bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB201: Understanding genetic variation in cancer using nanopore targeted sequencing
Authors: Iyer Shruti V. , Kramer Melissa , Goodwin Sara , McCombie W. Richard 
Published: July 2021

Abstract
Structural variations (SV), a hallmark of genomic instability in cancer can either activate oncogenes or inactivate tumor suppressor genes. SVs tend to be recurrent and have been associated with several cancer types. Next-generation sequencing (NGS) is mostly blind to large SVs, lacking sensitivity with false positive rates up to 89% in SV detection. Long-read, single-molecule sequencing platforms can address larger variations as they typically generate read lengths of tens of thousands of bases and have helped identify thousands of genomic features pertinent to cancer that were previously missed by short-read sequencing. However, the throughput and coverage offered by whole genome long read sequencing makes it infeasible to conduct large-scale genomic studies.Targeted sequencing significantly improves accuracy and coverage by offering the depth necessary to detect rare alleles in a heterogenous population of cells. Using the nanopore Cas9-targeted sequencing (nCATS), a PCR-free enrichment system from Oxford Nanopore Technologies, we targeted 10 prominent cancer genes in MCF 10A and SK-BR-3 breast cell lines. However, we observed that the number of reads generated for targets longer than 30kb were not sufficient to accurately call SVs. To further enhance this approach, we developed an Affinity-based Cas-9-Mediated Enrichment (ACME) step, that uses HisTag DynabeadsTM to pulldown non-target reads. With ACME we achieved ~ 75-fold enrichment of the BRCA2 region and 35-65x coverage of this ~90 kb target on our panel. We observed an increase in enrichment and coverage of other genes on the panel as well, with enrichment as high as 5000-fold for some genes. While ACME is a biochemical approach, recently, adaptive sequencing or “Read Until”, a computational approach that ‘rejects' non-target reads has been used by a couple of groups for target enrichment. Using UNCALLED, a variation of Read Until, we observed an ~10x coverage of our targets. Recognizing the potential and limitations of both, biochemical and computational approaches, our efforts now are directed towards a combined approach where we expect to achieve a minimum enrichment of 200-fold across all targets. With a 200-fold enrichment of a 3.5Mb target, we should get between 200x - 400x coverage of the target, which should be high enough to detect SVs in as low as 10% of the cells in the sample. This would support large scale SV analysis to help define the landscape of such variants in the population and identify regions of therapeutic or diagnostic interest.
Citation Format: Shruti V. Iyer, Melissa Kramer, Sara Goodwin, W. Richard McCombie. Understanding genetic variation in cancer using nanopore targeted sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB201.
Abstract LB215: Transglutaminase 2 maintains hepatocyte growth factor signaling to enhance the epidermal cancer stem cell phenotype
Authors: Chen Xi , Adhikary Gautam , Shrestha Suruchi , Xu Wen , Eckert Richard 
Published: July 2021

Abstract
Epidermal squamous cell carcinoma (SCC) is one of the most common cancers. Ultraviolet radiation exposure leads to DNA damage in keratinocyte stem cells leading to transformation. Epidermal cancer stem cells (ECS cells) display aggressive spheroid formation, invasion, and migration, and form rapidly growing and highly vascularized tumors. The transglutaminase 2 (TG2) cancer stem cell maintenance proteins is present at high levels in ECS cells and is required for maintenance of the ECS cell phenotype. Identifying how TG2 maintains the ECS cell phenotype is an important goal. RNA transcriptomic analysis, comparing gene expression in wild-type and TG2 knockout cells, reveals that hepatocyte growth factor (HGF) signaling is markedly reduced in TG2 knockout cells, a finding that was confirmed by showing that TG2 knockdown/knockout reduces HGF and MET mRNA and protein. HGF/MET signaling appears to play an important role in maintaining the cancer phenotype, as inhibition of HGF/MET reduces ECS cell spheroid formation, invasion and migration. Stem cell and EMT marker expression and MEK1/2 and ERK1/2 activity are also reduced. These changes phenocopy the response to TG2 knockdown. Treatment with MEK1/2 and ERK1/2 inhibitors suppresses the ECS cell phenotype indicating that MAPK signaling is a major HGF/MET target, and MET knockout reduces ECS cell tumor formation which is associated with reduced MEK1/2 and ERK1/2 activity. These findings suggest that TG2 maintains HGF/MET signaling which stimulates MEK1.2 and ERK1/2 activity to enhance the aggressive ECS cell cancer phenotype and drive tumor formation.
Citation Format: Xi Chen, Gautam Adhikary, Suruchi Shrestha, Wen Xu, Richard Eckert. Transglutaminase 2 maintains hepatocyte growth factor signaling to enhance the epidermal cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB215.
Abstract LB234: The Neuropilin-2 targeting antibody ATYR2810 inhibits non-small cell lung cancer tumor growth in monotherapy and combination therapy
Authors: Barber Alison G. , Xu Zhiwen , Rahman Justin , Goel Hira Lal , Mercurio Arthur M. , Burkart Christoph , Nangle Leslie A. 
Published: July 2021

