tbuckley/cabot-search huggingface dataset:
Abstract A028 Unraveling the complex interplay of genetic, environmental, and lifestyle factors in cancer predisposition: A comprehensive review and analysis
Authors: Peter Oloche O. David
Journal: Cancer Research (2024)

Abstract Cancer Predisposition is a complex and multifaceted topic that continues to intrigue researchers and scientists for decades. This thesis delves into the intricate web of factors that contribute to an individual's predisposition to cancer, aiming to unravel the mysteries surrounding this phenomenon. Through a comprehensive review of existing literature and cutting-edge research findings, the paper explores the genetic, environmental, and lifestyle factors that play a crucial role in predisposing individuals to cancer. By examining the interplay between genetic mutations, familial history, and environmental exposures, this study sheds light on the intricate mechanisms underlying cancer predisposition. Furthermore, the thesis investigates the role of epigenetic modifications, immune system dysregulation, and metabolic abnormalities in shaping an individual's susceptibility to cancer. The intricate interactions between these factors and their collective impact on cancer risk are analyzed, providing valuable insights into the underlying causes of cancer predisposition. By synthesizing the latest research findings in the field, this thesis offers a comprehensive overview of the complex nature of cancer predisposition and its multifactorial etiology. Ultimately, this study aims to contribute to our understanding of the intricate interplay between genetics, environment, and lifestyle in shaping an individual's susceptibility to cancer, paving the way for targeted prevention and personalized treatment strategies in the fight against this devastating disease. Citation Format: Peter Oloche O. David. Unraveling the complex interplay of genetic, environmental, and lifestyle factors in cancer predisposition: A comprehensive review and analysis [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 A028.
Abstract B029: Studies in human bone cell co-cultures reveal a potential mechanism underlying bone fractures in children treated with entrectinib and suggest a positive association with vitamin D
Authors: Sabrina Ehnert, Kevin A. Schulz, Alison K. Cardenas, Georgina Meneses-Lorente, Adrian Roth, Sabine Fürst-Recktenwald
Journal: Cancer Research (2024)

Abstract Introduction: Entrectinib, a NTRK, ROS1 and ALK inhibitor, approved in the US for adult patients with ROS1-positive metastatic non-small cell lung cancer and adult and pediatric patients older than 1 month of age with solid tumors that have a NTRK gene fusion, has been associated with the occurrence of bone fractures, particularly in pediatric patients. These fractures might be caused by an inhibition of signaling pathways relevant for bone development in children. Methods: To investigate the mechanism of the observed effect we used a suite of human bone cells representing both juvenile and adult bone physiology. These models were treated with Entrectinib and its major metabolite M5. Molecular as well as functional readouts were assessed to reveal the pathomechanism of the observed clinical findings. Results: Data showed, that Entrectinib induced a reduction of cellular markers of osteoblastic activity and a reduced formation of mineralized matrix. Conversely, Entrectinib had stimulating effects on osteoclast function indicative of bone resorption. 3D osteoblast-osteoclast cultures revealed decreased stiffness after Entrectinib treatment, confirming the cell signaling data. These findings were particularly pronounced in the absence of 17β-estradiol, characteristic for juvenile bone. Finally, pre-treatment with Vitamin D led to partially restored osteoblast function in vitro, while osteoclast function was suppressed. Conclusions: These experiments support the suspected on-target effect of Entrectinib underlying increased fractures in children with developing bone, offering potential mitigation strategies once these observations have been confirmed with clinical data. Citation Format: Sabrina Ehnert, Kevin A. Schulz, Alison K. Cardenas, Georgina Meneses-Lorente, Adrian Roth, Sabine Fürst-Recktenwald. Studies in human bone cell co-cultures reveal a potential mechanism underlying bone fractures in children treated with entrectinib and suggest a positive association with vitamin D [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 B029.
Abstract A079 Mechanisms of chemotherapy resistance in rhabdomyosarcoma
Authors: Sabateeshan Mathavarajah, Yueyang Wang, Yun Wei, Diego Antelo, David M. Langenau
Journal: Cancer Research (2024)

