tbuckley/cabot-search huggingface dataset:
Long-Term Tumor Stability After First-Line Treatment With Larotrectinib in an Infant With NTRK2 Fusion–Positive High-Grade Glioma
Authors: Jillian Simoneau, Patricia Robertson, Karin Muraszko, Cormac O. Maher, Hugh Garton, Rebecca Calvert, Carl Koschmann, Santhosh A. Upadhyaya, Rajen Mody, Noah Brown, Chandan Kumar-Sinha, Hemant Parmar, Sandra Camelo-Piragua, Andrea T. Franson
Journal: Journal of the National Comprehensive Cancer Network (2024)

Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK , ROS1 , NTRK , or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion–positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for &gt;3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.
Current advancements in nanotechnology for stem cells
Authors: P. Thamarai, S. Karishma, R. Kamalesh, Alan Shaji, A. Saravanan, Shabana Bibi, A.S. Vickram, Hitesh Chopra, Rimah Abdullah Saleem, Khalaf F. Alsharif, Abdulrahman Theyab, Mohamed Kamel, Mariam K. Alamoudi, Ajoy Kumer, Shivani Chopra, Mohamed M. Abdel-Daim
Journal: International Journal of Surgery (2024)
Reply: Development and validation of pFIB scores for exclusion of significant liver fibrosis in pediatric MASLD
Authors: Sander Lefere, Antonella Mosca, Christian Hudert, Ellen Dupont, Emer Fitzpatrick, Eirini Kyrana, Anil Dhawan, Laura Kalveram, Andrea Pietrobattista, Anja Geerts, Ruth De Bruyne
Journal: Hepatology (2024)
Abstract A009 Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas
Authors: Ashby Kissoondoyal, David Malkin
Journal: Cancer Research (2024)

Abstract Li-Fraumeni Syndrome (LFS) is a genetic predisposition disorder associated with pathogenic germline Tp53 mutations. A subset of LFS-associated neoplasms occurs at an increased risk within the first 5 years of life, with the most common being soft tissue sarcomas (STS). Histological characterization of STS is one of the primary approaches to guiding treatment. However, the heterogeneity of STS has necessitated a further understanding of the molecular etiology of these tumors. Examining sarcomas using a single-cell transcriptomic approach has shown unique subsets of cells with dysregulations in cell fate and differentiation. Within LFS-associated tumors, including LFS-STS a major event in tumorigenesis is the copy-neutral loss of heterozygosity (LOH). LOH was determined to occur much earlier than cancer onset in LFS, suggesting a dormancy period from the LOH until tumorigenesis; cancer-defining events in LFS are likely occurring prenatally. During embryogenesis, Tp53 is involved in differentiation and pluripotency regulation, as well as cell cycle control and apoptosis. Here we hypothesize that the emergence of STS in LFS mice is associated with distinct disturbances in the cell fate and differentiation pathways. Specifically, there will be deficits in cell fate determination and the organization of cells across multiple cell types in LFS-Sarcomas. Single-cell RNAseq was performed on spontaneous tumors and healthy matched muscle tissue from male and female C57BL/6J Trp53R172H/WT mice. Cell types were determined based on differential gene expression between clusters defined by principal component analysis. Despite tumor heterogeneity between mice, there were consistent disruptions of developmental pathways among tumor cells. Moreover, when comparing matched cell types across tumor and healthy muscle tissue we observed dysregulation of pathways promoting tumorigenesis, and cell fate determination in cells originating from tumor tissue. For the first time to our knowledge, this study examines the single-cell transcriptome of LFS-STS. Current literature has speculated on the presence of an early precancer state of LFS-associated tumors. This study will provide evidence to determine whether this precancer state can be determined in tumor samples, and identify elements that constitute this state. Moreover, we will determine changes in supporting non-tumor cells and whether they also exhibit dysregulations in cell state and differentiation. Together these findings will hopefully contribute to improvements in molecular subtyping across STS, and particularly within LFS individuals. Citation Format: Ashby Kissoondoyal, David Malkin. Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas [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 A009.
