bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2007: Use of an anti-IL-10 antibody to improve Mifamurtide efficacy on aggressive osteosarcoma cells
Authors: Nastasi Nicoletta , Subbiani Angela , Taddei Maria Letizia , Scala Lucia , Tamburini Angela , Favre Claudio , Calvani Maura 
Published: June 2022

Abstract
Osteosarcoma is a primary malignant bone tumor highly aggressive and metastasizing, composed of mesenchymal cells producing osteoid and immature matrix. Osteosarcoma is the most frequent bone tumor and it mainly affects children and adolescents. The main treatment option is a combination of surgery and chemotherapy. Research into new therapeutic strategies to improve the quality of life of patients is currently underway. The development of the anti-tumor immunostimulant drug Mifamurtide is part of this research. There are very conflicting opinions on the therapeutic validity of this drug. Therefore, we tested experimentally the effectiveness of Mifamurtide in three cell lines of osteosarcoma (MG-63, HOS, 143B) with different grades of malignancy, grown in co-culture with macrophage to allow the correct internalization of the drug. Through in vitro experiments, we analyzed the effects of Mifamurtide on tumor cell viability, on cellular signaling pathway and on macrophage polarization. Results show that Mifamurtide loses its effectiveness as the tumor malignity increases. The most aggressive tumor cells are not affected by the therapy, probably because they implement methods of resistance to apoptosis. Furthermore, they would be able to affect the tumor microenvironment to their own advantage. To better understand Mifamurtide impact on tumor microenvironment, we also performed a cytokine assay on the culture medium in which the cells grew. The most significant results were identified in the interleukine-10 (IL-10): IL-10 is expressed in higher quantities in the highest-grade osteosarcoma cells. This anti-inflammatory cytokine can inhibit the synthesis of pro-inflammatory cytokine and suppresses the antigen presentation capacity of APC cells. This allows cancer cells to evade immune surveillance mechanisms. In vivo and in vitro results show that the synergic use of an anti-IL-10 antibody in combination with Mifamurtide can improve its efficacy. Here, we provide experimental evidence that the addition of an anti-IL-10 antibody to Mifamurtide causes a significant death rate in more aggressive osteosarcoma cells and lower metastasis, compared to Mifamurtide only. In conclusion, considering our data, it could be proposed a new treatment protocol for metastatic osteosarcoma that includes the use of an anti-IL10 antibody integrated with the administration of Mifamurtide to increase its effectiveness in this clinical context.
Citation Format: Nicoletta Nastasi, Angela Subbiani, Maria Letizia Taddei, Lucia Scala, Angela Tamburini, Claudio Favre, Maura Calvani. Use of an anti-IL-10 antibody to improve Mifamurtide efficacy on aggressive osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2007.
Abstract 2025: Spatial transcriptomic profiling of progression markers in clear cell renal cell carcinoma
Authors: Mo Chia-Kuei , Wu Yige , Nadezhda Terekhanova , Wagma Caravan , Lal Preet , Chen Siqi , Deen Nataly Naser AL , Liu Ruiyang , Zhao Yanyan , Sato Kazuhito , Yao Lijun , Serasanambati Mamatha , Shinkle Andrew , Jayasinghe Reyka G. , Ding Li , Chen Feng 
Published: June 2022

Abstract
Next-generation sequencing enabled molecular landscaping and the discovery of novel tumor markers in ccRCC. However, the spatial relationships and histological features of the tumor microenvironment were lost during this process. Combining snRNA-seq, snATAC-seq, Spatial Transcriptomics (ST) technology, and immunofluorescence labeling, we discovered novel ccRCC progression tumor markers, and uncovered their spatial dependent expression pattern in both human ccRCC tumors and patient-derived xenograft (PDX). Using snRNA-seq and snATAC-seq, novel tumor progression markers such as NDRG1, MGST1, ABCC3 and PCSK6 were discovered, and their expressions were validated in ST. We found that one of the key novel tumor markers, CP, exhibited specific spatial expression patterns on tissue slides. The elevation of CP expression region is associated with a higher degree of hyalinization in ccRCC human tumor samples. Similarly, using immunofluorescence labeling, we validated the co-expression of CP and PCSK6 canonical ccRCC marker CA9. Overall, this study revealed novel ccRCC progression markers and linked their spatial expression pattern with histological features.
