bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4457: Open science medicinal chemistry: Towards a treatment for DIPG
Authors: Cramp Sue , Hamblin Nicole , O'Meara Jeff , Edwards Aled , Roberts Owen , Bullock Alex , Brennan Paul 
Published: August 2019

Abstract
Meds4Kids Pharma (M4K)1 is pioneering an open science approach to drug discovery, focussed on the discovery and development of small molecule therapeutics for orphan paediatric cancers. M4K seeks to test the hypothesis that an open science framework can be successfully applied not only to accelerate basic science, using the collective knowledge of the scientific community at large, but also to take an innovative new drug candidate all the way from discovery and clinical proof-of-concept through to product registration, by making use of regulatory data protections and market incentives. Since late 2017, Charles River Early Discovery has been providing in kind drug discovery services to help progress these efforts, including medicinal and synthetic chemistry. The first M4K project aims to generate an orally-available, brain-penetrant therapeutic to treat the diffuse intrinsic pontine glioma (DIPG). DIPG is a rare, aggressive and uniformly fatal childhood brain cancer with a median survival time of 9-12 months and for which there are currently no effective drug treatments. The disease has been shown to be associated with mutations in the ACVR1 gene (activin A receptor, type 1) also known as ALK2 kinase. Early support for the therapeutic hypothesis that an inhibitor of ALK2 kinase would have clinical benefit in DIPG, came from in vivo studies with non-selective ALK2 kinase inhibitors, which both killed DIPG cell lines harbouring the ALK2 mutation and extended lifespan in xenograft mouse models.2 Working collaboratively with M4K and their open science partners, we have made excellent progress towards the identification of potent, selective, brain penetrant ALK2 inhibitors starting from the known inhibitor LDN-214117, previously described for FOP (fibrodysplasia ossificans progressiva).3 Our current lead compound has an excellent in vitro and in vivo profile showing high oral bioavailability and brain penetration in a mouse PK study and is progressing to proof of concept studies. In addition we are progressing with the identification of a back-up series. References: 1. https://m4kpharma.com/ 2. Carvalho et. al. Neuro-Oncology, Volume 18, Issue suppl_6, 1 November 2016, Pages vi154, https://doi.org/10.1093/neuonc/now212.639 3. Mohedas et. al., J. Med Chem, 2014, 57 (19), 7900
Citation Format: Sue Cramp, Nicole Hamblin, Jeff O'Meara, Aled Edwards, Owen Roberts, Alex Bullock, Paul Brennan. Open science medicinal chemistry: Towards a treatment for DIPG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4457.
Abstract 4463: Tumor-derived cell-free DNA from bronchoalveolar lavage fluid (BALF): A potential liquid biopsy analysis in lung cancer patients
Authors: Gong Yuhua , Zhang Xinyu , Li Chun , Wang Weiran , Ye Maosong , Zhao Yancheng , Yi Xin , Xu Yaping , Hu Qin , Guan Yanfang , Yang Ling , Xia Xuefeng , Zhou Min , Huang Jian'an , Zhang Hua , Ren Tao , Shen Qian , Wang Kai , Hou Yingyong , Zhang Xin 
Published: August 2019

Abstract
Background: Bronchoalveolar lavage (BAL) is the most common technique for sampling the components of the alveolar space. Here, we evaluated the potential use of BAL fluid (BALF) in liquid biopsy in lung cancer.
Methods: This study enrolled 56 lung cancer patients. And 57 BALF (separated supernatant and precipitate) samples and 56 peripheral blood lymphocytes samples were collected. 57 formalin-fixed Paraffin-embedded (FFPE) tissues were also obtain. We utilized a 1021-gene NGS panel in matched tissue DNA, BALF supernatant cfDNA and BALF precipitate DNA to identify somatic mutations with white blood cell DNA as a germline control.
Results: Mutations were identified in 52 (~91.22%) BALF precipitate samples and 55 (~96.49%) BALF supernatant samples, comparing to 53 (92.98%) in tumor samples. EGFR mutations were observed in 22 BALF precipitate samples and 24 supernatant samples. Among these, 23 were also identified in matched tumor samples. One BALF precipitate samples specific and two BALF supernatant samples specific EGFR mutations were confirmed by Cobas assay. In addition, gene fusions including ALK, ROS1 and RET were found in 6 tumors, 4 BALF precipitate samples and 5 supernatant samples, respectively.
