tbuckley/cabot-search huggingface dataset:
Abstract A030 Secondary malignancies after radiotherapy treatment of pediatric cancer patients in Egypt over a six-year period
Authors: Charlotte L. Sackett, Mohamed S Zaghloul, Ahmed Aldesouky, Amr S Soliman, Chloe A. Teasdale
Journal: Cancer Research (2024)

Abstract Background: Pediatric cancer survivors are at risk of developing secondary malignant neoplasms (SMNs) due to exposure to prior treatment modalities, including radiotherapy (RT). We conducted a retrospective cohort study to examine whether initial RT dose was associated with a greater risk of developing SMNs among pediatric cancer patients in Egypt. Methods: We identified patients (8 days-18 years at enrollment in care) who had received RT for treating primary cancer at Children’s Cancer Hospital (CCHE) in Cairo, Egypt, between 2009 and 2015. Patients were classified into two exposure groups based on the median initial RT course dosage, where ≤3600 centrigray (cGy) and &amp;gt;3600 cGy were considered low and high RT exposure, respectively. The cumulative incidence of SMN accounting for the competing risk of death was compared by initial RT dose using the cumulative incidence function, and multivariable sub-distributional hazard (SHR) models were fitted to compare the hazards of SMN for children with low vs high initial RT dose. Results: Of the 3,132 patients included in this study, 60.1% were male and the median age at enrollment in care was 6.2 years (interquartile range: 3.5-10.7). Approximately half (50.6%) of the patients received a low initial RT dose. The cumulative incidence of SMN at 11.1 years was 3.05% (95% CI 1.15-5.93%) overall and 3.92% (95% CI 1.19-9.39%) and 2.01% (95% CI 0.77-4.38%) for low and high RT dose patients, respectively. Children who received high initial RT doses did not have higher hazards of developing SMN in bivariable (SHR 0.55, 95% CI 0.32-1.75) and multivariable models (aSHR 0.25, 95% CI 0.04-1.70). Conclusion: In this cohort of pediatric cancer patients in Egypt, high initial RT dose was not associated with increased hazards of SMN. Future research should extend follow-up time after the first decade following an initial cancer diagnosis to capture a more complete picture of SMN incidence. Other initiatives may include establishing national cancer registries in low- to middle-income countries to better track longitudinal cancer data in these populations. Citation Format: Charlotte L. Sackett, Mohamed S Zaghloul, Ahmed Aldesouky, Amr S Soliman, Chloe A. Teasdale. Secondary malignancies after radiotherapy treatment of pediatric cancer patients in Egypt over a six-year period [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A030.
Abstract B004: Putting function back into paediatric cancer genomics – modelling the therapeutic implications of novel genomic features
Authors: Teresa Sadras, Lauren M. Brown, Alice Salib, Pei Y. Liu, Chelsea Mayoh, Vanessa Tyrrell, Mark J. Cowley, Paul G. Ekert
Journal: Cancer Research (2024)