Citation Format: Chia-Kuei Mo, Yige Wu, Terekhanova Nadezhda, Caravan Wagma, Preet Lal, Siqi Chen, Nataly Naser AL Deen, Ruiyang Liu, Yanyan Zhao, Kazuhito Sato, Lijun Yao, Mamatha Serasanambati, Andrew Shinkle, Reyka G. Jayasinghe, Li Ding, Feng Chen. Spatial transcriptomic profiling of progression markers in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2025.
Abstract 2036: Multi-omic dissection of immunotherapy response groups in non-small cell lung cancer (NSCLC)
Authors: Kulasinghe Arutha , Monkman James , Kim Honesty , Mayer Aaron , Mehdi Ahmed , Matigian Nicholas , Cumberbatch Marie , Bhagat Milan , Ladwa Rahul , Mueller Scott , Adams Mark , O'Byrne Ken 
Published: June 2022

Abstract
Immunotherapies have led to long term benefits in a subset of non-small cell lung cancer (NSCLC) patients. Developing predictive biomarkers of response to therapy is currently an unmet clinical need. The composition of the cellular content of the tumour microenvironment (TME) is an important characteristic driving treatment resistance. In this study, we utilised spatial transcriptomics methods, including Nanostring digital spatial profiling (DSP) and multiplex IHC, to define the tumour/stroma (compartment) specific proteome and transcriptome from a cohort of 2nd line immunotherapy treated NSCLC patients. We identified by mIHC that CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in immunotherapy resistant tumours (p=0.012). Moreover, IL2 mRNA (p=0.001) in the stromal compartment was significantly increased in patients that were sensitive to ICI therapy, whilst CTLA-4 and IDO-1 were suppressed in responsive patients. Tumour compartment localised CD44 was depleted in the responder group and corresponded inversely with higher stromal expression of one of its ligands, SPP1 (p=0.008). Orthogonal validation of CD44 by multiplex immunofluorescence confirmed both its association with response and localisation to tumour cells rather than immune cell infiltrate. Cox survival analysis showed that tumour compartment CD44 expression was associated with a poorer prognosis (HR=1.61, p=0.01) whilst stromal localisation of CTLA-4 (HR=1.78, p=0.003) and ARG1 (HR=2.37, p=0.01) were associated with poorer outcome. Through a multi-omics approach, we demonstrate the utility of spatial mapping of NSCLC tumours and provide evidence for the role of a number of compartment-specific biomarkers which may aid in identifying those likely to respond to immunotherapy.
Citation Format: Arutha Kulasinghe, James Monkman, Honesty Kim, Aaron Mayer, Ahmed Mehdi, Nicholas Matigian, Marie Cumberbatch, Milan Bhagat, Rahul Ladwa, Scott Mueller, Mark Adams, Ken O'Byrne. Multi-omic dissection of immunotherapy response groups in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2036.
Abstract 2043: The role of CCL20 in response to radiation in head and neck squamous cell carcinomas
Authors: Rutihinda Cleopatra , Oweida Ayman J. , Delage Patrick , Moreau Léanie , Chelighem Safia , Saidi Nour Elhouda 
Published: June 2022

Abstract
Background: Radioresistance is responsible for most cases of tumor progression and recurrence in head and neck squamous cell carcinomas (HNSCC). Combined radiotherapy (RT) and immunotherapy (IT) treatment has improved survival for a minority of patients with inflamed tumors or tumors susceptible to RT-induced inflammation. To enhance the response of radioresistant tumors to radiation, an understanding of the factors that suppress anti-tumor immunity is necessary. In this regard, regulatory T cells (Tregs) are critical mediators of immune suppression in HNSCCs and their depletion improves tumor response to RT. In this study, we investigated how radiation modulates Treg infiltration through the chemokine CCL20. We hypothesized that radiation induces CCL20 secretion resulting in Treg infiltration and suppression of anti-tumor immunity and that blocking CCL20 could lead to improved response to RT.
