bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3480: Potential impact of voluntary exercise on patterns of metastasis in a colorectal cancer model
Authors: Wijler Liza A. , Raats Daniëlle A. , van Dijk Miriam , May Anne M. , Kranenburg Onno 
Published: September 2020

Abstract
Background: Physical activity (PA) is associated with a lower risk of colorectal cancer (CRC) initiation and death from CRC. However, evidence for a causal link between PA and disease progression is lacking. This study assesses the effect of voluntary exercise on metastases formation in a novel pre-clinical mouse model for late-stage metastatic CRC.
Methods: Murine colorectal tumor organoids were transplanted into the livers of immunocompetent C57Bl/6 mice using microsurgery. Animals were fed ad libitum. Voluntary exercise in tumor-bearing (TB) mice was modeled by offering running wheels for 0h/day (n=12), 3h/day (n=12) or 24h/day (n=12). Running wheel revolutions were cumulatively measured every 30min. PA was monitored by infrared cameras. Tumor progression was monitored using in vivo Bioluminescent Imaging. Food intake was measured by weighing. Body composition was monitored by echoMRI. All animals were sacrificed 12 weeks after tumor initiation.
Results: We have developed a novel model for exploring the effects of exercise on metastatic tumor progression in CRC. The model combines micro-surgical transplantation of tumor organoids, yielding spontaneously metastasizing CRC, with voluntary exercise. Voluntary exercise in both exercise groups led to an on average running distances of 2,3±0,3 km/night (total 221±29 km) in TB-3h animals and 6,6±3,0km/night (total 600±290km) in TB-24h animals. TB-3h and TB-24h animals developed more lean mass and lower fat mass compared to sedentary animals. Intermittent exercise had no effect on primary tumor growth and reduced metastasis. Vigorous exercise increased primary tumor growth (229606±186012) compared to TB-3h (152821±125902) and sedentary animals (165171±250993). Moreover, vigorous exercise non-significantly increased lung metastasis formation (2382±3539) compared to intermittent exercise (753±852) and to sedentary (1333±2902), while reducing metastatic spread to the liver and the peritoneal cavity was found.
Conclusions: These results suggest that exercise has the potential to influence the patterns and extent of metastasis in CRC, and that the degree of exercise is likely to be an important variable. Confirmation of these results in additional models, for instance using patient-derived organoids, is now warranted.
Citation Format: Liza A. Wijler, Daniëlle A. Raats, Miriam van Dijk, Anne M. May, Onno Kranenburg. Potential impact of voluntary exercise on patterns of metastasis in a colorectal cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3480.
Abstract 4582: Tumor matrix-targeted polymeric glyco-adjuvant for in situ cancer vaccination
Authors: Gray Laura T. , Wilson D. Scott , Ishihara Jun , Sasaki Koichi , Raczy Michal , Swartz Melody , Hubbell Jeffrey 
Published: September 2020

Abstract
Cancer vaccination is challenging due to a lack of strong, clinically approved adjuvants and difficulty in identifying cancer-specific antigens. Here, in order to address these challenges, we report the creation of a targeted therapeutic cancer vaccine with two components: (1) a mannosylated, toll-like receptor 7 (TLR7)-agonizing polymer, p(Man-TLR7), and (2) a fusion protein consisting of serum albumin (SA) fused to a collagen binding domain (CBD), namely the A3 domain of von Willebrand factor. p(Man-TLR7) has been shown to elicit strong CD8+ T cell responses, which are vital for the success of cancer vaccines. As such, we hypothesized that chemically linking p(Man-TLR7) to a tumor-targeting protein would localize our polymeric glyco-adjuvant to the tumor, promoting the immunogenic processing of endogenous tumor antigens and bypassing the need to pre-identify tumor-specific antigens. In the approach presented here, CBD-SA acts as our tumor-targeting protein by actively binding to