Abstract
Lung cancer remains one of the leading cancer types and is the foremost cause of cancer-related deaths, yet treatment options for advanced lung cancer remain limited. Novel therapies targeting factors critical to the progression of lung cancer are essential. Neuropilin-2 (NRP2) acts as a co-receptor for VEGF and has been correlated with aggressive cancer growth and metastasis. The expression of NRP2 has been shown to be upregulated in several cancers, including non-small cell lung cancer (NSCLC), and the expression of NRP2 in NSCLC is associated with increased invasive tumor growth in vitro as well as a significant decrease in patient survival. As shown previously, aTyr has developed ATYR2810, a domain-specific anti-human monoclonal antibody to NRP2 which blocks its binding to VEGF. Importantly, ATYR2810 blocks VEGF binding in a highly specific manner and does not affect the binding of Semaphorin-3F or subsequent Semaphorin-3F-induced dimerization of NRP2 and PlexinA1. In this study, we have used ATYR2810 to examine the effects of blocking VEGF-mediated NRP2 signaling both as monotherapy and in combination therapy. Using in vitro 3D colony formation assays, we found that ATYR2810 used as monotherapy led to a significant reduction in colony formation in the A549 NSCLC cell line. The effects of ATYR2810 were also examined in NSCLC xenografts, where the use of ATYR2810 as a single agent was found to result in the inhibition of tumor growth. Interestingly, the tumor growth inhibition observed with ATYR2810 as monotherapy was comparable to that of cisplatin monotherapy, suggesting that ATYR2810 may be a potent inhibitor of tumor growth in the A549 xenograft model. The effects of ATYR2810 combination therapy in NSCLC xenografts was also examined, and we found that the use of ATYR2810 in combination with either 5-FU or cisplatin enhanced tumor growth inhibition as compared to the use of either chemotherapeutic agent alone. Taken together, these results suggest that NRP2 may be an important target in aggressive NSCLC and that the use of our novel ATYR2810 antibody to block VEGF-mediated NRP2 signaling may serve as a valuable therapeutic agent both as monotherapy as well as in combination therapy.
Citation Format: Alison G. Barber, Zhiwen Xu, Justin Rahman, Hira Lal Goel, Arthur M. Mercurio, Christoph Burkart, Leslie A. Nangle. The Neuropilin-2 targeting antibody ATYR2810 inhibits non-small cell lung cancer tumor growth in monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB234.
Abstract LB252: Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models
Authors: Harrison Douglas , Gill Jonathan , Hingorani Pooja , Roth Michael , Zhang Wendong , Teicher Beverly , Earley Eric J. , Erickson Stephen W. , Gatto Gregory , Kurmasheva Raushan T. , Houghton Peter J. , Smith Malcolm A. , Kolb Edward A. , Gorlick Richard 
Published: July 2021