Abstract A069 The role of <i>ABCB1</i> in doxorubicin resistant SMARCB1-deficient cancers
Authors: Katie T. Skinner, Benjamin P. Lee, Jessica S Yoon, Andrew L. Hong
Journal: Cancer Research (2024)

Abstract SMARCB1 is a tumor suppressor gene and encodes a core subunit of the SWI-SNF chromatin remodeling complex. Loss of SMARCB1 leads to the development of highly aggressive pediatric malignancies, termed “SMARCB1-deficient cancers.” This includes malignant rhabdoid tumor, atypical teratoid rhabdoid tumor (ATRT), and renal medullary carcinoma (RMC). Survival rates in these patients remain low, and resistance to chemotherapeutic agents used to treat these cancers are common. One such chemotherapy is doxorubicin. Therefore, this project aims to reveal and understand the mechanisms of doxorubicin resistance in SMARCB1-deficient cancers. To address this question, we generated doxorubicin resistant (DR) cells from one ATRT and two RMC primary cell lines (BT16, PEDS005T, and RCRF1009T respectively) utilizing a dose escalation approach. This resulted in DR cell lines that are 10-fold to 30-fold resistant compared to the parental cell line. Upon generation of these stably resistant cell lines, we profiled their transcriptomes by RNA-sequencing and found an upregulation of the multidrug transporter ABCB1, also known as MDR1. To further probe these cell lines, we performed whole-genome sequencing (WGS) on two of our DR cell lines (BT16 and PEDS005T DR). Here, we found a chromosome 7 aneuploidy in BT16 DR cells, but no aneuploidy or mutations were seen in PEDS005T DR cells. ABCB1 is located on chromosome 7. We confirmed this aneuploidy via karyotyping. The mechanism of ABCB1 upregulation in the RMC DR cell lines remains unknown, suggesting multiple modalities leading to ABCB1 upregulation. We then overexpressed ABCB1 in two ATRT parental cell lines (BT16 and CHLA-06-ATRT) and one RMC cell line (PEDS005T) which led to enhanced short-term resistance. This contrasted to JMSU, a SMARCB1 wild-type bladder cancer cell line, where there was stable resistance. Together, this suggests that ABCB1 may be necessary but not sufficient to confer doxorubicin resistance in these SMARCB1-deficient cancer cells. These preliminary findings suggest that despite a common genetic driver (loss of SMARCB1), there may be different pathways to developing resistance to the DNA-damaging agent, doxorubicin. Furthermore, despite the well documented role of ABCB1 in drug resistance, there may be other factors involved in conferring stable resistance in the setting of SMARCB1-deficient cancers. Citation Format: Katie T. Skinner, Benjamin P. Lee, Jessica S Yoon, Andrew L. Hong. The role of ABCB1 in doxorubicin resistant SMARCB1-deficient cancers [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 A069.
