential therapeutic opportunities. Primary tumors from a cohort of patients with advanced-stage HGSC (n=154) enriched for those with HRD tumors and short survival (n=42) were analyzed using whole-genome sequencing, bulk RNA-sequencing, and DNA methylation profiling. A subset of HRD tumors (n=143) were characterized for immune cell densities by multiplex immunofluorescence. Clinicopathological features were assessed in 1,389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApv). Findings were validated in two international HGSC cohorts: the Ovarian Tumor Tissue Analysis consortium (n=5,875) and Multisciplinary Ovarian Cancer Outcome Group (n=895). In gBRCApv-carriers, residual disease following surgical cytoreduction was not associated with shorter OS unlike in non-carriers where it was strongly associated. While most patients with gBRCApv had a more favorable OS compared to non-carriers, a survival advantage was not apparent in those with variants located outside of BRCA1 exon 10/23 and BRCA2 exon 11/27. Patient survival correlated with HRD score, such that those with a score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42. While higher HRD scores were associated with better survival outcomes, most gBRCApv carriers with a short survival had tumor HRD scores that exceeded the threshold typically considered predictive of a good response to carboplatin or PARP inhibitors. BRCA2-deficient HGSC with loss of the tumor suppressor NF1 was associated with exceptionally favorable outcome (median OS 17 years), whereas amplification of both PIK3CA and RAD21, was associated with poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). The density of tumor-infiltrating CD8+ PD-1+ T cells was prognostic for OS in gBRCApv-carriers. In summary, rather than simply the presence or absence of a germline BRCA pathological variant influencing patient survival, the co-occurrence of specific somatic gene alterations, the extent of immune cell infiltration, the level of homologous recombination deficiency, and BRCA-variant location may modify clinical outcomes in patients with BRCA-deficient HGSC. Analysis of exceptional outcome patients, in this case gBRCApv-carriers with an atypically short survival, may identify determinants of outcome applicable to the wider HGSC patient population.

  Study EGAS00001008059

• Sequencing of patient tissue and patient derived organoids in colon cancer

  Multiome (ATAC + RNA) sequencing of cancerous primary tissue and cancer organoids derived from the same patient. Nanopore and whole exome sequencing of selected samples.

  Study EGAS00001008067

• Detection of cancers three years prior to diagnosis using plasma cell-free DNA

  A major goal of early cancer detection is to identify subclinical disease when the tumor burden is low, so that treatments are more effective. But how early can cancers be detected prior to clinical signs or symptoms? This question can be answered only through the evaluation of participants whose clinical course has not been altered by the study itself. We here describe such an evaluation, performed on prospectively collected plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) blood test. All eight of these participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six participants, the same mutations detected by the MCED test could be identified, but at 8.6 to 79-fold lower levels. These results demonstrate that it is possible to detect circulating tumor DNA (ctDNA) more than three years prior to clinical diagnosis, and provide benchmark sensitivities required for the success of ctDNA-based tests for this purpose.

  Study EGAS00001008068

• RRBS data from TRACERx non-small cell lung cancer (NSCLC) tumours and matched normal adjacent tissue.

  TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC).

  Study EGAS00001008071

• Atypical tetrasomy 18 in a hepatoblastoma patient

  Constitutive aneuploidy often underlies developmental defects, while copy-number alterations are recurrent somatic events in cancers. Rarely, mosaic aneuploidy links developmental defects and cancer development, yet its molecular basis remains elusive. We report the first cancer case in a tetrasomy 18 patient—a female who developed hepatoblastoma at age two and remains recurrence-free 24 months post-surgery and chemotherapy. Whole-genome sequencing and Fluorescent in situ hybridization (FISH) uncovered a complex rearrangement with eight breakpoints between 18p11.32 to 18q12.1, present in 10% of liver and blood cells. Haplotype analysis revealed a pre-zygotic origin, with mosaicism arising from early rescue by loss of the rearranged chromosome. Strikingly, all tumor cells retained this rearranged chromosome. Single-nucleus RNA-seq of liver and hepatoblastoma tissue traced the aneuploidy’s evolution during gametogenesis, organogenesis, and tumorigenesis. This study provides insights into mechanisms of aneuploidy-driven cancer, highlighting the interplay of mosaicism, developmental defects, and tumor evolution in a rare genetic syndrome.

  Study EGAS00001008072

• Whole exome and RNA sequencing of organoid samples derived from TRACERx patients

  Immune checkpoint blockade in non-small cell lung cancer (NSCLC) rarely leads to complete tumour remission, suggesting that tumours harbour subpopulations of cancer cells that can escape immune predation. However, while tumours consist of multiple genetically distinct clones, the extent to which separate tumour subclones differ intrinsically in their functional capacity for immune evasion remains largely unexplored. This has been challenging to address due to an inability to isolate and propagate individual tumour subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived platform that allows the functional analysis of immune escape at single clone resolution. We generated libraries of >20 separate NSCLC organoid lines per patient by isolating individual (clonal) organoids established from multiple spatially separated tumour regions. Each organoid subline was co-cultured with autologous tumour infiltrating lymphocytes (TIL) to evaluate their capacity to elicit a T cell response. Organoid lines derived from separate tumour regions, or from single clones within individual regions, differ vastly in their capacity to elicit a T cell response, showing the coexistence of intrinsically immune evading (‘hot’) and non-evading (‘cold’) clones in the same primary tumour. Organoid lines escaping T cell recognition represent genetically and transcriptionally unique subclones with a distinct evolutionary history, showing that evolutionary sculpting of subclonal diversity can have functional consequences for anti-tumour immunity. Notably, the identification of immune-evasive subclones would not have been possible using computational approaches alone, highlighting the unique value of functional co-culture platforms. This patient-derived functional co-culture platform reveals that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and provides an approach to prospectively identify, isolate and characterise immune evading subclones from patients with cancer.