Abstract Background: Rhabdomyosarcoma (RMS) is a childhood cancer that originates from soft tissue and shares features with skeletal muscle. RMS patients are treated with a combination of radiation, surgical resection, and chemotherapy (VAC; vincristine, actinomycin D and cyclophosphamide). Unfortunately, 30% of patients eventually develop relapsed tumors due to resistance to VAC or radiation, of whom have an abysmal 17% five-year survival rate. To date, the mechanisms underlying resistance to VAC is poorly understood in RMS tumors, which are desperately needed for devising new therapeutic avenues to target VAC chemoresistance and improve the outcomes for these patients. Methods: We have recently generated long-term VAC-resistant RMS cell lines (from RD and Rh41 parental lines) to model chemoresistance. These cell lines were acclimated to high dose VAC over a 3-month period. Afterwards, single clones were isolated from these chemoresistant cell lines and assessed for upregulation of the PIK3CA/AKT/ABC transporter pathway by Western blot analysis. Results: We find that within the pool of resistant clones, there are two distinct pathways that are upregulated to promote VAC-resistance, one that elevates the PIK3CA/AKT/ABC transport pathway to rapidly efflux drugs from RMS cells. Astonishingly, this same drug resistance pathway is activated in both fusion-positive and fusion-negative RMS. The upregulated ABC transporters are well known drug efflux pumps and include ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP. We next show that the increased transcription of these ABC transporters occurs through an AKT-dependent mechanism – akin to that described by our group for an investigational chemotherapy that combines DNA damaging agent temozolomide with Olaparib PARP-inhibitor (OT). Using an inhibitor of PIK3CA signaling, Alpelisib, we show that we can resensitize these chemoresistant cell lines to VAC and OT. Conclusions: VAC-resistance occurs in part through PIK3CA/AKT signaling to promote drug efflux. The PIK3CA/AKT pathway can be therapeutically targeted to resensitize tumors to VAC. Future studies will focus on determining the mechanisms of drug resistance in tumors that fail to upregulate the PIK3CA/AKT/ABC transport pathway. Citation Format: Sabateeshan Mathavarajah, Yueyang Wang, Yun Wei, Diego Antelo, David M. Langenau. Mechanisms of chemotherapy resistance 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 A079.
Abstract A081 Biomarker-driven targeting of NAD metabolism in rhabdomyosarcoma
Authors: Juan C. Vasquez, Prateek Bhardwaj, Sophia Zhao, Katelyn Noronha, Karlie Lucas, Ranjini Sundaram, Collin Heer, Raffaella Morotti, Josh Spurrier, Ranjit S Bindra
Journal: Cancer Research (2024)

