bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3708: Multiomic validation of canine simple carcinoma as a model for human basal-like breast cancer
Authors: Watson Joshua L. , Feng Yuan , Zhao Shaying 
Published: August 2019

Abstract
Roughly 20% of all breast cancer (BC) cases in humans are classified as basal-like breast cancer (BLBC), the deadliest subtype with a five-year survival prognosis lower than any other subtype. BLBC usually lacks the clinically targetable receptors estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). One of the main challenges in BLBC research is the lack of a spontaneous cancer model. To address this deficiency, we performed a comprehensive dog-human multiomic comparison. Briefly, we characterized the genomic and transcriptomic alterations of &gt;100 spontaneous canine mammary cancer cases, including simple carcinoma (SC), a common subtype in pet dogs, from our own data and published studies by others. We then evaluated the dog-human molecular homology by comparing our canine findings to the studies of BLBCs from The Cancer Genome Atlas (TCGA).
Our study shows a strong dog-human molecular homology. First, cross-species PAM50 classification indicates significant grouping of canine SC with human BLBC, but not other BC subtypes. This is supported by unsupervised clustering of a panel of recently published ~1800 cancer genes that characterize human BLBC. Second, gene set enrichment analysis with 44 BC molecular signatures, 20 of which are BLBC-specific, indicates that canine SCs have the same enrichment patterns as human BLBCs. Third, canine SCs show the same overall copy number alteration (CNA) patterns as human BLBCs. Specifically, canine SCs have significantly more amplified/deleted genes and a much greater percentage of the genome with CNA than other mammary cancer subtypes of the dog, which is also true for human BLBC. Furthermore, canine SC shares significantly more amplified/deleted genes with BLBC than any other BC subtypes. Importantly, these shared genes are strongly enriched in known BLBC signatures, including the 8q23-24 amplicon (containing the oncogene MYC) and chromosomal instability regulation. Finally, as with the PAM50 analysis, unsupervised cross-species clustering with amplified/deleted genomic regions and genes indicates a strong homology between canine SCs and human BLBCs.
In conclusion, canine SC faithfully recapitulates the molecular features of human BLBC, and can effectively serve as a much-needed spontaneous cancer model for BLBC research. Canine SC will accelerate basic research, e.g., providing a novel dog-human comparison strategy for cancer driver-passenger discrimination. Canine SC will also accelerate the bench-to-bedside translation by bridging the gap between preclinical studies in mice and human clinical trials.
Citation Format: Joshua L. Watson, Yuan Feng, Shaying Zhao. Multiomic validation of canine simple carcinoma as a model for human basal-like 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 3708.
Abstract 3714: Efficient derivation and expansion of tumor cell lines from primary and xenotransplanted pancreatic, ovarian and renal tumors
Authors: Hardt Olaf , Agorku David , Langhammer Anne , Zickgraf Franziska , Geist Felix , Noll Elisa M. , Eisen Christian , Bosio Andreas , Sprick Martin R. , Trumpp Andreas 
Published: August 2019

Abstract
Cancer cell lines are widely used as in vitro models to study tumor biology and for efficacy testing of novel anti-cancer therapeutics. In the past, most of this work has been done using established cell lines that have been cultured for decades. Extensive in vitro propagation has been shown to lead to the acquisition of multiple genetic and epigenetic alterations in cell lines, leading to decreased heterogeneity and the lack of tumor initiating as well as multi-lineage differentiation capacity. Consequently, established cell lines only insufficiently resemble the characteristics of tumors and thus have limited applicability as in vitro models for example. To overcome this hurdles, cell lines can be derived from primary cancer biopsies. However, this process is very inefficient for most tumor entities. In addition, most of the media used include largely undefined serum, such as FBS, which has been shown to drive primary tumor cell cultures to a more differentiated state when used over multiple passages. We have developed advanced, serum-free media for derivation and expansion of tumor cell lines from pancreatic, ovarian or renal tumors. Our media have been optimized concerning formulation, stability, and usability and allow for efficient generation of primary cell lines from both, patient and xenotransplanted tumors. Primary cell lines derived with our media retained their tumorigenic potential and could therefore be xenotransplanted and propagated in immunodeficient mice. Notably, the resulting tumors closely resembled the initial patient tumor as shown on the histomorphological as well as functional level. Moreover, the primary cell lines closely resembled essential characteristics of the parental tumor in vitro, including expression of subtype-specific markers, cellular heterogeneity, as well as genetic and epigenetic signatures. Taken together, we have developed serum-free medium for efficient derivation and expansion of tumor cell lines from primary and xenotransplanted pancreatic, ovarian and renal tumors, allowing for the establishment of easily accessible in vitro as well as corresponding xenografting vivo models. This facilitates the translation of in vitro findings directly into in vivo settings, allowing for more reliable pre-clinical modelling.