collagen in the tumor microenvironment via the CBD, in addition to utilizing the passive targeting of SA. Upon successful and reproducible generation of CBD-SA-p(Man-TLR7) conjugates, we observed that the conjugates retained the ability to bind both collagen I and collagen III. We then assessed the in vivo anti-tumor efficacy of our conjugates in B16F10 tumor-bearing mice, testing both murine CBD-SA-p(Man-TLR7) and human CBD-SA-p(Man-TLR7) conjugates to evaluate the translatability of our approach. We observed an 84% decrease in average B16F10 tumor size and improved overall survival compared to untreated controls when mice were treated with intravenously-delivered murine CBD-SA-p(Man-TLR7) in combination with anti-PD-1 and anti-CTLA-4 antibodies. In the case of intravenously-delivered human CBD-SA-p(Man-TLR7), a 60% decrease in average tumor size compared to untreated controls was observed when mice were treated with our vaccine as a monotherapy. Further improved anti-tumor efficacy (an 85% decrease in average tumor size compared to untreated controls) and improved overall survival were observed when we combined our human CBD-SA-p(Man-TLR7) vaccination with anti-PD-1 and anti-CTLA-4 antibodies. In conclusion, in situ vaccination with CBD-SA-p(Man-TLR7) is a translatable approach that synergizes with checkpoint antibody therapy to provide therapeutic benefit in treatment of a poorly immunogenic melanoma model.
Citation Format: Laura T. Gray, D. Scott Wilson, Jun Ishihara, Koichi Sasaki, Michal Raczy, Melody Swartz, Jeffrey Hubbell. Tumor matrix-targeted polymeric glyco-adjuvant for in situ cancer vaccination [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4582.
Abstract 5236: Complete response to selpercatinib (LOXO-292), a highly selective RET inhibitor, in a patient with RET fusion-positive breast cancer
Authors: Takeda Masayuki , Watanabe Satomi , Rothenberg S. Michael , Kherani Jennifer , French Pearl P. , Olek Elizabeth 
Published: September 2020

Abstract
Background: Activating RET gene fusions have been reported in diverse solid tumors but &lt;0.1% of breast cancers. Selpercatinib (LOXO-292), an investigational, highly selective and potent small molecule RET kinase inhibitor, has demonstrated significant anti-tumor activity in diverse RET fusion-positive solid tumor patients in an ongoing clinical trial (LIBRETTO-001, NCT03157128). Here we describe the first patient with RET fusion-positive breast cancer treated with selpercatinib.
Case summary: A 46-year-old Japanese woman presented with FDG-avid right axillary, right neck and mediastinal lymphadenopathy on PET-CT imaging. Ultrasound identified a hypoechoic nodule in the right breast; biopsy revealed malignant cells, ER(+), PgR(-), and HER2(-). She was diagnosed with stage IV adenocarcinoma of the right breast. Genomic testing results of a lymph node specimen identified a CCDC6-RET fusion with no other reported alterations, including none in BRCA1 or BRCA2. Consistent with local standard of care, she received treatment with tamoxifen plus goserelin from March through June 2019, but these were discontinued for progression in the right breast and new lesions in the left lower lung. Re-biopsy revealed that the molecular biology changed into triple-negative at the time of progression. On 10-Jul-19 she started treatment with selpercatinib at the recommended Phase 2 dose of 160 mg twice daily in the ongoing Phase 1/2 trial of selpercatinib. She experienced rapid clinical improvement, with resolution of right breast and neck pain and erythema. Spiral CT imaging on 31-Jul-2019 and 4-Sep-2019 demonstrated a partial response by RECIST 1.1 (tumor reductions -30% and -30%), with reduction in multiple right breast masses, axillary, neck and mediastinal lymphadenopathy and left lung metastases; repeat imaging on 30-Oct-19 demonstrated a complete response. At the time of this writing, she remains in response and on treatment for &gt;150 days, with all adverse events grades 1-2, and most recovered and none requiring dose interruption or modification.