Abstract A007 DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition
Authors: Madeline N. Hayes, Sarah Cohen-Gogo, Lynn Kee, Mehdi Layeghifard, Ivette Valencia-Sama, Anisha Rajaselvam, David Kaplan, Anita Villani, Adam Shlien, Daniel A. Morgenstern, Meredith S Irwin
Journal: Cancer Research (2024)

Abstract Background: Significant progress has been made in identifying mutations and defining biological heterogeneity in neuroblastoma (NB) using high-throughput sequencing approaches. However, functional roles for many specific genetic alterations in NB initiation, growth, and metastasis remain to be fully defined. Pathogenic and/or likely pathogenic (P/LP) alterations in genes involved in DNA Damage Response (DDR) pathways were identified in approximately 30% of patients enrolled in the SickKids Cancer Sequencing Program (KiCS). Despite being well studied in many adult cancers, roles for DDR disruption and potential therapeutic implications remains poorly understood for NB and other pediatric solid tumors. Aims: We aimed to define roles for DDR-deficiency in NB progression and assess the therapeutic potential of targeted agents using patient-specific DDR loss-of-function NB models. Methods: We incorporated loss-of-function mutations in atm, brca2, palb2, and bard1 into an established zebrafish MYCN-driven model of human NB and characterized tumor progression, transcriptional signatures, and response to candidate therapeutics in vivo. Human cell lines with DDR protein knock-down were used to assess candidate drug combinations in vitro. Results: Mutations in DDR genes were found to enhance tumor penetrance and metastasis in MYCN-driven zebrafish NB, and resulted in upregulation of proliferation, cell cycle checkpoint, and DNA damage repair transcriptional signatures. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Conclusions: Our data supports an in vivo functional role for DDR-deficiency in NB, as well as potential molecular vulnerabilities. Pre-clinical assessments in vitro and in vivo suggest therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes. Citation Format: Madeline N. Hayes, Sarah Cohen-Gogo, Lynn Kee, Mehdi Layeghifard, Ivette Valencia-Sama, Anisha Rajaselvam, David Kaplan, Anita Villani, Adam Shlien, Daniel A. Morgenstern, Meredith S Irwin. DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition [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 A007.
Abstract A060 Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas
Authors: Hannah L. Walker-Mimms, Nicole Londono, Yi Liao, Neelkamal Chaudhary, Mingxiang Teng, Fumi Kinose, Xueli Li, Andrii Monastyrskyi, Uwe Rix, Derek Duckett
Journal: Cancer Research (2024)

Abstract Ewing (ES) and clear cell (CCS) sarcomas are bone and soft tissue malignances and in advanced and relapsed disease overall survival rates remain dismal. For metastatic ES, five-year survival rates are between 15% and 30%. In CCS, the five-year survival rates are between 30% and 67%. Accordingly, there is a critical need for the development of novel targeted therapeutics for the treatment of these rare cancers. Both cancers are driven by fusion proteins; EWS-FLI1 in ES and EWS-ATF1 in CCS, which arise from separate chromosomal translocations: t(11;22)(q24;q12) and t(12;22)(q13;q12) respectively. Current approaches for developing new treatments focus on targeting the fusion proteins or their downstream targets. We performed a small molecule compound library screen of clinically used drugs and identified ES and CCS cells to be extremely sensitive to filanesib, a kinesin spindle protein (KIF11) inhibitor. KIF11 is known to play roles in cell cycle progression and mitotic spindle stability. Our preclinical efficacy studies demonstrated that filanesib promotes potent tumor growth inhibition in both EWS-FLI1 and EWS-ATF1 xenograft models in mice. We are currently investigating the mechanism underlying the relationship between KIF11 and EWS-FLI1 and EWS-ATF1. Prior studies have identified KIF11 within a EWS-ATF1 transcriptional complex and KIF11 has been shown to interact with the histone acetyltransferase (HAT) p300/CBP-Associated Factor (PCAF). HATs are necessary components for chromatin remodeling, which the oncogenic fusion proteins regulate. Future research directions involve elucidating the role of KIF11 in regulating the EWS-ATF1 and EWS-FlI1 transcriptional complexes. Additionally, to further improve the therapeutic response to filanesib, we are investigating potential synergistic relationships with other compounds. This work has been supported in part by the Flow Cytometry and the Molecular Genomics Cores at the H. Lee Moffitt Cancer Center &amp; Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt’s Cancer Center Support Grant (P30-CA076292) Citation Format: Hannah L. Walker-Mimms, Nicole Londono, Yi Liao, Neelkamal Chaudhary, Mingxiang Teng, Fumi Kinose, Xueli Li, Andrii Monastyrskyi, Uwe Rix, Derek Duckett. Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas [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 A060.