Citation Format: Olaf Hardt, David Agorku, Anne Langhammer, Franziska Zickgraf, Felix Geist, Elisa M. Noll, Christian Eisen, Andreas Bosio, Martin R. Sprick, Andreas Trumpp. Efficient derivation and expansion of tumor cell lines from primary and xenotransplanted pancreatic, ovarian and renal tumors [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 3714.
Abstract 3716: Conditional reprogramming technology for Next Generation Living Biobanks (NGLB)
Authors: Liu Xuefeng 
Published: August 2019

Abstract
As one of the next generation biobanks, living biobanks (iPSC, organoids, CRC, PDX, etc.) and related functional analyses are rapidly growing in basic research, clinics, and industry (especially immune-oncology and targeting therapies) as well. Most recently NCI launched PDMR (patient-derived model repository) using PDX, CRC and organoid cultures, NCI/ATCC/Broad/Sanger launched HCMI (Human Cancer Models Initiative) using Organoids and CRC cultures. In this study, we established a conditional reprogramming (CR) protocol which allows to generate cell cultures from cryopreserve fresh tissue specimens from surgery, core biopsies, needle biopsies, and brushed cells.It has been extremely difficult to generate primary cultures from tumor specimens, it has not been possible to expand and indefinitely propagate cells derived from adult tissues while retaining lineage-commitment, normal growth control and differentiation potential. The CR method rapidly expands both normal and malignant epithelial cells from diverse anatomic sites and mammalian species and does not require transfection with exogenous viral or cellular genes. Establishment of cell cultures from both normal and tumor tissue (many types) is highly efficient. The robust nature of the technique is exemplified by the ability to produce 2 x 106cells in 5 days from a core biopsy of breast tumor. Normal cultures retain a normal karyotype and differentiation potential and cell lines derived from tumors retain their tumorigenic phenotype. We were also able to generate their corresponding fibroblast cultures from the same specimens. These fibroblasts can be immortalized by exogenously expressed hTERT. This approach allows to establish in vitro "epithelial-stroma interactions" to study normal cell differentiation and tumor microenvironment. The ability to produce inexhaustible cell populations from small biopsies and cryopreserved specimens has the potential to transform biobanking repositories (termed as NGLB - next generation living biobanks) and current pathology practice by enabling genetic, biochemical, metabolomic, proteomic, and biological assays, including chemosensitivity testing as a functional diagnostics tool (or a living biomarker) for precision cancer medicine. CR cells can be also an inexhaustible resource to generate CR cells derived iPSC, organoids, and xenografts (CDXs).
Citation Format: Xuefeng Liu. Conditional reprogramming technology for Next Generation Living Biobanks (NGLB) [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 3716.
Abstract 3720: Blockade of the short-form of prolactin receptor induces FOXO3a/EIF-4EBP1-mediated cell death in uterine cancer
Authors: Wen Yun-Fei , Wang Ying , Ma Shaolin , Raicu Anca Chelari , Baggerly Keith A. , Sood Anil K. 
Published: August 2019

Abstract
Purpose: Extra-pituitary prolactin (PRL) is involved in development and progression of uterine carcinoma. However, the underlying mechanisms of PRL/PRLR axis in uterine cancer are not well understood, and current means of targeting this axis are limited. Here, we used a potent PRL antagonist (G129R) to interfere with oncogenic activities of uterine cancer cells and further inhibit tumor growth.