In total, there were 195 mutations identified in the tumor samples, of which 147 (~75.4%) mutations were detected in the matched BALF precipitate samples, 168 (~86.1%) mutations were detected in the matched BALF supernatant samples and 145 (~74.4%) mutations were shared in three types of samples. Tumor mutation burden (TMB) were calculated, and the consistency between tissue and BALF precipitate was 90% and the consistency between tissue and BALF supernatant was 94%.
Conclusions: Liquid biopsy using BALF shown high potential to profiling genetic alterations of patients with lung cancer, which might be implemented and standardized into clinical use.
Citation Format: Yuhua Gong, Xinyu Zhang, Chun Li, Weiran Wang, Maosong Ye, Yancheng Zhao, Xin Yi, Yaping Xu, Qin Hu, Yanfang Guan, Ling Yang, Xuefeng Xia, Min Zhou, Jian'an Huang, Hua Zhang, Tao Ren, Qian Shen, Kai Wang, Yingyong Hou, Xin Zhang. Tumor-derived cell-free DNA from bronchoalveolar lavage fluid (BALF): A potential liquid biopsy analysis in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4463.
Abstract 4467: Survival of patients with microsatellite instable (MSI) metastatic colorectal cancer (mCRC) upon systemic non-immunotherapy
Authors: Wensink G. E. , Elferink M. A. , May A. M. , Mol L. , Hamers P. A. , Punt C. J. , Vink G. R. , Roodhart J. M. , Koopman M. 
Published: August 2019

Abstract
Introduction: Data on survival of patients with MSI mCRC treated with systemic non-immunotherapy are scarce, which complicates the interpretation of recent immunotherapy trials. Our study examined survival in MSI mCRC patients in a retrospective observational cohort.
Methods: We performed a study involving 186 mCRC MSI patients (n=54 from the phase 3 CAIRO, CAIRO2 and CAIRO3 trials and n=132 from The Netherlands Cancer Registry 2015 and 2016). Overall survival from diagnosis of mCRC (OS), from start of first-line (OS1) and second-line therapy (OS2) to death of any cause were examined. Progression-free survival from start of first line (PFS1) and second-line therapy (PFS2) to progression or death of any cause were examined.
Results: Of the 186 patients, 57% were females, median age 67 years, 19% had liver-only metastasis, 31% peritoneal metastasis and 23% underwent metastasectomy. In 113 patients with known BRAF status, 51% had BRAF mutated tumors. The proportion of patients receiving first, second and third-line systemic treatment was 68%, 27% and 7%, respectively. For all patients, median OS was 13.8 months (95% confidence interval [C.I.] 11.8 - 16.3). In patients receiving at least one line of treatment median OS was 15.6 months (13.8 - 19.3), OS1 was 13.9 months (11.6-16.6) and PFS1 was 6.4 months (5.5 - 9.2). In the 48 patients receiving second-line therapy, median OS was 16.5 months (13.9 - 21.5), OS2 was 6.1 months (5.4 - 9.7) and PFS2 was 2.2 months (1.9 - 4.2). Patients starting second-line treatment with a performance score of 0-1, thus eligible for CHECKMATE-142, had an OS2 of 6.7 months (5.0 - 12.1).
Discussion: A direct comparison between our cohort and the CHECKMATE-142 cohort is not possible due to key differences in the patient populations: CHECKMATE-142 patients often received more than one therapy line prior to inclusion and displayed fewer BRAF mutant tumors. However, the survival from start of second-line in our cohort of approximately 7 months is inferior to the published CHECKMATE-142 results, where median OS was not reached after a median follow-up of 1 year in the nivolumab and the nivolumab and ipilimumab cohorts.
Conclusion: We present data on systemic non-immunotherapy in the largest cohort of trial and population-based mCRC MSI patients to date. Our results suggest that immunotherapy may offer a survival benefit for mCRC MSI patients.