Abstract A071 Mechanisms of radiation resistance in medulloblastoma
Authors: Bethany Veo, Dong Wang, John Desisto, Rajeev Vibhakar
Journal: Cancer Research (2024)

Abstract Medulloblastoma (MB) is the most prevalent malignant brain tumor in children that demonstrates clinical and genomic heterogeneity. Of the four major subgroups, Group 3 tumors (MYC-MB), and particularly the 3gsubtype, exhibit high levels of MYC, high rates of metastasis, and have the worst prognosis. Despite treatment with surgery, radiation and chemotherapy, Group 3 medulloblastoma patients are more likely to develop recurrent tumors which are far more aggressive resulting in a 5-year survival rate after recurrence of 12%. Thus, there is an imperative need to examine the underlying mechanisms mediating treatment resistance. Recent evidence has identified cellular plasticity, as a major driver of therapy resistance. To investigate whether epigenetic mediated cell plasticity contributes to Myc-MB therapy response we performed Single Nuclei Multiome ATAC + Gene Expression analysis of paired primary and relapsed tumors. We identified the emergence of novel progenitor populations in resistant tumors with stem-like gene expression networks and altered chromatin accessibility. These emergent popuoations demostrated new enhancer-promoer interactions and exhibited increased metabolic reprogramming with potential for theraputic targeting. Because radiation is one of the key treatment modalities for Myc-MB, we chose to model radiation resistance in further studies. Single-cell RNA sequencing of outgrown in vivo irradiated orthotopic xenograft MB tumors showed an overall upregulation of metabolic pathways with the enhancement of genes that mediate oxidative phosphorylation and glutamate metabolism centering on wild-type IDH1 (wtIDH1), consistent with our patient data. IR-resistant cells showed altered chromatin occupancy of H3K3me3 and H3K27Ac. Disruption of IDH1 activity in IR resistant cells in vitro altered the epigenomic landscape, facilitating reversion to the pre-irradiated state. Interestingly, we observed that pluripotent genes with bivalent regions (H3K4me3 and H3K27me3) were enhanced in radiation-resistant cells and suppressed by IDH1 inhibition. Metabolic mass spectrometry reveled that metabolites from the citric acid cycle and synthesis of unsaturated fatty acids were among the main metabolically elevated molecules in radiation-resistant cells consistnat with the observed epigenomic reprograming. IDH1 inhibition reversed the metabolic reprograming and resensitized MB cells to radiation. In total our data identify a novel mechanism of radiation resistance in medulloblastoma with potential theraputic implications. Citation Format: Bethany Veo, Dong Wang, John Desisto, Rajeev Vibhakar. Mechanisms of radiation resistance in medulloblastoma [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 A071.
Abstract B016: Unravelling personalized drug vulnerabilities in pediatric solid tumors—functional precision medicine approach
Authors: Sara Kuusela, Enni Martikainen, Katja Eloranta, Wenyu Wang, Romika Kumari, Swapnil Potdar, Giovanna Dashi, Jouko Lohi, Aino Mutka, Olli Tynninen, Jukka Kanerva, Virve Pentikäinen, Minna Koskenvuo, Vilja M. Pietiäinen
Journal: Cancer Research (2024)

Abstract Many pediatric cancer patients with high-risk primary, refractory, or relapsed tumors still lack effective treatment strategies and frequently suffer from both acute and delayed adverse drug effects, including secondary cancers. These tumors are generally characterized by very few druggable molecular alterations, diminishing the advantage of genetics in defining patient-specific treatments. The purpose of this study is to utilize the functional precision medicine approach to provide improved diagnostics and better therapy options for pediatric solid tumors through deep molecular and functional profiling in a patient-specific manner. Here, we describe the results of our current study, which includes exome sequencing for germline and somatic mutations, and transcriptomics analysis for fusion genes, as well as ex vivo drug testing of patient-derived cancer cells (PDCs) in real-time clinical set-up. Our current clinical data and sample collection, currently from 40 patients, include different types of pediatric solid tumors, such as central nervous system (CNS) tumors, sarcomas, and neuroblastomas. We have prepared PDC cultures and screened them using a 3D-drug sensitivity and resistance testing (DSRT) platform with an internationally defined pediatric solid tumor drug panel. Our results include the drug testing results of control cell lines and primary healthy cells to assess the general cytotoxicity of the drugs and patient-specific responses. We present our "fast-track" functional precision medicine concept, incorporated as part of biobank operations to return clinically relevant findings back to the treating clinicians, and exemplify the data returned to the clinics as well as its potential clinical impact. In conclusion, our findings demonstrate that the functional precision medicine approach can i) help to discover clinically relevant molecular events important for diagnosis and treatment, and ii) increase our biological understanding of drug vulnerabilities in pediatric cancers. Citation Format: Sara Kuusela, Enni Martikainen, Katja Eloranta, Wenyu Wang, Romika Kumari, Swapnil Potdar, Giovanna Dashi, Jouko Lohi, Aino Mutka, Olli Tynninen, Jukka Kanerva, Virve Pentikäinen, Minna Koskenvuo, Vilja M. Pietiäinen. Unravelling personalized drug vulnerabilities in pediatric solid tumors—functional precision medicine approach [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 B016.