Experimental Design: We performed integrated analyses by comparing expression of PRLR isoforms in a broad panel of tumors and normal countparts using TCGA and GTex databases. Therapeutic effects of G129R treatment in uterine cancers were assessed in both orthotopic PTENwt and PTENmut models. Additionally, we carried out reverse phase protein assay (RPPA) at in vivo condition from the resulting tumors and at in vitro conditions to interrogate downstream targets and mechanism of action for G129R. Further functional analyses including cell viability, cell cycle and nascent protein synthesis were accessed in two types of uterine cancer cells under serum-depleted condition.
Results: We found that PRLR_S1a, a short form of PRLR that is generated from alternative splicing during transcription, is expressed in human uterine cancers to a greater extent than other isoforms. Blocking activities of the PRL/PRLR_S1a axis with the antagonist G129R significantly reduced growth and progression of both orthotopic PTENwt and PTENmut uterine tumors. Data from reverse-phase protein arrays (RPPA) by in the resulting tumors showed that pathways involved in epithelial-mesenchymal transition such as PI3K/mTOR activities were significantly downregulated by G129R treatment. In addition, based on the RPPA data from the in vitro uterine cancer cells treated with G129R as monotherapy or in combination with PRL, we discovered a novel function of G129R in initiating cell death mediated by nuclear FOXO3a and inducing the G0/G1 arrest in both PTENwt and PTENmut uterine cancer cells. Furthermore, G129R decreased the nascent protein synthesis in these uterine cancer cells mediated by transcriptional suppressor EIF-4EBP1. Collectively, our findings reveal a new role of the PRLR_S1a isoform in uterine cancer and identify G129R as a potential therapeutic in uterine cancer.
Citation Format: Yun-Fei Wen, Ying Wang, Shaolin Ma, Anca Chelari Raicu, Keith A. Baggerly, Anil K. Sood. Blockade of the short-form of prolactin receptor induces FOXO3a/EIF-4EBP1-mediated cell death in uterine 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 3720.
Abstract 3722: Novel Optical Coherence Tomography (OCT) technology for no-invasive 3D ex vivo drug activity profiling
Authors: Dhar Sumeer , Ueda Akihiro , Muira Takemitsu , Kuromi Yasushi , Mori Yuki , Fujimoto Hiroki 
Published: August 2019

Abstract
Drug discovery and early to late drug development process have relied on 2D monolayer based in vitro assay platforms and small animal models. The limitations posed by 2D in vitro assays for evaluation of targeted and immunomodulatory agents have prompted researchers to develop novel 3D in vitro and ex vivo platforms utilizing the tumor microenvironment like conditions for better understanding of mechanisms of novel targeted and immunomodulatory drug/compound entities. Therefore, rapid development of robust 3D ex vivo cell culture as drug efficacy testing system for drug discovery, development and profiling of standard of care and Immunotherapeutic molecules have led to understanding the relevance of these platforms within the scientific and clinical community. 3D ex vivo platforms are being diligently evaluated as better predictive drug efficacy testing tools in preclinical as well as clinical space in the quest for profiling of novel anticancer entities (as single or two drug combinations). Within this context, there has been growing need in improved imaging and analysis of complex 3D structures (Multicellular tumor spheroids/Organoids) containing multiple cellular components such as, Tumor cells, stromal cells, various immune cells to monitor signaling pathways and assess immune events including T cell infiltration as drug efficacy measurement. At SCREEN LifeScience, we have developed a novel OCT based technology for imaging and analysis of complex 3D structures, such as, spheroid /organoid for growth & morphological profiling, quantification of internal cavities, drug sensitivity testing to capture the events leading to tumor cell death and assessing mechanism of drug action. Additionally, this technology allows us perform large tissue imaging, non-invasive monitoring of macro and sprouted neo-vasculature without the need for fluorescent staining for providing quantitative information about the vascular morphological changes, thereby allowing for the evaluation of anti-angiogenic drugs in real time. In summary, the OCT technology shown to be robust and versatile technology useful for studying multiple disease models, including cancer. Its utility in regeneration medicine is being further evaluated as a versatile non-invasive platform.
