tbuckley/cabot-search huggingface dataset:
Tumor cells generate astrocyte-like cells that contribute to SHH-driven medulloblastoma relapse
Authors: Duancheng Guo, Yuan Wang, Yan Cheng, Shengyou Liao, Jian Hu, Fang Du, Gang Xu, Yongqiang Liu, Kathy Q. Cai, Martin Cheung, Brandon J. Wainwright, Q. Richard Lu, Yi Zhao, Zeng-jie Yang
Journal: The Journal of Experimental Medicine (2021)

Astrocytes, a major glial cell type in the brain, play a critical role in supporting the progression of medulloblastoma (MB), the most common malignant pediatric brain tumor. Through lineage tracing analyses and single-cell RNA sequencing, we demonstrate that astrocytes are predominantly derived from the transdifferentiation of tumor cells in relapsed MB (but not in primary MB), although MB cells are generally believed to be neuronal-lineage committed. Such transdifferentiation of MB cells relies on Sox9, a transcription factor critical for gliogenesis. Our studies further reveal that bone morphogenetic proteins (BMPs) stimulate the transdifferentiation of MB cells by inducing the phosphorylation of Sox9. Pharmacological inhibition of BMP signaling represses MB cell transdifferentiation into astrocytes and suppresses tumor relapse. Our studies establish the distinct cellular sources of astrocytes in primary and relapsed MB and provide an avenue to prevent and treat MB relapse by targeting tumor cell transdifferentiation.
Abstract 1581: Nammisomes: Preclinical validation of a platform for selective and synchronized delivery of novel immunotherapy prodrug combinations to tumors
Authors: David R. Stover, Dhruba Bharali, Tahmineh Safaie, Bruce A. Hay, Rajesh K. Sharma, Scott Ayers
Journal: Cancer Research (2021)

Abstract The approval of checkpoint inhibitors, CAR-T cell therapies, and other immunotherapies has led to a significant improvement in cancer patient survival rates over the past 7 years. However, the pace of improvement has slowed lately as the field moves beyond the minority of patients with immune primed or accessible cancers. It is generally expected that rationale combinations of immunotherapies that provide mechanisms to both induce as well as maintain the immune responses in the face of tumor-derived immune checkpoint mediators, will be required to effectively treat these patients. Systemic exposure to such combinations often can give rise to severe toxicity profiles that limit their therapeutic efficacy. Nammisomes are an innovative and unique platform designed to deliver novel immune modulating prodrugs more selectively and synchronously to the tumor site. The immune active agents are conjugated to lipids to create prodrugs that self-assemble into a liposomal bilayer. By mixing multiple prodrugs at the desired ratio, co-formulations are produced with the optimum stoichiometry. These Nammisomes are iv injected and selectively enter tumors through the leaky vasculature within tumors, while remaining in circulation in normal tissues with intact blood vessels, The enriched phagocytic activity in tumor environments causes the release of the active agents within tumors relative to normal tissues limiting systemic exposure and toxicities. Preclinical efficacy and safety data of Nammisomes delivering combinations of a TLR agonist and a checkpoint inhibitor showing anti-tumor efficacy and tolerability in syngeneic mouse models will be presented. In summary, Nammisomes will be highlighted as a combination therapeutic modality to demonstrate the potential of this approach in anti-cancer therapy. Citation Format: David R. Stover, Dhruba Bharali, Tahmineh Safaie, Bruce A. Hay, Rajesh K. Sharma, Scott Ayers. Nammisomes: Preclinical validation of a platform for selective and synchronized delivery of novel immunotherapy prodrug combinations to tumors [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 1581.
T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model
Authors: Heather P. Llewellyn, Seda Arat, Jingjin Gao, Ji Wen, Shuhua Xia, Dalia Kalabat, Elias Oziolor, Richard Virgen-Slane, Timothy Affolter, Changhua Ji
Journal: Journal of Hepatology (2021)
Abstract 2722: Reprogramming of tumor-associated macrophages to M1-like macrophages using M1 macrophage-derived exosomes engineered to target IL-4 receptor and enhance M1 polarization
Authors: Byungheon Lee, Gowri Rangaswamy Gunassekaran
Journal: Cancer Research (2021)