Abstract One of the great promises of precision oncology programs lies in linking the specific genomic features of a tumour to therapies that directly or indirectly target these features.The ZERO Childhood Cancer Program (ZERO) is Australia’s national precision medicine program for childhood cancer. ZERO has demonstrated that precision guided therapy is associated with improved survival of children diagnosed with high-risk cancers, by identifying therapeutic options that would otherwise go unrecognised. However, there are many roadblocks preventing use of these therapies. One is the situation where a genomic feature is suspected of being a cancer driver and targetable, but has not been previously described. Another is encountering more familiar oncogenic lesions in atypical tumour contexts. This lack of direct clinical experience or preclinical data about the biological and therapeutic significance of the lesions means, the targeted therapies are often not used even when potential for clinical benefit. We are attempting to address this through an experimental program that generates models of individual genomic lesions to establish, at the bench, whether a genomic aberration is oncogenic and how it can be therapeutically targeted. Our focus has been on to novel variants predicted to activate receptor tyrosine kinase signalling found in the ZERO program.We will show we use a variety of approaches, including CRISPR/Cas9 engineering of novelkinase activating lesions in cytokine dependent cell lines to measure whether they are sufficient to transform these cells from cytokine dependence to independence. Further, we compare how driver fusions engineered in the endogenous genome compare, with respect to transforming capacity and responses to targeted therapies, to exogenous over-expression of the same fusions By studying rare or unique variants, we have identified novel mechanisms of tyrosine kinase activation, and identified therapeutic options for individual cancers, so meeting a definition of precision medicine. Further, we contend that understanding the biology of rare or unique variants does more than recover lost therapeutic opportunities for clinicians and families, it also provides important new knowledge about the biology of childhood cancer. Citation Format: Teresa Sadras, Lauren M. Brown, Alice Salib, Pei Y. Liu, Chelsea Mayoh, Vanessa Tyrrell, Mark J. Cowley, Paul G. Ekert. Putting function back into paediatric cancer genomics – modelling the therapeutic implications of novel genomic features [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B004.
Abstract A006 Targeting boundary cap cells leads to mouse <i>Smarcb1</i>-deficient peripheral nerve tumors recapitulating human peripheral rhabdoid tumors
Authors: Zhi-Yan HAN, Mamy Andrianteranagna, Stéphanie Fitte-Duval, Valeria Manriquez, Magali Frah, Rachida Bouarich, Sandrina Turcynski, Arnault Tauziède-Espariat, Kevin Beccaria, Julien Masliah-Planchon, Christine Bourneix, Delphine Guillemot, Stéphanie Reynaud, Gaelle Pierron, Maëva Veyssiere, Owen Hoare, Céline Chauvin, Grégory Thomson, Didier Surdez, Pascale Varlet, Christelle Dufour, Volodia Dangouloff-Ros, Joshua J. Waterfall, Eliane Piaggio, Olivier Delattre, Piotr Topilko, Franck Bourdeaut
Journal: Cancer Research (2024)

Abstract Malignant rhabdoid tumors (MRT) are rare aggressive tumors of infancy characterized by the biallelic inactivation of SMARCB1. Their lineage of origin remains uncertain, but increasing evidence suggest a neural-crest origin. By analyzing the transcriptome of MRT occurring in peripheral and cranial nerves, we observe that their expression profiling was not distinct from any other tumor localization. We therefore investigated whether the development of Smarcb1-deficient tumors emerging from embryonic precursors of peripheral nerves in mice could recapitulate human MRT. we generated conditional Smarcb1 knockout in the Prss56-Cre mouse strain thereby targeting boundary cap cells which are neural crest derived Schwann cell precursor. All Smarcb1Flox/Flox;Prss56Cre+/+ showed ataxia within a median of two months, due to the development of massive intracranial tumor in the ponto-cerebellum angle. Smarcb1Flox/Flox;Prss56Cre+/- mainly developed paraplegia related to nerve root tumors, within a median delay of 7 months. Interestingly, transcriptome profiling confirmed the good correlation between mouse peripheral nerve tumors and human MRT; intracranial tumors in this new model correlated with MYC-ATRTs but with some specific features not observed in their human counterparts. All tumors harbored a significant immune infiltration, with some clonal T-cell expansion. Altogether, the Smarcb1Flox/Flox;Prss56-Cre mouse tumors offer a new model for human MRT and promising perspectives for immune-based innovative treatments. Citation Format: Zhi-Yan HAN, Mamy Andrianteranagna, Stéphanie Fitte-Duval, Valeria Manriquez, Magali Frah, Rachida Bouarich, Sandrina Turcynski, Arnault Tauziède-Espariat, Kevin Beccaria, Julien Masliah-Planchon, Christine Bourneix, Delphine Guillemot, Stéphanie Reynaud, Gaelle Pierron, Maëva Veyssiere, Owen Hoare, Céline Chauvin, Grégory Thomson, Didier Surdez, Pascale Varlet, Christelle Dufour, Volodia Dangouloff-Ros, Joshua J. Waterfall, Eliane Piaggio, Olivier Delattre, Piotr Topilko, Franck Bourdeaut. Targeting boundary cap cells leads to mouse Smarcb1-deficient peripheral nerve tumors recapitulating human peripheral rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A006.
Abstract A080 PRC1/BMI1 activity alters chromatin accessibility to regulate differentiation in atypical teratoid rhabdoid tumors
Authors: Irina Irina Alimova, Gillian Murdock, Angela M. Pierce, Dong Wang, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Cancer Research (2024)

