tbuckley/cabot-search huggingface dataset:
Abstract 5781: Establishment of a 3D <i>ex-vivo</i> assay as a preclinical drug testing platform for personalized cancer therapy
Authors: Sumeer Dhar, Francesca Chiovaro, Tamara Tanos, Tomas Hejhal, Seife Heilemariam, Jens Kelm, Anja Irmisch, Mitchell Levesque
Journal: Cancer Research (2017)

Abstract In vitro cell based drug testing tools have been widely used in drug discovery and early development to evaluate novel drug entities for further evaluation in preclinical in vivo models. However, a poor correspondence with in vivo models has compelled oncologists to pursue complementary in vitro strategies with better outcomes. Within this realm, a 3D ex vivo platform is being extensively used to evaluate the activity of cytotoxic drugs, targeted molecules, and antibodies. To increase the translational value of this model, maintenance of the tumor microenvironment (immune and other stromal cells) is highly pertinent. We have established a 3D ex vivo assay as a patient drug testing platform for personalized medicine therapies in collaboration with our clinical partners. In this study we setup the protocols for obtaining single cell suspensions from biopsy and/or tumor resection samples from patients presenting with Urothelial cancers, Renal cell carcinoma, Pancreatic, NSCLC, Ovarian, and Melanomas to generate 3D microtumors in 96 well format cultured over a period of 7-15 days. The microtumors were monitored for growth characteristics, biomarker phenotype and drug activity profile. As expected the growth characteristics for each tumor varied, corresponding very well with clinical disease progression. Subsequently, these microtumors were assessed using a standard clinical immunohistochemistry diagnostics approach to evaluate disease specific biomarkers and were compared to the clinical diagnostics profile of the patients. The biomarker profile from 3D derived tumor samples showed concordance with the patient diagnostics profile. In the instances were clinical information and treatment regimens were available, the microtumors were tested and followed with single and pairwise drug treatments. The ex vivo 3D treatment outcome clearly reflected the clinical outcome. Currently, this platform is being used to develop 3D ex vivo immune-competent models to study immunomodulatory therapies. Based on the overall data we conclude that the 3D ex vivo assay system offers a highly pertinent platform to perform chemosensitivity testing providing predictive information on the clinical outcome, which enables oncologists to redefine individualized chemo/targeted treatments. Citation Format: Sumeer Dhar, Francesca Chiovaro, Tamara Tanos, Tomas Hejhal, Seife Heilemariam, Jens Kelm, Anja Irmisch, Mitchell Levesque. Establishment of a 3D ex-vivo assay as a preclinical drug testing platform for personalized cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5781. doi:10.1158/1538-7445.AM2017-5781
Abstract 4802: Immune dysfunction and fungal infection contribute to esophageal carcinogenesis
Authors: Feng Zhu, Jami Willette-Brown, Na-young Song, Peilin Zhang, Yinling Hu
Journal: Cancer Research (2017)

Abstract Human esophageal cancer is the sixth leading cause of cancer death worldwide. More than 90% of esophageal cancer is esophageal squamous cell carcinoma (ESCC). While the etiological causes remain unclear, esophageal mucosal fungal infection is very common in esophageal cancer patients, including patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) who have more than 20-fold risk of ESCC when compared to the healthy population. Here, we report that kinase-dead Ikka knock-in mice (hereafter referred to as mutant mice) develop APECED-like autoimmune disease due to developmental defects in thymus and lack of central tolerance. Similar to human APECED patients who develop esophageal mucosal fungal infection on average at the age of five, mutant mice develop fungal infection in oral cavity and esophagus as early as seven weeks old. About 20% of mutant mice develop ESCC during aging, which exhibits specific molecular signatures observed in human ESCC, such as p16 gene silencing, elevated EGFR phosphorylation and PD-L1 expression, etc. Autoreactive T cell depletion, or central tolerance reconstitution and/or normal T cell transfer prevents fungal infection and ESCC development in mutant mice. Importantly, antifungal drug treatment inhibits inflammation and ESCC development in mutant mice. However, oral inoculation of Clasdosporium, one of the major fungal species isolated from mutant mice, increases the tumor incidence from 20% to 63% in mutant mice. These results reveal that immune dysfunction and fungal infection is associated with ESCC development, which sheds new light on ESCC etiological factors, prevention and treatment. Citation Format: Feng Zhu, Jami Willette-Brown, Na-young Song, Peilin Zhang, Yinling Hu. Immune dysfunction and fungal infection contribute to esophageal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2017-4802
Abstract 4919: Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression
Authors: Jeremy T. Miyauchi, Danling Chen, Matthew K. Choi, Kenneth Shroyer, David Selwood, Stella E. Tsirka
Journal: Cancer Research (2017)