Abstract Tumor-associated macrophages (TAMs) are M2-polarized protumoral macrophages, whereas inflammatory macrophages are M1-polarized antitumoral macrophages. Interleukin-4 receptor (IL-4R) is expressed in M2 macrophages at higher levels than M1 macrophages. In this study, we aimed to inhibit tumor growth using M1 macrophage-derived exosomes engineered to target IL-4R and reprogram TAMs into M1 macrophages. M1 exosomes were transfected with NF-κB p50 siRNA and miR-511-3p as cargoes to enhance M1 polarization (Exo-si/mi) and surface-modified with IL4RPep-1, an IL-4R-binding peptide, to target IL-4R of M2 macrophages (IL4R-Exo-si/mi). The engineered exosomes showed sizes similar with parental exosomes, and IL4RPep-1 was retained on the exosomes and not degraded in the presence of serum up to 24 h. IL-4R-targeted exosomes were internalized into M2 macrophages and delivered cargoes through IL-4R more efficiently than untargeted exosomes. Whole-body fluorescence imaging showed that IL-4R-targeted exosomes homed to tumors at higher levels than to liver unlike to untargeted exosomes. Intravenous administration of IL4R-Exo-si/mi decreased the levels of M2 markers and immune-suppressive cells including TAMs, while increasing the levels of M1 markers and immune-stimulatory cells including M1 macrophages in tumor and spleen and subsequently inhibited tumor growth more efficiently than Exo-si/mi as well as M1 exosomes. These results suggest that IL-R-targeted exosomes carrying NF-κB p50 siRNA and miR-511-3p inhibit tumor growth by reprogramming TAMs into M1 macrophages and increasing anti-tumor immunity and hold a potential for caner immunotherapy. Citation Format: Byungheon Lee, Gowri Rangaswamy Gunassekaran. Reprogramming of tumor-associated macrophages to M1-like macrophages using M1 macrophage-derived exosomes engineered to target IL-4 receptor and enhance M1 polarization [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 2722.
Xpert® bladder cancer monitor and bladder epicheck® in the follow up of patients affected by intermediate risk non muscle invasive bladder cancer (nmibc): Preliminary data
Authors: C. D’Elia, E. Trenti, D.M. Folchini, S. Pycha, C. Mian, C. Schwienbacher, E. Hanspeter, A. Pycha
Journal: European Urology (2021)
Abstract 622: Gene panel-based immune profiling of human cancers
Authors: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2021)

Abstract It is now well accepted that patients with inflamed tumors are more likely to benefit from immunotherapies targeting immune checkpoints such as CTLA4, PD1 and PD-L1.Several factors determine a tumor's immune status and identifying patients who may benefit from immunotherapy and determining which immune therapy to administer depends largely on the patient's tumor immunophenotype. We have developed an approach for immunoprofiling using a focused gene set (115 genes) and scoring system that assesses cell specific types and immune functions. This approach was developed in a preclinical cancer models and is being evaluated and tested in human cancers. We previously extracted data for the gene set and employed unsupervised network clustering to differentiate and classify cancer samples of patients from The Cancer Genome Atlas (TCGA) into immunologically distinct clusters. Here continue or examination and overview clinical features associated with individual clusters. A total of 8477 patients from the TCGA research network were profiled which included 28 solid cancer types. A total of 10 immune clusters (IC 1-10) were identified with a median cluster size of 971 patients with sizes ranging from 178 to 1570. All cancer types were represented in the ICs with mostly normal distribution except for IC 6 which was composed of 40% breast cancer patients and IC10 of which 1/5 of the cases were head-neck squamous cell carcinomas. ICs 2, 5 and 8 were associated with the poorest survival with median times at 73, 51 and 65 months, respectively. Conversely, patients in IC 9 experienced the longest overall survival, median time 148 months. The aggregate inflammation score, which measures overall tumor inflammation was positively correlated to overall survival (P=0.0109). IC 9 was correlated with the highest survival times and was positively associated with primary signatures related antitumor immunity such as high IFN gamma, cytotoxicity, and CD8 T cell and NK cell signatures. IC 8 was characterized with poor survival times and was associated with signatures related with immunosuppressive cells including granulocytic myeloid derived suppressor cells, M2 polarized macrophages and TH17 T cells, and an adenosine high signature. In addition, cases from this cluster also had low CTL signatures. Our findings show that gene expression data from a focused gene and our scoring algorithm could be used to differentiate and classify patients into various groups of immunologically distinct tumors types. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Gene panel-based immune profiling of human cancers [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 622.
A multi-modal delivery strategy for spinal cord regeneration using a composite hydrogel presenting biophysical and biochemical cues synergistically
Authors: Weitao Man, Shuhui Yang, Zheng Cao, Jiaju Lu, Xiangdong Kong, Xiaodan Sun, Lingyun Zhao, Yi Guo, Shenglian Yao, Guihuai Wang, Xiumei Wang
Journal: Biomaterials (2021)
Abstract 2285: The capability of <i>NTRK</i> fusion detection by next-generation sequencing/FISH/IHC in 25976 solid tumor patients
Authors: Yuan Peng, Hui Chen, Xiaochen Zhao, Zhijun Han, Yuezong Bai
Journal: Cancer Research (2021)