Abstract Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor and characterized by SMARCB1 deletion. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. We performed an RNAi-based functional genomic screen to identify key epigenetic regulators that co-operate with SMARCB1 loss and contribute to tumorigenesis in ATRT. 406 genes associated with epigenetic regulation in patient derived ATRT cell lines were targeted. This screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as one of the top targets essential for ATRT cell growth. Using RNA-seq and ChIP-Seq analysis we demonstrated that BMI1 co-operates with SMARCB1 deletion to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. We found that genetic inactivation of BMI1 suppresses ATRT cell clonogenicity in vitro and decreases S-phase length. By Doxycycline-inducible SMARCB1 re-expression system we revealed activation of proapoptotic proteins p16 and p21. With immunoprecipitation for BMI1, followed by mass spectrometry analysis we demonstrated that re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. Moreover, inhibition of BMI1 significantly prolongs mice survival and decreases tumor size as evaluated by IVIS imaging system and T2-MRI. Thus, we demonstrated that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex and that PRC1/BMI1 inhibition is a novel therapeutic approach in ATRT. Citation Format: Irina Irina Alimova, Gillian Murdock, Angela M. Pierce, Dong Wang, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar. PRC1/BMI1 activity alters chromatin accessibility to regulate differentiation in atypical teratoid rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A080.
Abstract A010 The role of <i>TP53</i> on transposable elements in pediatric cancer
Authors: Brianne Laverty, Shilpa Yadahalli, Vallijah Subasri, David Malkin
Journal: Cancer Research (2024)

Abstract Background: Transposable elements (TEs) are dynamic repetitive regions which generate mutations and structural variants. TP53 plays a crucial role in suppressing TE movement to maintain genomic stability. The relationship between TP53 and TEs has been extensively studied in tumours, but not the germline. Individuals with germline TP53 pathogenic variants have Li-Fraumeni Syndrome (LFS), a cancer predisposition syndrome with a high lifetime risk of cancer in various tissues. This study aims to characterize the TE landscape in individuals with Li-Fraumeni Syndrome and determine how this contributes to their increased cancer risk. Methods: MELT and xTea were used to identify TEs in children with (n=48) or without (n=198) a germline TP53 variant. TE calls were merged with SURVIVOR and variants were annotated with AnnotSV. To assess the influence of TP53 on TE location, we quantified TEs across genomic windows and identified the top 100 significantly different regions with the Mann-Whitney U test, adjusting for multiple comparisons. We used these regions to develop a gradient-boosted tree model with 5-fold cross-validation to predict TP53 status. Results: Individuals with germline TP53 variants harboured significantly fewer ALU and LINE1 elements in their germline genome compared to the control dataset (p&amp;lt;0.001). The phenomenon was consistent across chromosomes and significant in chromosomes 5 and 11 (FDR&amp;lt;0.05). A gradient-boosted tree model was able to differentiate patients with and without a germline TP53 variant with an AUPRC of 0.77 on an unseen test set. Conclusion: Germline TP53 variants may effect the frequency and location of germline TE insertions, which may influence nearby genomic variations and lead to cancer development. Analyzing TEs in individuals with LFS will enhance our understanding of accelerated cancer development in these patients, informing future research for diagnostic and therapeutic approaches. Citation Format: Brianne Laverty, Shilpa Yadahalli, Vallijah Subasri, David Malkin. The role of TP53 on transposable elements in pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A010.
Abstract A073 Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B
Authors: Nina Weichert-Leahey, Thomas Look
Journal: Cancer Research (2024)