Abstract Introduction/Background: New treatments are needed to improve survival in rhabdomyosarcoma (RMS). Cells primarily synthesize nicotinamide adenine dinucleotide (NAD+) through the Preiss-Handler and Salvage pathways driven by nicotinic acid phosphoribosyltransferase (NAPRT) and nicotinamide phosphoribosyltransferase (NAMPT), respectively. NAMPT inhibitors (NAMPTi) have been tested in clinical trials, but their efficacy has been limited by lack of appropriate biomarkers for patient selection. Here, we sought to determine if RMS harbors NAPRT silencing that confers a synthetic lethal interaction with NAMPTi. Methods: NAPRT expression was evaluated by immunohistochemistry (IHC) in human tumor samples. In vitro cell viability assays were performed in RMS cell lines using a panel of NAMPT inhibitors. RMS cells isogenic for NAPRT expression were generated via overexpression or CRISPR/Cas9 KO. For in vivo experiments, orthotopic tumor-bearing mice were treated with vehicle control or OT-82 at 25 mg/kg/dose by oral gavage with or without nicotinic acid (NA) at 25 mg/kg/dose once daily for 3 days per week. Results: In vitro, NAPRT negative isogenic RMS cells showed an exquisite sensitivity to a panel of NAMPT inhibitors. When NA was supplemented to model physiologic conditions, NAPRT+ cells were rescuved while cells harboring loss of NAPRT remained sensitive. In vivo, NAMPTi treatment induced significant tumor regression and improved survival in a NAPRT null RMS xenograft model even in the presence of NA, while NAPRT+ tumors did not response to NAMPTi when combined with NA supplementation. IHC staining in a collection of RMS tissue microarrays obtained from the Children’s Oncology Group demonstrated loss of NAPRT protein expression in roughly 25% of tumors.Conclusion: Overall, these data suggest that NAPRT loss may serve as a therapeutic target in RMS by inducing a synthetic lethal interaction with NAD+ depleting agents. Future studies will determine if NA supplementation can mitigate toxicity and widen the therapeutic index, paving the way for the development of biomarker-driven clinical trials in RMS. Citation Format: Juan C. Vasquez, Prateek Bhardwaj, Sophia Zhao, Katelyn Noronha, Karlie Lucas, Ranjini Sundaram, Collin Heer, Raffaella Morotti, Josh Spurrier, Ranjit S Bindra. Biomarker-driven targeting of NAD metabolism 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 A081.
Abstract B008: Decoding the primary site-specific regulation of rhabdomyosarcoma metastasis
Authors: Katie E. Hebron, Kristine Isanogle, Elijah F. Edmondson, Amy James, Simone Difilippantonio, Marielle E. Yohe
Journal: Cancer Research (2024)

Abstract The prognosis for patients with high-risk rhabdomyosarcoma (RMS), a pediatric sarcoma characterized in part by defective skeletal muscle (myogenic) differentiation, has remained stagnant at &amp;lt;30% for over forty years. With &amp;gt;15% of patients presenting at diagnosis with metastasis, a defining factor of high-risk disease, there is an urgent need for new therapies. Some primary tumor locations are associated with a higher incidence of metastasis and poorer outcomes. However, the biology (and potential for therapeutic intervention) driving this prognostic factor is poorly defined.To analyze the influence of the primary tumor location on RMS invasion and metastasis, we evaluated cell line xenografts (CDX) implanted in a favorable site, the tongue, versus an unfavorable site, the hindlimb. We evaluated invasion and metastasis from each primary tumor site by histopathology and measured gene expression changes by bulk RNAseq.Despite the tongue being deemed a favorable primary site, perineural invasion or intravascular tumor emboli (60% versus 0%), sentinel lymph node metastasis (25-100% versus 0%), and clinically significant lung metastases (&amp;gt;10% lung area or symptomatic mice; 20% versus 0%) were observed more frequently in tongue xenograft-bearing mice than hindlimb xenograft-bearing mice. The expression of myogenic differentiation markers is higher in tongue CDX than in hindlimb CDX, but expression of these markers is reduced upon metastasis. These phenotypes are maintained when cells are returned to 2D culture, suggesting a stable shift in the differentiation state. Interestingly, CDX of sentinel lymph node metastasis-derived cells were more invasive and metastatic than parental CDX when implanted in the tongue, but not when implanted in the hindlimb.Our work, the first direct evaluation of RMS invasion and metastasis by primary tumor location, demonstrates that the primary tumor location influences RMS metastasis and that tumor cell-intrinsic properties alone are insufficient to increase invasion and metastasis. Ongoing work aims to identify the mechanisms by which the primary tumor microenvironment regulates invasion, enhancing our understanding of the biology of RMS metastasis and offering an opportunity to employ a precision medicine-based approach to targeting metastasis. Citation Format: Katie E. Hebron, Kristine Isanogle, Elijah F. Edmondson, Amy James, Simone Difilippantonio, Marielle E. Yohe. Decoding the primary site-specific regulation of rhabdomyosarcoma metastasis [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 B008.
Abstract B069: ACCESS: Advancing childhood cancer experience, science and survivorship in Canada
Authors: Stephanie A. Grover, Christine J. Williams, Adrienne Co-Dyre, David Malkin, James A. Whitlock, on behalf of the ACCESS consortium
Journal: Cancer Research (2024)