Abstract Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor’s spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1’s b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Moreover, transplanting bone marrow from mice with Nrp1-deficient macrophages to wild type recipient mice led to reductions in tumor growth, al-be-it not to the extent seen in knockout mice. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. Citation Format: Jeremy T. Miyauchi, Danling Chen, Matthew K. Choi, Kenneth Shroyer, David Selwood, Stella E. Tsirka. Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4919. doi:10.1158/1538-7445.AM2017-4919
Abstract 944: Chemokine receptor signaling as a new tool to improve lung cancer diagnostics and therapy
Authors: Katalin Nagy-Major, Jörg Sänger, Harshad R. Kulkarni, Peter Fix, Almut Kunze, Amelie Lupp, Reiner Bonnet, Werner Seeger, Richard P. Baum, Patricia Grabowski, Rajkumar Savai
Journal: Cancer Research (2017)

Abstract Background: The tumor microenvironment plays a critical role in cancer development, progression, and control. We demonstrated in vitro and in vivo that a bidirectional crosstalk between tumor-associated macrophages and cancer cells via CCR2-CCL2 and CX3CR1-CXCL1 signaling is fundamental for lung cancer growth and metastasis offers new treatment concepts. Aim: Our working hypothesis is to develop a new platform for specific chemokine receptor (CCR2) PET imaging and a range of theranostic applications in lung cancer. For this purpose, we planned to define the CCR2 expression in NSCLC as well as in SCLC, tumor cells as well as immune/inflammatory cells. Material and Methods: This is a multicenter trial with patients from Zentralklinik Bad Berka GmbH (n =100 NSCLC, n=100 SCLC). All patients gave informed consent according to the declaration of Helsinki. FFPE material was available in all cases. CCR2 CXCR4 and CX3CR1 expression was determined by immunohistochemistry with the avidin-biotin-peroxidase-complex. Results: Analyzing 96 NSCLC (47 adenocarcinoma, 49 squamous cell carcinoma) and 45 SCLC tumor samples, we found CXCR4 and CCR2 chemokine receptor expression in tumor, immune and inflammatory cells. In NSCLC, co-expression between CCR2 and CXCR4 staining was very high concerning their expression on tumor cells rising with higher tumor stages, proliferation rate and grading. CCR2 expression in immune cells was restricted to lower stages; the same pattern could be observed in 45 SCLC tumor samples where CCR2 expression on immune cells was found especially in limited disease rather than in metastatic disease; CXCR4 expression in tumor cells was found to be high in all stages of SCLC. To evaluate the therapeutic efficacy of CCR2 antagonism in vivo, we injected LLC1 s.c. into WT mice treated with CCR2 antagonist (RS504393) or vehicle. Notably, tumor growth was significantly inhibited in CCR2 antagonist-treated mice as compared with vehicle-treated mice. Discussion: Our preliminary results show a significant portion of CCR2 positive tumors - NSCLC as well as SCLC which would qualify for a CCR2-based imaging as well as - demonstrated in our mice models - CCR2 inhibitory strategies. This should be evaluated in further preclinical trials. Citation Format: Katalin Nagy-Major, Jörg Sänger, Harshad R. Kulkarni, Peter Fix, Almut Kunze, Amelie Lupp, Reiner Bonnet, Werner Seeger, Richard P. Baum, Patricia Grabowski, Rajkumar Savai. Chemokine receptor signaling as a new tool to improve lung cancer diagnostics and therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 944. doi:10.1158/1538-7445.AM2017-944
Abstract 2537: MicroRNA targeting anti-apoptotic and G2/M pathways as therapeutic targets for castration resistant prostate cancer
Authors: Pheruza Tarapore, Sarah To, Bin Ouyang, Yuet-Kin Leung, Ana Cheong, Shuk-mei Ho
Journal: Cancer Research (2017)