Methods: Human (Cal27, SCC9) and mouse (MOC1, MOC2) cell lines with different immune phenotypes were irradiated at doses of 2Gy or 10Gy. Conditioned media (CM), RNA and protein were collected for the assessment of CCL20. qPCR was used to determine CCL20 gene expression. In vivo, MOC2 cell were were implanted into the right buccal cavity of mice and the effect of neutralizing CCL20 antibody was determined alone and in combination with RT. Blood samples were collected before and after RT for the analysis of serum levels of CCL20. Tumor samples were analyzed by flow cytometry to determine immune infiltrates, including CD8 T cells and Tregs.
Results: Cal27 and MOC2 tumors had a gene signature associated with immunosuppression and Treg infiltration whereas SCC9 and MOC1 tumors displayed a gene signature associated with an inflamed microenvironment. In vitro, high-dose radiation significantly induced CCL20 in Cal27 and MOC2 cells relative to control. Multiplex analysis of chemokines from conditioned media samples showed that induction of CCL20 was associated with increased secretion of GM-CSF by MOC2 and Cal27 cells. In vivo, inhibition of CCL20 alone resulted in a significant decrease in tumor growth compared to control in MOC2 tumors. The combination of RT and anti-CCL20 showed a significant decrease in tumor volume compared to RT alone.
Conclusion: Our data suggests that high-dose radiation promotes the induction of CCL20 secretion by tumor cells which is responsible for attraction of Tregs. Inhibition of CCL20 secretion using anti-CCL20 antibodies can slow down tumor growth and enhance the response to radiation.
Citation Format: Cleopatra Rutihinda, Ayman J. Oweida, Patrick Delage, Léanie Moreau, Safia Chelighem, Nour Elhouda Saidi. The role of CCL20 in response to radiation in head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2043.
Abstract 2067: NL-201, a de novo engineered IL2/IL15 mimic, synergizes with radiation to generate potent antitumor immunity
Authors: Li Xuefeng , Huntoon Kristin , Wang Yifan , Walkey Carl , Kim Betty Y. , Jiang Wen 
Published: June 2022

Abstract
There is a growing interest in combining radiotherapy (RT), a standard of care treatment for many cancer types, with immunotherapeutic agents to improve efficacy. One such approach is RT in combination with high-dose recombinant interleukin 2 (IL-2), which elicits anti-tumor immune responses by stimulating T-cell and NK cell populations. Although effective for some patients, the overall clinical benefit of high-dose recombinant IL-2 is limited by toxicity and the expansion of regulatory T cells (Tregs) through signaling events mediated by IL2RΑ (CD25).
In this study, we examined RT in combination with NL-201, a highly potent and stable CD25-independent IL-2 and IL-15 receptor agonist with enhanced affinity for IL2RΒ and IL2RΓ. Single-agent NL-201 was well-tolerated in mice, yielded tumoricidal activity, expanded peripheral T cells, and enhanced the infiltration of effector T cells and dendritic cells (DCs) into murine breast cancers. In combination with RT, NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, resulting in increased type I interferon (IFN) production in DCs and, consequently, greater tumor infiltration by T cells and more efficient priming of antigen-specific T cells by professional antigen-presenting cells (APCs). The immune stimulatory mechanisms triggered by the NL-201 and RT combination resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic murine breast cancers, including those spread to the central nervous system. Genetic knockout of STING in host cells abrogated the activity of the NL-201 and RT combination, thus confirming the crucial role of innate immune sensors in the combination treatment’s antitumor responses. Additionally, when combined with PD-1 antibodies, NL-201 significantly improved growth inhibition of metastatic breast cancers that were previously resistant to checkpoint blockade.
We demonstrated that the CD25-independent IL-2 and IL-15 receptor agonist, NL-201, in combination with RT is well-tolerated and elicits robust anti-tumor activity through both innate and adaptive responses, including in checkpoint resistant tumors and brain metastases. Furthermore, we identify a unique mechanism in which NL-201 synergizes with RT, likely via the direct activation of STING in DCs. Taken together, the results provided herein support further preclinical and clinical investigation of this novel combination regimen in both localized and metastatic settings.
Citation Format: Xuefeng Li, Kristin Huntoon, Yifan Wang, Carl Walkey, Betty Y. Kim, Wen Jiang. NL-201, a de novo engineered IL2/IL15 mimic, synergizes with radiation to generate potent antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2067.