Citation Format: Sumeer Dhar, Akihiro Ueda, Takemitsu Muira, Yasushi Kuromi, Yuki Mori, Hiroki Fujimoto. Novel Optical Coherence Tomography (OCT) technology for no-invasive 3D ex vivo drug activity profiling [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 3722.
Abstract 3728: Inverse effect of 28Si and 56Fe radiation on intestinal tumorigenesis vs. carcinogenesis in APC1638N/+ mice
Authors: Kumar Santosh , Suman Shubhankar , Kallakury Bhaskar V.s. , Moon Bo-Hyun , Fornace Albert J. , Datta Kamal 
Published: August 2019

Abstract
Space radiation is a major risk factor for gastrointestinal (GI) cancer in astronauts and is a matter of concern. Earlier we have reported higher relative effects for intestinal tumorigenesis in APC1638N/+ mice after exposure to different heavy ion radiation spanning a range of LET values. The purpose of the current study was to histologically grade intestinal tumors into adenoma vs. adenocarcinoma and assess relative effects of different heavy ion radiation on tumorigenesis vs carcinogenesis. Tumors from male APC1638N/+ mice 150 d after exposure to whole-body sham, γ (0.3 keV/μm), 12C (13 keV/μm), 28Si (70 keV/μm), or 56Fe (148 keV/μm) radiation were harvested, fixed, paraffin embedded, and sectioned. Radiation doses were 0.1 Gy, 0.5 Gy and a equitoxic dose of 2.0 Gy γ-rays. H&E stained tumor sections from at least 50 tumors per study group were used for histological grading into adenoma and adenocarcinoma. Hotspot mutations for p53 and Kras genes were assessed using targeted PCR followed by amplicon sequencing in 20 tumors per study group. Our previous published data showed that among the three LETs tested relative intestinal tumorigenic effects (relative to γ-rays) peaked at a LET of 70 keV/μm (28Si) with 13 keV/μm (12C) showing the least effect and 148 keV/μm (56Fe) showing an intermediate effect. In contrast, the current study demonstrates that the frequency of adenocarcinoma peaked after 56Fe with the least effect after 12C and an intermediate effect after 28Si. Relative to γ-rays, the carcinoma frequencies were 42.4+0.9, 13.2+0.61 and 8.0+1.14 higher after 56Fe at doses of 0.1, 0.5 and 2.0 Gy respectively. Whereas the relative carcinoma frequencies of 34.2+1.35, 14.0+0.95 and 9.0+2.25 were observed after 28Si at doses of 0.1, 0.5 and 2.0 Gy respectively. While Kras mutation analysis of tumors did not show any difference among radiation types, p53 mutation analysis demonstrate a higher number of mutations in exon 5 in 56Fe relative to 28Si samples. Collectively, our data show that while LET-dependent tumorigenic effects followed a parabolic shape, carcinogenic effects followed a more linear-like pattern with highest adenocarcinoma percentage and frequency at 148 keV/μm (56Fe). Although inverse effects of LET on tumorigenesis vs. carcinogenesis could in part be attributed to the beams’ differential physical properties, our mutation data on p53 supports differential effects of the beams on tumor suppressor mutation.
Citation Format: Santosh Kumar, Shubhankar Suman, Bhaskar V.s. Kallakury, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta. Inverse effect of 28Si and 56Fe radiation on intestinal tumorigenesis vs. carcinogenesis in APC1638N/+ mice [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 3728.
Abstract 3733: Development of photoimmunotherapy for colon cancer in nude mice models
Authors: Hollandsworth Hannah , Amirfakhri Siamak , Filemoni Filemoni , Razemjooie Sahar , Yazaki Paul , Hoffman Robert , Bouvet Michael 
Published: August 2019

Abstract
Introduction: Photoimmunotherapy (PIT) uses tumor specific monoclonal antibodies conjugated to photosensitizer phthalocyanine dye IR700 to produce cytotoxicity. To date, there is no published data on the use of PIT in colorectal cancers, which could be useful as an adjunct to surgery to prevent local recurrence, or as a primary therapy.