Abstract
Background. Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with activity against all four PI3K class I isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ). Copanlisib was approved for use by the FDA in the treatment of refractory follicular lymphoma in 2017. Preclinical data have suggested that deregulation of the PI3K pathway is a key driver of multiple malignancies. The relevance of this pathway in osteosarcoma tumorigenesis remains a subject of debate, however, whole genome and RNA sequencing data have revealed several PI3K aberrations in osteosarcoma tumor samples. The in vivo effects of copanlisib were studied in the Pediatric Preclinical Testing Consortium osteosarcoma xenograft models. Methods. The in vivo anticancer effects of copanlisib were assessed in a panel of 6 osteosarcoma models (OS-2, OS-9, OS-31, OS-33, OS-36, and OS-60). Copanlisib was administered by oral gavage at a dose of 10 mg/kg/day, two days on and five days off, repeated weekly for 4 weeks. Time to event and tumor volume responses were defined and analyzed utilizing standard PPTC statistical methods. Results. Copanlisib was well tolerated in the models with minimal weight loss and no treatment related mortality as compared to controls. Copanlisib induced prolonged event-free survival (EFS) in 5/6 osteosarcoma models (p&lt;0.05, Gehan-Wilcoxon). Tumor regression (mean minimum attained relative tumor volume (minRTV) &lt; 1.0) was not observed for any of the tested models. 3/6 models exhibited lower min RTV compared to untreated controls (p &lt; 0.05, Wilcoxon rank sum). All osteosarcoma models showed progressive disease as their objective response measure. Conclusions. While copanlisib induced prolonged EFS in 5/6 osteosarcoma models, no tumor regression was seen, with all models developing progressive disease suggesting minimal activity. While copanlisib did not result in tumor regression, further study is needed to fully explore the role of the PI3K pathway in the pathogenesis of osteosarcoma.
Citation Format: Douglas Harrison, Jonathan Gill, Pooja Hingorani, Michael Roth, Wendong Zhang, Beverly Teicher, Eric J. Earley, Stephen W. Erickson, Gregory Gatto, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Edward A. Kolb, Richard Gorlick. Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB252.
Abstract LB254: PKA signaling: a friend or foe to pediatric medulloblastoma
Authors: Kaushik Itishree , Srivastava Sanjay 
Published: July 2021

Abstract
Pediatric brain tumor is the leading cause of cancer-related deaths in pediatric patients ranging 0-19 years of age. Medulloblastoma is one of the most commonly occurring brain tumor in children. Sonic hedgehog (Shh) activated subgroup of medulloblastoma is considered to be highly aggressive and metastatic in nature. Recent studies and oncomine, a cancer microarray database has shown that GABAA receptor is down regulated in pediatric medulloblastoma. In this study, we have evaluated the anti-cancer effects of an anthelminthic drug ‘moxidectin' a GABAA receptor agonist. Treatment of medulloblastoma cells with moxidectin, resulted in reduced Protein kinase A (PKA) activity. Leading to the inhibition of Gli1, a major transcription factor of non-canonical Shh signaling. Moxidectin has inhibited the proliferation of Daoy, UW426, UW228, ONS76, and PFSK1 medulloblastoma cells and significantly induced apoptosis in a concentration and time dependent manner in all the cell lines. Western blotting and immunofluorescence microscopy demonstrated that moxidectin treatment significantly induced GABAA receptor expression and inhibited cAMP mediated PKA signaling. As a result, the non-canonical activation of Gli1 and its downstream effector molecules such as Pax-6, Oct-4, Sox-2 and Nanog were also inhibited by moxidectin treatment. Efficacy of moxidectin was also evaluated in subcutaneous and intracranial medulloblastoma tumor models. Our results demonstrated that daily oral administration of 2.5 mg/kg moxidectin suppressed the growth of medulloblastoma tumors by 55-70% in subcutaneous and intracranial models. Ex-vivo analysis of tumors by western blotting, IHC, TUNEL and H&E staining revealed that moxidectin suppressed medulloblastoma tumor progression by inhibiting PKA/Gli1 signaling axis indicating the significance of this pathway in medulloblastoma progression. To our knowledge, this study for the first time focuses on GABAA receptor agonist mediated PKA/Gli1 signaling inhibition. Most importantly, moxidectin is an FDA approved drug and is already in clinical use for the treatment of river blindness in humans with an established safety record, therefore any positive findings from our studies will prompt further clinical investigation into repositioning moxidectin for the treatment of MB patients.
Citation Format: Itishree Kaushik, Sanjay Srivastava. PKA signaling: a friend or foe to pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB254.
Abstract ND02: BT7480: A completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137
Authors: Keen Nicholas J. 
Published: July 2021