Abstract 2124: ATRA mediated inhibition of myeloid-derived suppressor cells overcomes resistance to immune checkpoint inhibition in murine models of LKB1-deficient non-small cell lung cancer
Authors: Crosson William P. , Li Rui , Salehi-Rad Ramin , Lim Raymond J. , Abascal Jensen W. , Kahangi Bitta P. , Reyes Edgar Perez , Dumitras Camelia , Jing Zhe , Krysan Kostyantyn , Tran Linh M. , Liu Bin , Dubinett Steven M. 
Published: June 2022

Abstract
Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of patients harbor somatic mutations in both Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes. LKB1 loss has been identified as a driver of primary resistance to ICI therapy. Tumors from patients that possess these mutations are characterized by an increase in the population of myeloid derived suppressor cells (MDSCs). MDSCs are thought to play a critical role in promoting tumor progression by blocking the tumor killing function of cytotoxic T cells in the tumor microenvironment (TME). Our studies revealed all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized murine models of non-small cell lung cancer (NSCLC) with LKB1 and KRAS co-mutations to PD-1 blockade. Combination therapy with anti-PD-1 and ATRA improved local and systemic T cell proliferation and generated systemic tumor-specific immunity. We observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models. We demonstrated that ATRA suppresses tumor growth through the inhibition of immunosuppressive MDSCs in the TME, and preliminary data indicates that ATRA increases intracellular reactive oxygen species (ROS) and IFN signaling in MDSC. Our findings implicate MDSCs as a potential mediator of immunosuppression in Lkb1-deficient NSCLC and provide a rationale for utilizing ATRA in combination with anti-PD-1 therapy in patients with Lkb1-deficient NSCLC refractory to ICIs.
* B. Liu and S. M. Dubinett contributed equally to this work
Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen W. Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Camelia Dumitras, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Bin Liu, Steven M. Dubinett. ATRA mediated inhibition of myeloid-derived suppressor cells overcomes resistance to immune checkpoint inhibition in murine models of LKB1-deficient non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2124.
Abstract 2135: Targeting N-Myc in neuroblastoma cells with selective Aurora kinase A degraders
Authors: Tang Jian , Moorthy Ramkumar , Demir Ozlem , Baker Zachary D. , Naumann Jordan A. , Jones Katherine F. , Grillo Michael J. , Haefner Ella , Shi Ke , Levy Michaella J. , Aihara Hideki , Harris Reuben S. , Amaro Rommie E. , Levinson Nicholas M. , Harki Daniel A. 
Published: June 2022

Abstract
Overexpression of the MYCN proto-oncogene is one of the strongest biomarkers for poor prognosis in neuroblastoma patients. N-Myc, encoded by MYCN, is a highly attractive yet “undruggable” target in neuroblastoma drug discovery. N-Myc is a short-lived protein in normal neuronal progenitor cells; however, in MYCN-amplified neuroblastoma cells, overexpressed N-Myc is stabilized by high levels of Aurora kinase A (Aurora-A). Several Aurora-A allosteric modulators have been developed to disassociate N-Myc binding and promote its degradation. These compounds function through a competitive mechanism against N-Myc, and clinical trial results suggest limited efficacy in high-risk neuroblastoma patients where N-Myc is highly expressed. To develop Aurora-A modulators with greater effects in destabilizing N-Myc, targeted degradation of Aurora-A was investigated in this study. First, we developed a highly selective Aurora-A-binding ligand by chemically modifying ribociclib, which targets CDK4/6. Next, a series of potent Aurora-A/N-Myc degraders were developed using proteolysis targeting chimaera (PROTAC) technology. Our lead compound, HLB-0532259, was found to substantially decrease N-Myc levels in neuroblastoma cells following the degradation of Aurora-A with nanomolar potency. Mechanistic studies suggest that HLB-0532259 binds to Aurora-A in an uncompetitive manner with respect to N-Myc, which contributes to its high potency for degrading the Aurora-A/N-Myc pool. Mass spectrometry analysis demonstrates that HLB-0532259 possesses remarkable proteome-wide selectivity for Aurora-A and N-Myc degradation. Further studies have revealed that HLB-0532259 exhibits nanomolar cytotoxicities against a panel of MYCN-amplified neuroblastoma cells, good pharmacokinetic properties, and favorable therapeutic outcomes in a xenograft neuroblastoma mouse model. Taken together, our data strongly support HLB-0532259 as a promising lead compound for neuroblastoma therapy.