Citation Format: G. E. Wensink, M. A. Elferink, A. M. May, L. Mol, P. A. Hamers, C. J. Punt, G. R. Vink, J. M. Roodhart, M. Koopman. Survival of patients with microsatellite instable (MSI) metastatic colorectal cancer (mCRC) upon systemic non-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4467.
Abstract 4490: PARP inhibitor efficacy depends on CD8+ T-cell recruitment via the STING pathway in BRCA-deficient models of triple-negative breast cancer
Authors: Pantelidou Constantia , Sonzogni Olmo , Taveira Mateus De Oliveira , Mehta Anita K. , Wang Dan , Kothari Aditi , Li Michelle K. , Visal Tanvi H. , Guerriero Jennifer L. , Wulf Gerburg M. , Shapiro Geoffrey I. 
Published: August 2019

Abstract
Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8+ T cell infiltration and activation in vivo, and that depletion of CD8+ T cells severely compromises anti-tumor efficacy. Olaparib-induced T cell recruitment is mediated through activation of the STING/TBK1/IRF3 pathway in tumor and dendritic cells and is more pronounced in HR-deficient compared to HR-proficient TNBC cells. CRISPR-knockout of STING in cancer cells prevents type I IFN production and is sufficient to abolish PARP inhibitor-induced T cell infiltration in vivo. These findings elucidate a novel mechanism of action of PARP inhibitors and provide mechanistic rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC.
Citation Format: Constantia Pantelidou, Olmo Sonzogni, Mateus De Oliveira Taveira, Anita K. Mehta, Dan Wang, Aditi Kothari, Michelle K. Li, Tanvi H. Visal, Jennifer L. Guerriero, Gerburg M. Wulf, Geoffrey I. Shapiro. PARP inhibitor efficacy depends on CD8+ T-cell recruitment via the STING pathway in BRCA-deficient models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4490.
Abstract 4501: Loss of miR-21 delays myc-driven prostate cancer progression in the hi-myc transgenic mouse model
Authors: Zennami Kenji , Rafiqi Fatima , Liao Ross , Sealover Kim , Simons Brian , Sumitomo Makoto , Shiroki Ryoichi , Lupold Shawn 
Published: August 2019

Abstract
Introduction and Objectives: MicroRNA 21 (miR-21) is overexpressed in virtually all types of cancers including prostate cancer (PCa). We have previously reported that the androgen receptor (AR) induces miR-21 expression, and that elevated miR-21 is sufficient to drive PCa growth and castration resistance. However, the role of miR-21 in PCa initiation and progression has not been fully elucidated. To determine if the absence of miR-21 inhibits or delays prostate cancer incidence or progression, we crossed miR-21 KO mice with Hi-Myc mice. In this study, we identify that loss of miR-21 delays Myc-driven prostate cancer progression in the Hi-Myc transgenic mouse model.
Methods: miR-21 KO mice were backcrossed to FVB mice to generation F10. Resulting miR-21 WT or KO FVB progeny were crossed with Hi-Myc mice to generate Hi-Myc/miR-21 WT or KO mice. Prostates were harvested at 4 weeks (n=10), 3 months (n=10), 5 months (n=58), 6 months (n=25), 8 months (n=20) of age and prostate weight, histology, miR-21 expression levels and protein expression levels were quantified. Proliferation and apoptosis were examined by immunohistochemistry using Ki-67 and cleaved caspase-3.
Results: Cancerous prostates of Hi-Myc mice showed high miR-21 expression at 5m and 8m, when compared to FVB controls, suggesting high miR-21 expression in the Myc-driven prostate cancer. Hi-Myc/miR-21 KO mice demonstrated a marked reduction in adenocarcinoma when compared to Hi-Myc/miR-21 WT mice at 5m. This is apparent in the reduced weight of effected prostate lobes of Hi-Myc/miR-21 KO versus WT mice at 8m. Protein levels of established miR-21 target genes, PDCD4 and PTEN, were up-regulated in the prostates of Hi-Myc/miR-21 KO mice. Also, IHC showed lower Ki-67 and higher cleaved caspase-3 positive cells in miR-21 KO than WT. However, miR-21 KO did not affect prostatic intraepithelial neoplasia (PIN) development.