Abstract Purpose: Despite the low prevalence of oncogenic neurotrophin receptor kinase (NTRK) fusion among most solid tumors, the encouraging results of tropomyosin receptor kinase (Trk) inhibitors such as larotrectinib and entrectinib have prompted the screening of eligible patients. Here, we aimed to report the prevalence of NTRK fusion in the Chinese solid tumor patients and to compare NTRK fusion evaluation with targeted next-generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Methods: A total of 25976 tumor samples from Chinese solid tumor patients were collected between January 2017 and June 2020. All samples were assessed with targeted NGS in a CLIA-certified laboratory. NTRK genes fusions were confirmed by FISH (ZytoLight SPEC NTRK1/2/3 Dual Color Break Apart Probe) and/or pan-TRK IHC (clone EPR17341). Results: In total, 47/25976 (0.2%) patients harbored one or more NTRK fusions. NTRK fusions were found in 15 cancer types including thyroid (1/92, 1.1%), sarcoma (3/547, 0.5%), neuroendocrine (1/183, 0.5%), GIST (1/265, 0.4%), endometrium (1/274, 0.4%), esophagus (1/293, 0.3%), colorectum (14/4548, 0.3%), head neck (1/375, 0.3%), lung (16/8950, 0.2%), ovary (1/625, 0.2%), breast (1/706, 0.1%), biliary tract (2/1530, 0.1%), liver (2/2282, 0.1%), stomach (1/1505, 0.1%), and others (1/3801, 0.03%). Among these 47 patients, 11 were further confirmed by both FISH and IHC and 3 were confirmed only by IHC. 36.4% (4/11) of the patients had completely concordant NTRK status (NGS+/FISH+/IHC+). 45.5% (5/11) of the patients had consistency between NGS and FISH (NGS+/FISH+). 71.4% (10/14) of the patients had consistency between NGS and IHC (NGS+/IHC+). Moreover, there were two novel fusions includingTEX10-NTRK2 (NGS+/FISH+/IHC+) in head and neck cancer and PTPN22-NTRK1 (NGS+/IHC+) in ovarian cancer, which is the first case of ovarian cancer with NTRK fusion. Conclusions: NGS was effectively help to screen patients with novel or reported NTRK fusion, who may benefit from NTRK inhibitor therapy. And NGS showed good consistency with IHC. Further prospective study is needed to compare the impact of the NTRK status identified by NGS and IHC on NTRK inhibitors efficacy. Citation Format: Yuan Peng, Hui Chen, Xiaochen Zhao, Zhijun Han, Yuezong Bai. The capability of NTRK fusion detection by next-generation sequencing/FISH/IHC in 25976 solid tumor patients [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 2285.
Abstract 895: Multi-trajectory models of multiple myeloma progression among patients with monoclonal gammopathy of undetermined significance
Authors: Maira A. Castaneda Avila, Kate L. Lapane, Sharina Pearson, Jerry Gurwitz, Yanhua Zhou, Mara Epstein
Journal: Cancer Research (2021)