Abstract In Canada, roughly 1,500 children and adolescents are diagnosed with cancer each year. Advocacy for enhanced childhood cancer research and care in Canada by patients, families and the academic community led to a $23M investment through the Canadian Institutes of Health Research to establish a national pediatric cancer consortium (termed ‘ACCESS’). ACCESS’ mission is to ensure every child with cancer in Canada has access to the latest scientific advances, diagnostic tools, therapies, and supportive care leading to better outcomes and quality of life. ACCESS is a unique collective of scientists, healthcare providers, industry leaders, partner organizations, advocates, patients, and their families who are conducting research, changing policy, and developing new tools to ensure better lives for children who experience cancer in Canada and for their loved ones. The goal is to implement transformative change in the delivery of fair, fast, effective, and safe cancer care for all children. ACCESS is driven and led by people with lived experience of pediatric cancer and framed by the patient journey. In its first year, ACCESS has unified a national community. It has: connected a community of more than 700 people and stimulated a culture of open communication in which diverse viewpoints, including those of people with lived experience of cancer, are sought and valued; built productive and effective partnerships to connect and leverage the work of organizations working to improve childhood cancer; initiated 20 new innovative pan-Canadian research studies that impact all aspects of the patient journey, including new Canadian-led clinical trials; developed an educational hub for all ACCESS members, and produced accessible communications materials such as webinars, a newsletter and a comprehensive website; developed national best practice standards and tools for research and care; started to address the complex policy, regulatory and practical barriers that prevent equitable access to cancer diagnosis and treatment for all children in Canada.Future priorities include development of a national data system for pediatric cancer, modernizing pediatric clinical trials to reduce barriers to participation in Canada, and the development of a national strategy for pediatric cancer. Citation Format: Stephanie A. Grover, Christine J. Williams, Adrienne Co-Dyre, David Malkin, James A. Whitlock, on behalf of the ACCESS consortium. ACCESS: Advancing childhood cancer experience, science and survivorship in Canada [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 B069.
Abstract A038 Plasma exosome concentrations in healthy canines and dogs with osteosarcoma
Authors: Jaron M. Magstadt, Courtney H. Labé, Meagan Wojtysiak, Kyle DuVal, Ali Khammanivong, Lauren J. Mills, Amber Winter, Caitlin Feiock, Kelly Reid, Mitzi Lewellen, Logan G. Spector, Brenda J. Weigel, Jaime F. Modiano, Kelly M. Makielski
Journal: Cancer Research (2024)

Abstract Canine osteosarcoma is a common disease that shares many clinical and biological features with human osteosarcoma. We have previously demonstrated the potential of using mRNA signatures derived from exosome cargo to detect minimal residual disease in dogs undergoing treatment for osteosarcoma. Our goal is to continue exploring the potential of exosomes in cancer diagnosis and treatment by understanding how exosomes contribute to the biology of osteosarcoma. For this study, we compared exosome concentrations in the plasma of 26 healthy dogs and 29 dogs with various cancers, including 8 dogs with osteosarcoma. Dogs with cancer had higher exosome concentrations than the healthy dogs (p=0.0007), as did the subset of dogs with osteosarcoma. Specifically, the average exosome concentration in the samples from healthy dogs was 5x1011 (+/-2.72x1011) particles/mL, with a normal distribution ranging from 7.22x1010 to 1x1012, whereas the average exosome concentration in the samples from dogs with osteosarcoma was 1.14x1012 (+/-1.41x1012) particles/mL, with a non-parametric distribution ranging from 1.16x1011 to 4.4x1012. Ongoing work includes expanding the data set with archival samples, as well as evaluating potential relationships between exosome concentrations and disease-free survival in dogs with osteosarcoma. In conclusion, the difference in plasma exosome concentrations between healthy dogs and dogs with osteosarcoma, and specifically the heterogeneous distribution of exosomes in the plasma of dogs with osteosarcoma suggests that this could be one feature used in combination with analyses of exosome cargo to aid in prognosis and manage treatment of patients with osteosarcoma. Citation Format: Jaron M. Magstadt, Courtney H. Labé, Meagan Wojtysiak, Kyle DuVal, Ali Khammanivong, Lauren J. Mills, Amber Winter, Caitlin Feiock, Kelly Reid, Mitzi Lewellen, Logan G. Spector, Brenda J. Weigel, Jaime F. Modiano, Kelly M. Makielski. Plasma exosome concentrations in healthy canines and dogs with 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 A038.
Abstract B078: Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Faye M. Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana Karam, Natalie J. Serkova, Nicholas K. Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan A. Dahl
Journal: Cancer Research (2024)