Conclusions: Our results demonstrate that miR-21 delays Myc-driven prostate cancer progression through reduced proliferation and enhanced apoptosis, and that endogenous miR-21 suppresses prostatic PDCD4 and PTEN protein expression levels. Therefore, targeting of miR-21 or its downstream target genes may be useful for cancer prevention or cancer therapy.
Citation Format: Kenji Zennami, Fatima Rafiqi, Ross Liao, Kim Sealover, Brian Simons, Makoto Sumitomo, Ryoichi Shiroki, Shawn Lupold. Loss of miR-21 delays myc-driven prostate cancer progression in the hi-myc transgenic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4501.
Abstract 4509: Overexpression of CADM1 enhances malignant features of small-cell lung cancer
Authors: Funaki Toko , Ito Takeshi , Murakami Yoshinori 
Published: August 2019

Abstract
Small-cell lung cancer (SCLC) is one of the representative intractable cancers with the 5-year survival of less than 10 %. Novel approaches to the treatment of SCLC are required because recurrence arises inevitably after the initial chemotherapy. CADM1 was originally identified as a tumor suppressor of non-small cell lung cancer (NSCLC) which encodes a member of immunoglobulin superfamily cell adhesion molecules. CADM1 consists of an extracellular domain with three immunoglobulin-like loops, a trans-membrane domain and a short cytoplasmic domain containing a protein 4.1-binding motif (4.1BM) and a PDZ-II-binding motif. We have reported that CADM1 is highly expressed in 90% of human SCLC cell lines and promotes subcutaneous tumor formation of SCLC cells in nude mice. In this study, we performed clinicopathological evaluation of CADM1 in SCLC and analyzed the molecular mechanisms of malignant progression of SCLC by overexpressing CADM1. Firstly, we performed immunohistochemical analysis of CADM1 expression in high-grade neuroendocrine tumor (HGNEC) of the lung, including SCLC and large cell neuroendocrine carcinoma (LCNEC). We found that CADM1 protein was expressed in 75% (33/44) of SCLC tumors and correlated with the nodal involvement in lung HGENC. To understand pathological significance of CADM1 overexpression in SCLC, we introduced a full-length CADM1 and its mutants in the extracellular or intracellular domain into SCLC cells, SBC5, lacking endogenous CADM1 expression and assessed their malignant features in comparison with control SBC5 cells. CADM1 expression significantly enhanced colony formation in soft agar and subcutaneous tumor formation in nude mice of SBC5, whereas a mutant in 4.1BM did not. Then, we screened chemical library of 170 small molecules of known function to identify compounds which inhibit anchorage-independent growth of SCLC cells enhanced by CADM1. Inhibitors of PI3K, Akt and PKA significantly suppressed cell growth of SBC5, suggesting that CADM1 activates PI3K/Akt and PKA signaling pathways through its 4.1BM and promotes anchorage-independent growth of SCLC cells. We also found that orthotopic injection of NCI-N417 cells overexpressing CADM1 into the lung of nude mice significantly enhanced their metastasis to mediastinal lymph nodes. These results suggest that CADM1 enhances tumor growth and metastasis of SCLC cells probably by activating PI3K/Akt and PKA pathways through its binding proteins at 4.1BM.
Citation Format: Toko Funaki, Takeshi Ito, Yoshinori Murakami. Overexpression of CADM1 enhances malignant features of small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4509.