Abstract B048: Galectin-3 regulation of immunosuppression in Ewing sarcoma
Authors: Yunash Maharjan, Adriana C. Tufino, Sreya Dey, Elina Mukherjee, Kelly M. Bailey
Journal: Cancer Research (2024)

Abstract Objective: Ewing sarcoma is a fusion oncoprotein-driven cancer most commonly diagnosed in adolescents. Utilizing single-cell RNAseq of human Ewing tumors, we have previously demonstrated that Galectin-3, an immunosuppressive lectin family member protein, is expressed in both Ewing tumor cells and in CD8 T cells in the Ewing tumor microenvironment, a finding not noted in CD8 T cells infiltrating osteosarcomas. Galectin-3 serves to modulate tumor immunobiology through multiple mechanisms, including interactions with the immune checkpoint protein LAG3. In addition to Galectin-3, Galectin-3BP (binding protein) is also expressed in Ewing sarcoma and can bind to and modulate Galectin-3 function. Here, we aim to determine the role of Galectin-3 and Galectin-3BP on Ewing tumor immunosuppression. Methods: CHLA10 and TC32 human Ewing sarcoma tumor cells -/+ LGALS3 (gene encoding galectin-3) expression were generated using CRISPR/Cas 9 technology. T cells primed again human Ewing tumor cells were generated. The galectin-3 inhibitor TD-139 was also utilized. In vitro IncuCyte live cell monitoring assays, ELISA, and co-culture apoptosis assays were conducted. In vivo analyses of tumor growth, metastasis, and immune cell infiltration were conducted on Ewing tumors developed in immunocompetent, humanized mice and immunodeficient NSG mice. Peripheral blood and spleen controls were also analyzed. Results: CRISPR/Cas 9 knock-out of LGALS3 in both CHAL10 and TC32 cell lines was successful. GSEA of RNAseq data demonstrate distinct developmental signatures and flow cytometry analyses demonstrate altered immune cell signatures in LGALS3 KO Ewing tumors versus controls developed in humanized mice. ELISA demonstrates Galectin-3 is secreted by some Ewing tumors, the functional implications of which are under ongoing investigation. Expression of Galectin-3 and Galectin-3BP alone versus co-expression impacts the net effect of on Ewing tumor behavior. Conclusion: This work contributes to the understanding of galectin-3 on inflammatory responses and tumor progression in Ewing sarcoma. Understanding the complex relationship of Galectin-3 and Galectin-3BP on immunobiology provides valuable clues to best disrupt Galectin-3 mediated immunosuppression and promote enhanced tumor control. Citation Format: Yunash Maharjan, Adriana C. Tufino, Sreya Dey, Elina Mukherjee, Kelly M. Bailey. Galectin-3 regulation of immunosuppression 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 B048.