Methods: Humanized anti-CEA antibody (m5A) was conjugated to IR700CW dye (LI-COR). In vitro PIT was performed using a human colon cancer cell line LS174T. Cancer cells (2x103) were seeded on a 96-well plate and incubated for 24 hours. m5A-IR700CW containing media was added to the cells. Cells received either 2 minutes of PIT or no treatment. PIT was administered at 4 J/cm2, 8 J/cm2 or 16 J/cm2. Cell viability was measured on a microplate reader with CellTiter 96 Aqueous One Solution (Promega, Madison, WI). Subcutaneous implantation of LS174T was performed on the bilateral flanks of four male nude mice. Tail vein injection of 25 micrograms of m5A-IR700CW reconstituted in 100 microliters PBS was performed for each mouse. Animal imaging was performed with a LI-COR Pearl Trilogy imaging system. Right flank tumors of three mice were treated with a 690 nm laser at 150 mW/cm2 for 30 minutes, delivering a total of 270 J/cm2. A non-treated mouse served as the control. Images were obtained prior to PIT, immediately after PIT and 10 minutes, 20 minutes, 30 minutes and 24 hours after treatment. Maximum fluorescence intensity was measured at each time point. Tumor size was measured prior to treatment, 24 hours, 48 hours, 5 days and 10 days after treatment.
Results: In vitro PIT was effective to kill the cancer cells in a dose response manner. In vivo PIT decreased tumor fluorescence intensity in a time-dependent manner. PIT arrested tumor growth in all mice, compared to the control, which demonstrated continuous tumor growth.
Conclusion: PIT affects cancer cell death in vitro and arrests tumor growth in colon cancer models.
Citation Format: Hannah Hollandsworth, Siamak Amirfakhri, Filemoni Filemoni, Sahar Razemjooie, Paul Yazaki, Robert Hoffman, Michael Bouvet. Development of photoimmunotherapy for colon cancer in nude mice models [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 3733.
Abstract 3740: Ionizing radiation-induced transcriptomic changes in triple-negative breast cancer cells reveal putative mechanisms of treatment resistance
Authors: Lin Victor T. , Lama-Sherpa Tshering D. , Samant Rajeev S. , Shevde Lalita A. 
Published: August 2019

Abstract
Breast cancer is the most common malignancy and the second leading cause of cancer-associated deaths in women. Of these, triple-negative breast cancers (TNBCs) remain the most difficult to treat. Unlike hormone-driven breast cancers, TNBCs that remain in remission past the five-year mark rarely relapse and are considered functionally cured. Thus, investigating mechanisms of treatment resistance in order to improve remission rates is of paramount importance. In this study, we use RNA-Seq to analyze global transcriptomic changes in TNBC cells in response to DNA damage induced by ionizing radiation (IR). Applying gene set enrichment analysis (GSEA), we have identified a number of expression signatures that represent putative mechanisms of resistance to treatment. In prior work, we have demonstrated the role of the transcription factor Gli1, the terminal effector of the Hedgehog (Hh) signaling pathway, in regulating the expression of DNA repair proteins in response to genotoxic damage with cisplatin. We have previously shown that Hh inhibition blunts the expected upregulation of specific proteins involved in single-strand DNA repair in ovarian cancer cells. Here, we expand on our earlier studies by examining TNBC cells with high levels of Hh activity and querying how global transcriptomic changes in response to IR are altered by Hh inhibition. Our data suggest that rational manipulation of these pathways may sensitize TNBCs to treatment and improve the functional cure rate of these tumors.
Citation Format: Victor T. Lin, Tshering D. Lama-Sherpa, Rajeev S. Samant, Lalita A. Shevde. Ionizing radiation-induced transcriptomic changes in triple-negative breast cancer cells reveal putative mechanisms of treatment resistance [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 3740.