  Study EGAS00001008092

• This study generated Oxford Nanopore long read sequencing data of cancer cell line mixtures for validating long-read variant calls in cancer genomics

  Long-read sequencing (LRS) improves genome alignment and facilitates resolving variants in complex genomic regions, making it a promising approach for cancer variant detection and biomarker discovery. Here, we evaluate the performance of LRS to detect somatic variants across different tumour purities and sequencing depths by comparing to somatic variants from short-read sequencing. We generated experimental mixtures of cancer cell lines and matched normal cell lines to simulate 10 tumour purities (ranging from 0 to 100% tumour content). This resulted in 22 samples which were sequenced using whole genome LRS to a targeted depth of 60x and somatic variants were identified. We downsampled sequencing data to explore the optimal read depth for somatic variant detection. Our results show that long-read variant calling tools achieve recall rates comparable to short-read gold standards. While a tumour sequencing depth of 30x to 60× is generally sufficient for detecting common variants, particularly structural variants (SVs), sequencing the matched normal sample at adequate depth is crucial for accuracy. Notably, we found variants unique to LRS that may represent real and previously undetected events. This study highlights key factors for optimising cancer genome sequencing with LRS and provides a comprehensive dataset of cell line mixtures for future research and tool development.

  Study EGAS00001008107

• Aneuploidy in Pancreatic Cancer

  Aneuploidy in Pancreatic Cancer

  Study EGAS00001008198

• Raw bulk TCRseq data fromTIL and non-TIL expanded TRACERx samples in the manuscript Bulk TCRseq from TRACERx samples from 'Subclonal immune evasion in non-small cell lung cancer'

  Immune checkpoint blockade in non-small cell lung cancer (NSCLC) rarely leads to complete tumour remission, suggesting that tumours harbour subpopulations of cancer cells that can escape immune predation. However, while tumours consist of multiple genetically distinct clones, the extent to which separate tumour subclones differ intrinsically in their functional capacity for immune evasion remains largely unexplored. This has been challenging to address due to an inability to isolate and propagate individual tumour subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived platform that allows the functional analysis of immune escape at single clone resolution. We generated libraries of >20 separate NSCLC organoid lines per patient by isolating individual (clonal) organoids established from multiple spatially separated tumour regions. Each organoid subline was co-cultured with autologous tumour infiltrating lymphocytes (TIL) to evaluate their capacity to elicit a T cell response. Organoid lines derived from separate tumour regions, or from single clones within individual regions, differ vastly in their capacity to elicit a T cell response, showing the coexistence of intrinsically immune evading (‘cold) and non-evading (‘hot) clones in the same primary tumour. Organoid lines escaping T cell recognition represent genetically and transcriptionally unique subclones with a distinct evolutionary history, showing that evolutionary sculpting of subclonal diversity can have functional consequences for anti-tumour immunity. Notably, the identification of immune-evasive subclones would not have been possible using computational approaches alone, highlighting the unique value of functional co-culture platforms. This patient-derived functional co-culture platform reveals that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and provides an approach to prospectively identify, isolate and characterise immune evading subclones from patients with cancer.

  Study EGAS00001008118

• Sequencing data from a highly cost-effective cell-free DNA methylome test

  Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for non-invasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan, a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multi-cancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA.

  Study EGAS00001008125

• Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

  The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT’s regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as druggability for future translational studies and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

  Study EGAS00001008140

• PDX_models_from_Latin_America_RNAseq

  Acral melanoma (AM) is a subtype of cutaneous melanoma that occurs on glabrous skin of the hands and feet (palms, soles and nail apparatus) and which is relatively more common in non-European descent populations such as those of Latin America. Compared to other subtypes, it is poorly studied and experimental models that faithfully reproduce human AM features are urgently needed. We report the generation and preliminary characterisation of a collection of patient-derived xenografts of acral melanomas (AM-PDX) from Latin-American patients. PDX came from Brazilian and Mexican patients cared for at the Instituto Nacional de Câncer (INCA) and the Instituto Nacional de Cancerologia (INCan). The majority of the samples are acral lentiginous melanomas, ulcerated, with > 4mm Breslow depth and > 2 mitosis / mm2. Samples were mechanically fragmented and subcutaneously implanted in NSG mice and then collected for molecular analysis.

  Study EGAS00001008150

• Detection of human brain cancers using genomic and immune cell characterization of cerebrospinal fluid through CSF-BAM

  Detection of human brain cancers using genomic and immune cell characterization of cerebrospinal fluid through CSF-BAM

  Study EGAS00001008199