Abstract Retinoic acid re-organizes the enhancers regulating the expression of these key transcription factors in neuroblastoma and establishes a new differentiated cell state characterized by MYCN downregulation and proliferative arrest. However, the epigenetic and growth suppressing effects of retinoic acid are completely reversible in vitro, leading to cell proliferation. We sought to determine if retinoid-induced differentiation can be forced to progress to terminal neuronal maturation by the addition of inhibitors of enzymes modifying the epigenome. We conducted a drug screen using more than 450 epigenetic modifiers to treat neuroblastoma cells either with each compound alone or in combination with retinoic acid to determine whether any compound augments the antiproliferative effects of retinoic acid. We found that an inhibitor of the histone acetyltransferases KAT6A/B synergistically inhibits neuroblastoma growth in combination with retinoic acid in vitro and enhances neuroblastoma differentiation. We used a xenograft model of retinoid-sensitive neuroblastoma cells in mice to test if the combination treatment with isotretinoin and a KAT6 inhibitor is more effective than isotretinoin alone to induce permanent neuroblastoma differentiation in vivo. We found that isotretinoin is very effective in suppressing neuroblastoma proliferation, however its effects are completely reversible upon drug removal leading to rapid tumor re-growth. In contrast, when isotretinoin is combined with a KAT6 inhibitor, tumors cannot re-grow after isotretinoin removal and remain differentiated. In conclusion, our studies nominate KAT6A/B inhibition combined with isotretinoin as a promising approach to improve outcome for patients with neuroblastoma. Citation Format: Nina Weichert-Leahey, Thomas Look. Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A073.
Abstract A056 Intertumoral epigenetic heterogeneity in response to a novel therapy in Ewing sarcoma
Authors: Emily Isenhart, Ajay Gupta, Joyce Ohm
Journal: Cancer Research (2024)

Abstract Like many pediatric cancers, Ewing sarcoma (EwS) is a genomically quiet disease. Driven by an oncogenic fusion protein, usually EWSR1-FLI1, the epigenome of this genetically homogenous cancer is a driver of clinical outcomes, where heightened epigenetic heterogeneity within tumors is associated with metastatic disease. While prognosis for localized disease is moderate, outcomes are dismal for patients who present with advanced, relapsed, or refractory disease and there is a lack of targeted therapies in this setting. We have previously described a targeted combination therapy harnessing DDK and WEE1 inhibition exploits elevated endogenous replication stress in EwS to force cells into mitotic catastrophe in vitro. While our experiments evaluating the efficacy of this combination in vivo have been extremely encouraging, the data have shown that individual mice receiving the same treatment have variable patterns of outgrowth after treatment cessation, with some mice demonstrating moderate increases in tumor volume and some mice demonstrating little to no tumor outgrowth. This differential response to therapy is most likely to occur through epigenetic dysregulation. Thus, we aim to interrogate intertumoral epigenetic heterogeneity and examine epigenetic profiles associated with treatment response using samples from in vivo studies. Samples were analyzed from a CDX model using TC32 cells injected subcutaneously. Reduced representation bisulfite sequencing was performed on a control arm (n = 5) and the following three treatment arms, where the DDK inhibitor is TAK-931 (simurosertib) and the WEE1 inhibitor is MK1775 (adavosertib): 1) Irinotecan + Temozolomide (n=9), 2) Irinotecan (full dose) + DDKi + WEE1i (n=7), 3) Irinotecan (half dose) + DDKi + WEE1i (n=9), for a total of 30 samples. Our analysis of this data evaluates epigenetic changes between treatment conditions and increases our understanding of epigenetic heterogeneity in EwS. Citation Format: Emily Isenhart, Ajay Gupta, Joyce Ohm. Intertumoral epigenetic heterogeneity in response to a novel therapy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A056.
Abstract A043 Plasma circulating proteomic markers are associated with metastatic spread and outcome in osteosarcoma
Authors: Baptiste Audinot, Damien Drubay, Maria Eugenia Da Costa, Gael Moquin Beaudry, Marta Jimenez, Birgit Geoerger, Nathalie Gaspar, Samuel Abbou, Antonin Marchais
Journal: Cancer Research (2024)