Abstract Background: Understanding the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma is needed to identify patients who would benefit from closer clinical surveillance. Given that two of the defining criteria of multiple myeloma are renal failure and anemia, we described the trajectories of creatinine and hemoglobin over time in patients with a diagnosis of MGUS. Methods: We analyzed data from 429 patients who were diagnosed with MGUS at a large provider group in central Massachusetts between 2007 and 2015 and were followed up through 2018. Patients diagnosed with MGUS were identified by a previously validated case-finding algorithm using health claims and electronic health record data. Group-based trajectory modeling was used to identify groups of patients with distinct laboratory value trajectories of creatinine (mg/dL) and hemoglobin (mg/dL). Results: The study sample was mostly non-Hispanic white (85.1%) with a mean age of 75 years at MGUS diagnosis. Three multi-trajectory groups were identified. Patients in Group 1 (54.3%) and Group 2 (43.1%) had increasing serum levels of creatinine and decreasing levels of hemoglobin over time, with group 2 having higher increments. Group 3 (2.6%) patients had increasing levels of creatinine and stable low levels of hemoglobin. Patients with MGUS in group 2 were older, less likely to have a prior cancer diagnosis, and had fewer comorbidities than other groups. Twenty-one patients (4.9%) developed multiple myeloma during the study period, with incidence proportions of 0.5%, 1.5%, and 1.6%, respectively for patients in groups 1, 2, and 3. Conclusion: The data suggest that certain subpopulations of patients with MGUS can be characterized by biomarker trajectories over time. Future research should further investigate how these trajectories may be related to risk of progression to multiple myeloma. Citation Format: Maira A. Castaneda Avila, Kate L. Lapane, Sharina Pearson, Jerry Gurwitz, Yanhua Zhou, Mara Epstein. Multi-trajectory models of multiple myeloma progression among patients with monoclonal gammopathy of undetermined significance [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 895.
Association of resilience and perceived stress in patients with alopecia areata: A cross-sectional study
Authors: Jane J. Han, Sara J. Li, Cara J. Joyce, Laura J. Burns, Kiana Yekrang, Maryanne M. Senna, Justin M. Ko, Kathie P. Huang, Arash Mostaghimi
Journal: Journal of the American Academy of Dermatology (2021)
Abstract LB091: Long-term statin use and risk of colorectal cancer: A prospective cohort study
Authors: Yin Zhang, Andrew T. Chan, Jeffrey A. Meyerhardt, Edward L. Giovannucci
Journal: Cancer Research (2021)

Abstract Importance Statin use has been examined as a potential chemopreventive strategy against colorectal cancer (CRC), with conflicting findings reported. Prior studies have not been able to investigate this topic with adequate follow-up time. Objective To examine prospectively the association between long-term statin use and CRC risk. Design setting and participants The Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) are large prospective cohorts of US women and men. Participants who were alive and free of cancer at the time when information on their statin use was first assessed were eligible for inclusion (100,300 women and 47,991 men), and were followed for up to 26 years (NHS: 1994-2016; HPFS: 1990-2016). Exposures Overall status and duration of statin use. Main outcome and measures Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for exposures and CRC risk. Results We documented 2,924 incident CRC cases during follow-up. In fully-adjusted analyses, compared to participants who never used statins, longer duration of statin use was associated with higher risk of overall CRC (HR, 95%CI was 1.09, 0.98-1.20 for ever use; 1.06, 0.94-1.19 for 1 to 5 years; 1.10, 0.96-1.27 for 6 to 10 years; 1.10, 0.86-1.41 for 11 to 15 years; 1.56, 1.13-2.16 for &amp;gt;15 years; vs. never users, P=.02 for trend). The risk elevation was driven by proximal colon cancer (1.22, 1.05-1.41 for ever use; 1.17, 0.99-1.39 for 1 to 5 years; 1.21, 0.99-1.48 for 6 to 10 years; 1.27, 0.91-1.78 for 11 to 15 years; 2.22, 1.49-3.30 for &amp;gt;15 years; vs. never users, P&amp;lt;.001 for trend) rather than cancers of distal colon or rectum. The results became more robust in sensitivity analyses among participants with hypercholesterolemia. Conclusion and relevance This study does not support benefit of statin use in CRC chemoprevention. Long-term statin use was associated with increased CRC risk (predominantly driven by proximal colon cancer). Citation Format: Yin Zhang, Andrew T. Chan, Jeffrey A. Meyerhardt, Edward L. Giovannucci. Long-term statin use and risk of colorectal cancer: A prospective cohort study [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 LB091.
First-in-Human Study of the Biodistribution and Pharmacokinetics of 89Zr-CX-072, a Novel Immunopet Tracer Based on an Anti–PD-L1 Probody
Authors: Laura Kist de Ruijter, Jahlisa S. Hooiveld-Noeken, Danique Giesen, Marjolijn N. Lub-de Hooge, Iris C. Kok, Adrienne H. Brouwers, Sjoerd G. Elias, Margaret T.L. Nguyen, Hong Lu, Jourik A. Gietema, Mathilde Jalving, Derk J.A. de Groot, Olga Vasiljeva, Elisabeth G.E. de Vries
Journal: Clinical Cancer Research (2021)