Conclusion: Selpercatinib demonstrated anti-tumor activity in a patient with RET fusion-positive breast cancer. To our knowledge, this is the first report of a breast cancer patient with a sustained response to selective, RET-targeted therapy and adds to the diversity of RET fusion-positive tumor types that may benefit from selective RET inhibition.
Citation Format: Masayuki Takeda, Satomi Watanabe, S. Michael Rothenberg, Jennifer Kherani, Pearl P. French, Elizabeth Olek. Complete response to selpercatinib (LOXO-292), a highly selective RET inhibitor, in a patient with RET fusion-positive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5236.
Abstract 5471: CNSigs: An R package for the identification of copy number signatures
Authors: Tallman David , Stockard Sinclair , Weber Zachary T. , Asad Sarah , Collier Katharine , Adams Elizabeth , Bey Jerome , Stover Daniel G. 
Published: September 2020

Abstract
Copy number aberrations (CNAs) are gains and losses of large genomic segments present across most cancer types and are a hallmark of cancer genomic alterations. However, the processes underlying CNAs and characteristic patterns of CNAs are poorly understood. Using single nucleotide variant (SNV) data, bioinformatic advances have identified underlying mutational signatures resulting from distinct mutational processes. Mutational signatures have led to a variety of discoveries, several of which are being investigated in clinical management of cancer. The development of algorithms able to uncover similar signatures for CNAs, rather than SNVs, is still in its infancy. Here we present an analysis package for the R programming language called CNSigs that allows for the robust and reproducible derivation of copy number signatures. Based on a list of extracted copy number features previously verified in ovarian cancer, we utilize mixed model approaches and non-negative matrix factorization to derive CNA signatures across cancer types. The development of a package to derive signatures from copy number data allows further investigation of underlying processes that may be responsible for these CNA fingerprints. To verify the reproducibility of the signatures, we derived signatures from two independent breast cancer datasets that use distinct copy number segmentation approaches. From these independent datasets we were able to recover the same signatures with high accuracy. We identified five signatures that are distinct from known breast cancer receptor-based or expression-based subtypes, yet reveal unique associations with underlying mutations, mutational processes, and transcriptional programs. To validate robustness, we applied the pipeline to 11 different cancer types from the TCGA dataset and showed that we were able to derive signatures from all of these cancer types of varying sample sizes. We identified certain signatures that cut across tumor types, while others are distinct to individual cancers. This work lays the groundwork for further analysis into the underlying molecular processes leading to these copy number signatures seen across cancer types. The CNSigs package also allows researchers to easily analyze their own samples to look for signatures in their copy number profiles and to compare these to signatures previously derived for their cancer type.
Citation Format: David Tallman, Sinclair Stockard, Zachary T. Weber, Sarah Asad, Katharine Collier, Elizabeth Adams, Jerome Bey, Daniel G. Stover. CNSigs: An R package for the identification of copy number signatures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5471.
Abstract 5542: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, enhances immune mediated tumor killing and induction of immunogenic cell death
Authors: Ferrari Nicola , Ward George , Munck Joanne , Jueliger Simone , Davis Matthew , Gewinner Christina , Ferraldeschi Roberta , Lyons John , Sims Martin John 
Published: September 2020

Abstract
Introduction: ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor receptor superfamily mediated cell death and enhance anti-tumor immune responses. Herein, we describe the profile of ASTX660 in a range of preclinical tumor models and evaluate ASTX660's ability to enhance immune mediated killing of tumor cells, both in vitro and in vivo.
Methods: ASTX660 was tested in a panel of human and mouse tumor cell lines, assessing proliferation, apoptosis and immunogenic cell death (ICD). ASTX660 was tested alone or with recombinant Death Receptor ligands. Additionally, we used a novel co-culture system of tumor cell lines with anti-CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement along with induction of apoptosis and ICD markers were analysed by Western blotting and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilised to evaluate the efficacy of ASTX660 in the presence or absence of an effective immune response.