Abstract
BT7480, a completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137. It is also the first example (to our knowledge) of a fully synthetic, low MW (~7.5kDa, less than 1/20th of an IgG), peptide-based approach to targeting either Nectin-4 or CD137. The costimulatory immune receptor CD137 has been recognized for its potential as a drug target in cancer alongside checkpoint inhibitors, but this promise has not been realized for patients due to toxicity (principally hepatic toxicity) and limited efficacy of current biologic based therapies. Thus, alternative approaches to this important target are warranted. Bicycles® are small, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied this disruptive technology to the problem, identifying CD137 binding Bicycles and chemically linking these to specific tumor antigen binding Bicycles to generate multifunctional “bi-specific” like molecules that induce tumor antigen dependent, tumor localized agonism of CD137. We termed these Tumor-targeted Immune Cell Agonists (TICAs™). BT7480 is a TICA that was designed to deliver highly potent CD137 agonism to Nectin-4 overexpressing tumor tissue. Nectin-4 is expressed at high levels in bladder, breast and lung tumors and at low levels in normal tissue and thus is an attractive target for localized immunotherapy. BT7480 binds potently to Nectin-4 expressing cells and engages CD137 expressed on immune cells in trans, leading to potent Nectin-4-dependent CD137 agonism in primary human PBMC/tumor cell co-culture assays. Treatment of Nectin-4 expressing tumors in immunocompetent mice with BT7480 induces complete tumor regressions and subsequent resistance to tumor re-challenge. Time-course examination of the treated tumors revealed a unique mechanism of action - rapid activation of myeloid cells (&lt;24h) concomitant with a pulse of secretion of chemokines and cytokines peaking at 2-3 days, leading to a dramatic infiltration of cytotoxic T-cells on days 4-5. This is distinct from the reported behavior of checkpoint inhibitors such as PD1/PDL1 inhibitors. In the presentation we will describe the discovery work that led to the identification of BT7480, including a crystal structure of the CD137/Bicycle complex (the first reported low molecular weight ligand of this receptor), chemical optimization and structure of the molecule, it's PK and PD behavior, preliminary safety data and route to the clinic.
Citation Format: Nicholas J. Keen. BT7480: A completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND02.
Abstract NG10: A metastasis map of human cancer cell lines
Authors: Jin Xin , Demere Zelalem , Nair Karthik , Ali Ahmed , Ferraro Gino B. , Natoli Ted , Deik Amy , Petronio Lia , Tang Andrew A. , Zhu Cong , Wang Li , Rosenberg Danny , Mangena Vamsi , Roth Jennifer , Chung Kwanghun , Jain Rakesh K. , Clish Clary B. , Heiden Matthew G. Vander , Golub Todd R. 
Published: July 2021

Abstract
Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical due to the inherent scale limitation of the in vivo models. Here we introduce an in vivo barcoding strategy capable of determining the metastatic potential of human cancer cell lines in murine xenografts at scale. We validated the robustness, scalability and reproducibility of the method, and applied it to 500 cell lines spanning 21 solid cancer types. We created a first-generation Metastasis Map (MetMap) that reveals organ-specific patterns of metastasis and allows relating those patterns to clinical and genomic features. We demonstrated the utility of MetMap by exploring the molecular basis of breast cancers capable of metastasizing to the brain - a principal cause of death in these patients. Breast cancers that were brain metastatic had unexpected genetic, expression, and metabolic evidence of altered lipid metabolism. Perturbing lipid metabolism curbed brain metastasis development and limited the outgrowth of cancer cells in the brain, suggesting a therapeutic strategy to combat the disease. These results illustrated the utility of MetMap as a step towards next-generation approach for high-throughput metastasis research.
Citation Format: Xin Jin, Zelalem Demere, Karthik Nair, Ahmed Ali, Gino B. Ferraro, Ted Natoli, Amy Deik, Lia Petronio, Andrew A. Tang, Cong Zhu, Li Wang, Danny Rosenberg, Vamsi Mangena, Jennifer Roth, Kwanghun Chung, Rakesh K. Jain, Clary B. Clish, Matthew G. Vander Heiden, Todd R. Golub. A metastasis map of human cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG10.
Abstract SY22-02: Personalized cancer vaccines: Antigen selection and translation into the clinic
Authors: Bhardwaj Nina 
Published: July 2021