Abstract Purpose: CX-072, a PD-L1–targeting Probody therapeutic, is engineered to be activated by tumor proteases that remove a masking peptide. To study effects on biodistribution and pharmacokinetics, we performed 89Zr-CX-072 positron emission tomography (PET) imaging. Experimental Design: Patients received ∼1 mg, 37 MBq 89Zr-CX-072 plus 0, 4, or 9 mg unlabeled CX-072 and PET scans at days 2, 4, and 7. After that, treatment comprised 10 mg/kg CX-072 q2 weeks (n = 7) + 3 mg/kg ipilimumab q3w 4× (n = 1). Normal organ tracer uptake was expressed as standardized uptake value (SUV)mean and tumor uptake as SUVmax. PD-L1 expression was measured immunohistochemically in archival tumor tissue. Results: Three of the eight patients included received 10-mg protein dose resulting in a blood pool mean SUVmean ± SD of 4.27 ± 0.45 on day 4, indicating sufficient available tracer. Tumor uptake was highest at day 7, with a geometric mean SUVmax 5.89 (n = 113) and present in all patients. The median follow-up was 12 weeks (4–76+). One patient experienced stable disease and two patients a partial response. PD-L1 tumor expression was 90% in one patient and ≤1% in the other patients. Mean SUVmean ± SD day 4 at 10 mg in the spleen was 8.56 ± 1.04, bone marrow 2.21 ± 0.46, and liver 4.97 ± 0.97. Four patients out of seven showed uptake in normal lymph nodes and Waldeyer's ring. The tracer was intact in the serum or plasma. Conclusions: 89Zr-CX-072 showed tumor uptake, even in lesions with ≤1% PD-L1 expression, and modest uptake in normal lymphoid organs, with no unexpected uptake in other healthy tissues.
Abstract 1400: SWI/SNF chromatin remodeling complex regulation of YAP-dependent enhancers drives therapeutic resistance in triple-negative breast cancer
Authors: Yihao Li, Xintao Qiu, Hui Liu, Xiaoqing Wang, Renee C. Geck, Alok Tewari, Kin-Hoe Chow, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X. Liu, Alex Toker, Myles Brown
Journal: Cancer Research (2021)

Abstract Outcomes for patients with triple negative breast cancer (TNBC) remain poor despite significant advances in the treatment of other breast cancer subtypes. We report an epigenetic mechanism leading to the adaptive resistance of TNBC to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodeling leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenografts (PDX) models. Treatment-induced YAP/TEAD accessible chromatin was observed in a subpopulation of PDX cells by single cell analysis of accessible chromatin. Thus, combinatorial therapies based on the YAP and mTORC1 dependent feedback loop have the potential to improve the efficacy of FGFR inhibitors in TNBC. Citation Format: Yihao Li, Xintao Qiu, Hui Liu, Xiaoqing Wang, Renee C. Geck, Alok Tewari, Kin-Hoe Chow, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X. Liu, Alex Toker, Myles Brown. SWI/SNF chromatin remodeling complex regulation of YAP-dependent enhancers drives therapeutic resistance in triple-negative breast cancer [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 1400.