Results: ASTX660 antagonised IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels and disruption of the XIAP:SMAC protein complex. In murine T cell lymphoma cell lines ASTX660 treatment was associated with an increase in apoptosis and ICD. In immunocompetent mice, administration of ASTX660 delivered a complete regression of BW5147 tumor growth which was not seen in mice deficient in T and B cells. To confirm human relevance, ASTX660 also enhanced anti-CD3 stimulated PBMC-dependent killing of tumour cell lines.
Conclusion: The combination of the direct effects of ASTX660 on tumor cells and ASTX660 dependent effects on immune responses adds to the description of ASTX660's mode of action and our ongoing understanding of the clinical efficacy in T cell Lymphoma(1). Reference: A Hollebecque et al. 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Citation Format: Nicola Ferrari, George Ward, Joanne Munck, Simone Jueliger, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin John Sims. ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, enhances immune mediated tumor killing and induction of immunogenic cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5542.
Abstract 5652: Dual CD73 enzyme blocker to reverse immune suppression
Authors: Yuan Jijun 
Published: September 2020

Abstract
Abstract:
CD73 is a cell surface enzyme that converts adenosine monophosphate to adenosine, a well-known immunosuppressive mediator that inhibits the cytotoxic function of T cells and natural killer cells. Tumors utilize this mechanism to escape attack by the immune system. Many attempts were made to antagonize the enzyme activity of CD73, including antibody drugs and small molecules. However, most current CD73 enzyme blockers were screened against tumor membrane CD73 and focused only on the membrane format of CD73. Our recent findings show that not only the membrane enzyme on tumor cells, but also the soluble format of CD73 shed off by tumor cells play important roles in generating immunosuppressive adenosine. To reverse the immune suppression exerted by CD73, both the membrane and the soluble format need to be blocked. We screened hundreds of anti-CD73 antibodies against soluble CD73 presented in tumor patient (CRC/LC/HCC/Melanoma) serum, and two candidates GB7002-01 and GB7002-04 were selected with great inhibition potency against tumor membrane CD73 and soluble CD73 in patient serum. GB7002-01/04 exhibited superior T cell proliferation promoting abilities in immune suppressive environment. To be precise, GB7002-01/04 totally reversed the T cell proliferation suppressive effects of pathological concentration of AMP. Moreover, this release of immune suppression was translated to better tumor killing by PBMC in the presence of GB7002-01/04. Humanized GB7002-01/04 has been put into in vivo efficacy study, preliminary toxicity and PK study. As we are observing anti-tumor efficacy, safety, and stability of these two candidates, they are promising agents for extended clinical exploration in several cancer indications.
Citation Format: Jijun Yuan. Dual CD73 enzyme blocker to reverse immune suppression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5652.
Abstract 6209: Monocytes phagocytose neutrophil extracellular traps (NETs) and differentiate into pro-inflammatory macrophages
Authors: Saito Akira , Ozawa Hideyuki , Takahashi Kazuya , Kimura Yuki , Tojo Mineyuki , Kumagai Yuko , Kanamaru Rihito , Tsukui Hidenori , Sata Naohiro , Kitayama Joji 
Published: September 2020

Abstract
Background: Macrophages are multipurpose phagocytes with various functions. Neutrophil extracellular traps (NETs) are web-like structures ensnare microbes which were composed of dsDNA, histones, and antimicrobial peptides. NETs are generally degraded by DNAse and macrophages, however, it is unknown how the degradation of NETs affects the local immune response thereafter. Here, we investigated the interaction between NETs and peripheral blood monocytes (PBMo).