Abstract Background: Osteosarcoma is the most frequent bone cancer in children and young adults. Histological response and control of primary metastases are the main prognostic clinical factors, but are insufficient to identify the ∼30% of hard-to-treat patients and are not predictive of the response to combinations of chemotherapies or biological treatments. Our aim was to evaluate if circulating proteomic analyses could predict tumor progression. Methods: 88 plasma samples from newly diagnosed patients with osteosarcoma in the OS2006 trial were sequenced using the OLINK Explore panel (3072 proteins) and 88 more coming from the SARCOME13 trial will be used as a validation cohort. Results: Principal component analysis defined co-circulating proteins associated to critical biological pathways involved in osteosarcoma oncogenesis, such as cell adhesion, cell survival/growth, bone formation and extracellular matrix organization. Cox survival analysis associated circulating bone formation pathway with OS(HR=1.10 [1.03;1.17], p=0.006) and PFS(HR=1.12 [1.05;1.19], p=&amp;lt;0.001). These circulating pathways were also associated with presence of metastases at diagnosis (odd ratio = 1.33 [1.12;1.72], p=0.006). These results are being validated on SARCOME13 data. Conclusion: Proteomic plasma markers quantification in patients with osteosarcoma at diagnosis capture a biological signal significantly associated to prognosis and the presence of metastasis at diagnosis. Citation Format: Baptiste Audinot, Damien Drubay, Maria Eugenia Da Costa, Gael Moquin Beaudry, Marta Jimenez, Birgit Geoerger, Nathalie Gaspar, Samuel Abbou, Antonin Marchais. Plasma circulating proteomic markers are associated with metastatic spread and outcome in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A043.
Abstract A001: PAX3-FOXO1-induced transcriptional dysregulation in rhabdomyosarcoma
Authors: Bradley T. Stevens, Yang Zhang, Randolph K. Larsen, Grace E. Adkins, Jack D. Hopkins, Darden W. Kimbrough, Matthew R. Garcia, Mark E. Hatley, Brian J. Abraham
Journal: Cancer Research (2024)

Abstract The survival rate for high-risk rhabdomyosarcoma (RMS) has not increased above 20% in the last thirty years. This insufficiency persists despite thorough molecular characterization of existing models and patient tumors, which has demonstrated that the most challenging RMS tumors harbor chromosomal translocations generating PAX3-FOXO1 (P3F) or PAX7-FOXO1 (P7F) oncofusion transcription factors. The presence of P3/7F largely explains the alveolar subtype of RMS. However, the molecular mechanisms by which P3/7F drives tumor onset and the extent to which they are required after establishment of RMS remain unclear. In recent work, we challenged the dogma that fusion-positive RMS arises from incompletely differentiated muscle cells by demonstrating that P3F-bearing endothelial precursors form RMS tumors ex vivo and in vivo. This observation proposes an explanation for why RMS is observed throughout the body including in sites devoid of skeletal muscle. Here, we describe a novel constructionist model of RMS in which the P3F protein is added to induced pluripotent stem cell-derived endothelial precursors. The inducible alveolar rhabdomyosarcoma (iARMS) system faithfully recapitulates tumor-relevant aspects of RMS biology, including histology, tumor-formation, and the upregulation of signature expression programs. P3F expression during endothelial-directed differentiation blocked endothelial maturation and reprogrammed cell identity toward skeletal muscle-like cells that form ARMS tumors in mice. The iARMS system reproducibly generates RMS over a 15-day timecourse, providing a unique model to examine gene-regulatory dynamics induced by P3F during RMS transformation. In addition to the expected upregulation of hallmark RMS factors, including MYOD1 and MYF6, we observed a cadre of additional transcription factor proteins that were induced and may contribute to transformation, as well as signature endothelial genes that became downregulated. P3F activated a set of enhancers that drove these expression patterns. P3F induced specific genetic dependencies in iARMS cells as observed in knockout screens. Our results define the fundamental cell identity changes underpinning P3F-induced transformation into FP-RMS and nominate collaborative transcription and non-transcription proteins that might be vulnerable to therapeutic attack. Citation Format: Bradley T. Stevens, Yang Zhang, Randolph K. Larsen, Grace E. Adkins, Jack D. Hopkins, Darden W. Kimbrough, Matthew R. Garcia, Mark E. Hatley, Brian J. Abraham. PAX3-FOXO1-induced transcriptional dysregulation in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A001.