Abstract 4511: Prostate cancer-specific enrichment of TP53 missense mutations elicits differential, context-dependent biochemical and biologic outcomes
Authors: McCann Jennifer J. , Vasilevskaya Irina , PoudelNeupane Neermala , Dean Jeffry , Mandigo Amy , Leeuw Renee De , McNair Chris , Schiewer Matthew , Knudsen Karen 
Published: August 2019

Abstract
Prostatic adenocarcinoma (PCa) remains the second leading cause of cancer death in men in the United States. While organ-confined disease can be successfully treated with surgery or radiation, patients with advanced disease undergo androgen deprivation therapy (ADT), which targets the androgen receptor (AR) signaling axis. This approach effectively treats the disease as PCa cells are exquisitely dependent on AR signaling for proliferation and survival. Unfortunately, cancer progression resumes after 2-3 years and results in a lethal stage of disease, termed castration-resistant prostate cancer (CRPC). While PCa typically demonstrates low overall mutational burden, TP53 is frequently mutated in both primary and advanced disease. These mutations are most commonly missense mutations in the DNA binding domain of TP53, and can occur in the presence or absence of a wildtype TP53 allele. Interestingly, specific enrichment of certain TP53 mutations frequently occurs in PCa when compared to other cancers, and similar to many other cancers, these mutations occur in the presence or absence of wildtype TP53. Using hormone therapy sensitive and CRPC cells, a panel of cell lines was generated to model these mutations in the presence or absence of wildtype TP53 expression. Defining the TP53 missense mutant-sensitive transcriptomes demonstrated context dependent, differential gene expression between TP53 missense mutants, related to the expression of wildtype TP53 in those cells. This also applied to cistrome analysis, illustrating an expansion of the p53 cistrome upon expression of mutant TP53. Furthermore, expression of p53 mutants also elicited context dependent effects on canonical p53 functions, thereby modulating distinct, downstream biological outcomes. Consequently, these data define the distinct and context dependent roles that mutant TP53 plays in PCa progression.
Citation Format: Jennifer J. McCann, Irina Vasilevskaya, Neermala PoudelNeupane, Jeffry Dean, Amy Mandigo, Renee De Leeuw, Chris McNair, Matthew Schiewer, Karen Knudsen. Prostate cancer-specific enrichment of TP53 missense mutations elicits differential, context-dependent biochemical and biologic outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4511.
Abstract 4518: IL-4/IL-13 stimulated tumor-associated macrophages enhance breast cancer cell invasion through Rho-GTPase signaling
Authors: Little Andrew C. , Pathanjeli Pragathi , Wu Zhifen , Bao Liwei , Goo Laura , Yates Joel A. , Merajver Sofia D. 
Published: August 2019

Abstract
The high metastatic potential of inflammatory and other aggressive breast cancer is the major determinant of mortality. Recently, it has become clear that signals from the tumor microenvironment (TME) harbor the capacity to enhance cancer cell dissemination. Of the various cells that comprise the TME, macrophages are the most abundant in solid tumors. Therefore, we aimed to better understand the relationship between macrophage-breast cancer cell crosstalk. Intriguingly, in our previous work we showed that inflammatory breast cancer (IBC) cells are hyper-migratory in response to macrophage conditioned media. Additionally, we found this process is regulated by the Rho-GTPase, RhoC. Recent advances in tumor associated macrophage (TAM) biology have led to the understanding that TAM populations in the TME are diverse, primarily due to directional differentiation promoted by unique secreted components from the various cells in the TME. Therefore, this study aimed to understand which subpopulation of M2-like TAMs had the greatest impact on breast cancer cell aggressiveness. Our data show that stimulation of the triple negative breast cancer (TNBC) cell model, MDA-MB-231, and the IBC TNBC cell line, SUM-149, with media extracts from IL-4/IL-13 stimulated M2 macrophages (M2a) elicit the strongest migratory and invasive responses. Subsequently, we stimulated RhoA or RhoC knockout (CRISPR) MDA-231 and SUM-149 cells with M2a conditioned media to address their role in regulating migratory/invasive responses. In brief, we find that RhoA and RhoC, in part, regulate M2a-TAM induced responses. Secretome analysis of M2a-TAM conditioned media reveals high levels of vascular endothelial growth factor (VEGF) and chemokine (C-C motif) ligand 18 (CCL-18). Functional studies suggest that VEGF and CCL-18 synergistically enhance cellular invasiveness. Moreover, pretreatment with the ROCK inhibitor Y-27632 or GSK429286A drastically inhibited VEGF, CCL-18, or M2a induced migratory responses. These data suggest that the Rho-GTPases regulate M2a-mediated breast cancer cell invasion and potentially offer a novel approach for the treatment of metastatic breast cancer through potential prevention of progression.
Citation Format: Andrew C. Little, Pragathi Pathanjeli, Zhifen Wu, Liwei Bao, Laura Goo, Joel A. Yates, Sofia D. Merajver. IL-4/IL-13 stimulated tumor-associated macrophages enhance breast cancer cell invasion through Rho-GTPase signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4518.