Method: 5 × 105 Polymorphonuclear leukocytes(PMNs), PMNs irradiated with UV for 15 minutes (UV-PMN) and PMNs stimulated by PMA for 15min and extensively washed (PMA-PMN) were placed on 6 well plate and cultured for 2 hours and NETs formation was visualized by SYTOX green. Peripheral blood was obtained from healthy volunteers and CD14+ PBMo were purified by positive selection using the magnetic cell separation system. The PBMo were co-cultured with those PMNs at 37°C in 5% CO2 conditions for 3 days. The differentiation of macrophage was evaluated by the expression of M1/M2 markers by flowcytometry. Cytokine production was evaluated using the Cytokine Array system. The macrophages were co-cultured with autologous T cells stimulated with anti-CD3 mAb and the effect on T cell proliferation was evaluated with CFSE dilution assay.
Results: PMA-PMN, but not PMN or UV-PMN, produced massive SYTOX(+) NETs within 2 hours. Co-culture of the NETs with PBMo stained with PKH26 showed NETs are phagocytosed by monocytes within 24 hours. PBMo co-cultured with PMA-PMN showed significantly enhanced expression of CD86, and reduced expression of CD163 as compared to those co-cultured with PMNs or UV-PMN. However, the expression of CD86 was suppressed if PMA-PMN were pretreated with 100 u/ml DNase I. The supernatant of the co-culture with PMA-PMN showed markedly increased levels of IL-1β and TNF-α. PBMo co-cultured with PMA-PMN strongly promote the proliferation of autologous T cells. However, the enhanced T cell growth were significantly suppressed by the pretreatment of NETs with DNase I.
Conclusion: Monocytes appear to differentiate to proinflammatory macrophages after the phagocytosis of NETs. In tumor-bearing host, NETs are known to be increased in circulating blood, which may promote tumor associated inflammatory process.
Citation Format: Akira Saito, Hideyuki Ozawa, Kazuya Takahashi, Yuki Kimura, Mineyuki Tojo, Yuko Kumagai, Rihito Kanamaru, Hidenori Tsukui, Naohiro Sata, Joji Kitayama. Monocytes phagocytose neutrophil extracellular traps (NETs) and differentiate into pro-inflammatory macrophages [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6209.
Abstract 6213: Extracellular vesicles MDM2-DNA derived from dedifferentiated liposarcoma induces MMP2 production from preadipocytes
Authors: Casadei Lucia , Calore Federica , Deshmukh Ameya , Zewdu Abeba , Fadda Paolo , Braggio Danielle , Wabitsch Martin , Croce Carlo M. , Lev Dina , Pollock Raphael 
Published: September 2020

Abstract
Dedifferentiated liposarcoma (DDLPS) is molecularly characterized by wt p53 and MDM2 gene amplification causing MDM2 protein over-production, the key oncogenic process in DDLPS. Commonly located in fat-bearing retroperitoneal areas, almost 60% of DDLPS patients undergo multifocal recurrence, typically amenable to palliative treatment only, and occasionally develop distant metastasis. These factors lead to an abysmal 10% 10 year overall survival rate. Tumor cell-derived extracellular vesicles (EVs) can facilitate loco-regional malignancy dissemination by depositing molecular factors that participate in the development of pre-metastatic niches for tumor cell implantation and growth. High number of MDM2 DNA molecules was identified within EVs from DDLPS patient serum (ROC vs normal; 0.95) as well as from DDLPS cell lines. This MDM2 DNA could be transferred to preadipocytes (P-a), a major and ubiquitous cellular component of the DDLPS tumor microenvironment (TME), with subsequent P-a production of matrix metalloproteinase 2 (MMP2), a critical component in the metastatic cascade. Since multifocal loco-regional DDLPS spreading is the main cause of the remarkably high lethality of this disease, a better understanding of the underlying oncogenic processes and their regulatory mechanisms is essential to improve the outcome of this devastating disease.
Citation Format: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Paolo Fadda, Danielle Braggio, Martin Wabitsch, Carlo M. Croce, Dina Lev, Raphael Pollock. Extracellular vesicles MDM2-DNA derived from dedifferentiated liposarcoma induces MMP2 production from preadipocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6213.