Abstract Background: Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated promoter proximal pause-release of Pol II is a conserved regulatory mechanism for synchronous transcriptional induction best described in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Design/Method: In order to examine the dynamics of chromatin reorganization following radiotherapy, we performed a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma (DIPG) and other pediatric high-grade gliomas (pHGG) following IR exposure. We interrogated IR-induced gene expression in the presence or absence of PTEFb blockade, including both mechanistic and functional consequences of concurrent inhibition or genetic depletion. We utilized culture models with live cell imaging to assess the therapeutic synergy of PTEFb inhibition with IR, as well as the therapeutic index of this intervention relative to normal controls. Finally, we employed orthotopic models of pHGG treated with conformal radiotherapy and CNS-penetrant PTEFb inhibitors in order to assess tolerability and anti-tumor effect in vivo. Results: Rapid genome-wide redistribution of active chromatin features and PTEFb facilitates Pol II pause-release to drive nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb imparts a transcription elongation defect, abrogating canonical adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival.Conclusion: These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies. Citation Format: Faye M. Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana Karam, Natalie J. Serkova, Nicholas K. Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan A. Dahl. Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [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 B078.
Abstract IA021: Neogenes induced by oncogenic chimeric transcription factors as potential targets for therapy
Authors: Floriane Petit, Ana Lalanne, Céline Collin, Joshua Waterfall, Olivier Lantz, Olivier Delattre
Journal: Cancer Research (2024)

Abstract We recently showed that oncogenic chiemeric transcription factors (OCTF) of various pediatric cancers induce the expression of highly tumor-specific long intergenic non coding RNAs which are not expressed in normal tissues and which we called neogenes. Since recent reports indicate that such LincRNA may not be as non-coding as initially thought we sought for potential peptides encoded by these neogenes. Using the EWSR1::FLI1 chimera of Ewing sarcoma as a paradigm of such chimeras and through Riboseq profiling and whole cell proteomics we indeed show that some of these neogenes encode peptides. Immunopeptidomic experiments were performed on a series of Ewing sarcoma cell lines and PDX and further showed that peptides encoded by Ewing-specific neogenes are associated with MHC-Class I molecules at the surface of Ewing cells. Ewing peptide-specific CD8 T-cells were isolated from healthy donors. We show that these cytotoxic T-cells can be activated by Ewing cells to secrete cytokins, They can also kill Ewing cells. This killing is specific for the MHC-Class I types, specific for Ewing sarcoma cells as compared to other tumor types and is strictly deendent upon the expression of EWSR1::FLI1 that regulates the neogenes and of the expression of the neogene encoding the peptide. These data support the idea that OCTF-specific neogenes may constitute an interesting resource for various immunotherapy approaches including vaccination, BiTE or TCR-T-cell therapy. Citation Format: Floriane Petit, Ana Lalanne, Céline Collin, Joshua Waterfall, Olivier Lantz, Olivier Delattre. Neogenes induced by oncogenic chimeric transcription factors as potential targets for therapy [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 IA021.