Abstract
Personalized cancer vaccination targets specific cancer mutations of the individual patient's tumor, also referred to as neoantigens. Such “bespoke” vaccines are now being tested in multiple cancers and in combination with checkpoint inhibitors. This session will discuss our computational methods for antigenic epitope prediction, antigen selection (personalized and shared neoantigens derived from frame-shift mutations), validation in vitro and in vivo and future directions for the field.
Citation Format: Nina Bhardwaj. Personalized cancer vaccines: Antigen selection and translation into the clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY22-02.
Abstract 101: The Tanzanian Pediatric Cancer Network: A Comprehensive Evaluation of the Incidence of Presenting Patients and Access to Pediatric Cancer Care in Tanzania
Authors: Maillie Luke , Mutagonda Alice , Chirande Lulu , Rehema Laiti , Jumanne Shakilu , Meleki Elton , Serventi Furaha , Alloyce Julius , Afyusisye Franco , Sanchez Sebastian , Sisk Matthew , Voeten Marie Jose , Kawira Ester , Joas Heronima , Scanlan Trish , Schroeder Kristin 
Published: July 2021

Abstract
Purpose: In sub-Saharan Africa, cancer treatment facilities are often scarce and centered in urban areas, which means many patients must travel long distances to reach cancer care. Still, little is known about how this distribution of cancer centers impacts patients' ability to access care.
Methods: Records of all pediatric patients (&lt;18yo) treated for cancer in Tanzania in 2019 through the Tanzanian Pediatric Cancer Network were reviewed. This network represents all 9 hospitals currently treating children with cancer in Tanzania. Demographic and diagnostic information was recorded. ArcGIS was used to estimate patients' travel times from home addresses to cancer care. AccessMod was used to calculate 4-hour access for the population.
Results: In 2019, a total of 821 pediatric patients were diagnosed with cancer with an incidence of 1.42/100,000 population. The most common diagnoses were Wilms tumor (17.2%, n=134), retinoblastoma (16.8%, n=131), and acute lymphoblastic leukemia (15.9%, n=124). There was regional variation by diagnosis, with the Lake Zone having the highest incidence of Burkitt lymphoma (0.29; average 0.15) and retinoblastoma (0.5; average 0.33). Reported regional incidence inversely correlated to distance to cancer treatment facility. Median travel time to cancer care for patients was 4.55 hours. Currently 74.5% of the population lives within 4 hours of existing cancer care facilities, and it would require adding cancer care capacity to 8 additional facilities to reach 95% coverage.
Conclusions: This is the first comprehensive evaluation of the incidence of presenting pediatric cancer patients in Tanzania. Only 18.8% of the estimated pediatric patients with cancer in Tanzania were treated in 2019. The reported incidence was lower in areas further away from treatment centers, suggesting the importance of increased access to cancer care facilities as part of a future national scale-up strategy.
Citation Format: Luke Maillie, Alice Mutagonda, Lulu Chirande, Laiti Rehema, Shakilu Jumanne, Elton Meleki, Furaha Serventi, Julius Alloyce, Franco Afyusisye, Sebastian Sanchez, Matthew Sisk, Marie Jose Voeten, Ester Kawira, Heronima Joas, Trish Scanlan, Kristin Schroeder. The Tanzanian Pediatric Cancer Network: A Comprehensive Evaluation of the Incidence of Presenting Patients and Access to Pediatric Cancer Care in Tanzania [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 101.