Citation Format: Jian Tang, Ramkumar Moorthy, Ozlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F. Jones, Michael J. Grillo, Ella Haefner, Ke Shi, Michaella J. Levy, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki. Targeting N-Myc in neuroblastoma cells with selective Aurora kinase A degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2135.
Abstract 2147: Synthetic lethality of VRK1 in VRK2-methylated cancers
Authors: So Jonathan , Mabe Nathaniel , Englinger Bernhard , Kwon Jason , Shim Brian , Filbin Mariella , Stegmaier Kimberly , Hahn William 
Published: June 2022

Abstract
Paralogs are a source of synthetic lethal interactions which lend themselves to novel bio-marker linked targeted therapeutics. From genome-wide essentiality measurements in over 900 cancer cell lines, we find VRK1 dependency in VRK2-methylated adult and pediatric gliomas and neuroblastomas. VRK2 methylation was mainly seen in IDH-mutant gliomas and H3.3-G34R-mutant DIPG. Knockout of VRK2 was able to sensitize cells to VRK1 knockout. Overexpression of kinase-active but not kinase inactive VRK2 rescued VRK1 knockout. Global phosphoproteomics in VRK1 and VRK2 knockout cells demonstrate increased phosphorylation of targets involved with DNA damage and decreased phosphorylation of nuclear membrane targets. VRK1 and VRK2 were found to phosphorylate BANF1, which is involved in nuclear membrane re-formation during mitosis. Taken together, we show that VRK1 is a viable target in VRK2-methylated adult and pediatric gliomas, and neuroblastomas.
Citation Format: Jonathan So, Nathaniel Mabe, Bernhard Englinger, Jason Kwon, Brian Shim, Mariella Filbin, Kimberly Stegmaier, William Hahn. Synthetic lethality of VRK1 in VRK2-methylated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2147.
Abstract 2148: Pre-clinical models recapitulating the spectrum of response of BRCA associated pancreatic cancer
Authors: Golan Talia , Stossel Chani , Raitses-Gurevitch Maria , Atias Dikla , Beller Tamar , Gallinger Steven , Berger Raanan 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease, with the majority of patients diagnosed at an advanced stage. Comprehensive genomic analysis identified the homologous recombination deficiency (HRD) subgroup which is predominantly enriched in patients harboring germline BRCA1/2 mutations (glBRCA) and presents ~7% and up to 15% in selected high-risk populations. Tumors with HRD are susceptible to DNA-damaging agents and PARP inhibition. However, not all patients demonstrate a similar response, and a spectrum is observed. We analyzed the clinical outcome of ninety-one glBRCA PDAC patients treated at Sheba Medical Center. We identify three main subgroups of response spanning from ~25% patients refractory to first line platinum agents and ~9% patients with durable long-term response with no evidence of disease for over three years. The majority of the patients display a prolonged response to platinum and PARPi maintenance (&gt;24 months) followed by acquired resistance. We generated patient derived xenograft (PDX) models and an ex-vivo culture system (EVOC) from naïve to treatment tissue and at clinical resistance. In vivo efficacy to platinum agents and PARPi demonstrates that these models recapitulate the specific clinical spectrum of response. We demonstrate the utility of both pre-clinical models in their ability to predict response to platinum-based agents and PARPi, with EVOC having a potential to assist in medical decisions while treating the patient. Whole genome sequencing of the tumors revealed that BRCA monoallelic tumors are associated with innate resistance while biallelic tumors reflect sensitivity to platinum agents and PARPi. In the acquired resistance models, the main identified mechanism of resistance was due to reversion mutations in 4/6 of samples. Whole genome analysis demonstrates high mutational and neo-antigen load in majority of the glBRCA tumors. In a preliminary study, we show the efficacy of anti PD1 in a novel humanized glBRCA PDAC PDX model. This extensive preclinical and clinical collection of BRCA associated PDAC, enables further understanding and investigation of this unique subtype in aim to develop alternative treatments to overcome resistance.
Citation Format: Talia Golan, Chani Stossel, Maria Raitses-Gurevitch, Dikla Atias, Tamar Beller, Steven Gallinger, Raanan Berger. Pre-clinical models recapitulating the spectrum of response of BRCA associated pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2148.