Abstract Prostate cancer (PC) is one of the most common cancers in men. Unfortunately, limited treatment options currently exist for those who have developed advanced castration-resistant PC (CRPC). G-1 is a GPER1/GPR30 agonist, and a promising candidate for CRPC therapy. G-1 is effective in halting the growth of CR tumors but not those grown in intact hosts. These findings suggest GPER1 is a therapeutic target for CRPC. We found that G-1, through activation of GPER1, inhibited growth of CRPC cells via cell-cycle arrest at the G2-M phase, probably leading to mitotic catastrophy. However, the exact mode of action of G-1 was not known. To better understand the pathways involved in G-1 action, we conducted a genome-wide mRNA-seq and miRNA-seq study on G-1 treated xenografts. We identified a panel of novel G-1-associated tumor suppressive miRNAs and genes. Moreover, Ingenuity Pathway Analysis revealed that the G-1 differentially regulated genes are involved in “Cellular Growth and Proliferation”, “endocrine function” and “Cancer” pathways. We validated the expression of the key miRNA (miR-34c, miR-10b, miR-138 and miR218) and genes in G-1 treated castration resistant xenografts and cell lines (C4-2 and 22Rv1). Furthermore, we have shown the tumor suppressor function of these miRNA in cell survival, migration, and invasion. The predicted target genes were next examined for decreased expression by qRT-PCR. We confirmed decreased expression of some of the downstream targets, which consist of genes involved in cell cycle regulation (CCNA and CCND, CDK1, CDK4, PLK1), cell survival (Bcl2, Survivin), cell migration/F-actin formation (LASP, PCDH7, ITGA9, ROBO1, SLIT1) and G2/M checkpoint (CDK1, PLK1, BCL-2 Survivin). Thus these miRNAs - miR-34c, miR-10b, miR-138 and miR218 - are ideal candidates for therapy of CRPC. Citation Format: Pheruza Tarapore, Sarah To, Bin Ouyang, Yuet-Kin Leung, Ana Cheong, Shuk-mei Ho. MicroRNA targeting anti-apoptotic and G2/M pathways as therapeutic targets for castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2537. doi:10.1158/1538-7445.AM2017-2537
Abstract LB-130: Tumor regression in novel triple therapy BRAF mutant metastatic melanoma patient-derived preclinical models
Authors: Antoneicka L. Harris, Michael Thompson, Svetomir Markovic, William Durham, Louis Dawson, Daniel Small, John A. Copland
Journal: Cancer Research (2017)

Abstract Metastatic melanoma (MM) is the most aggressive type of skin cancer contributing to approximately 80% of all skin cancer related deaths. In 2016, it was estimated that more 76,000 cases would be diagnosed in the United States. The high metastatic potential and aggressive clinical behavior of this disease makes it a major health problem. As a consequence there has been notable development in for novel targeted (i.e. BRAF inhibitors) and immune therapies (i.e. anti-PD1 and CTLA4 inhibitors). However, despite improvements in patient outcomes, most patients develop resistance within 6-11 months on dual BRAF/MEK inhibition, and 5 months on immune therapy, highlighting the need to identify new therapies that improve disease management and patient survival. Increased expression of CyclinD1 has been reported to occur as a mechanism of resistance to BRAF inhibition, resulting in reactivation of the canonical activating pathway in melanoma, MAPK. Thus, we hypothesize that combined inhibition of CDK4/6 and MAPK signaling will provide a novel anti-tumor synergy drug combination superior to current standard of care in BRAF mutant patient-derived preclinical models. Using MM human tissue from patients we developed 3 BRAF mutant preclinical models investigating a novel triple therapy drug combination BRAFi/MEKi/CDK4/6i. Protein analysis and drug proliferation assays were used to design the novel combination. In vivo, we found statistically significant differences in tumor inhibition between the novel combination and the current standard of care. The triple therapy also showed promising results, in vivo, when assessed as a salvage therapy following tumor escape from BRAFi/MEKi combination treatment. Citation Format: Antoneicka L. Harris, Michael Thompson, Svetomir Markovic, William Durham, Louis Dawson, Daniel Small, John A. Copland. Tumor regression in novel triple therapy BRAF mutant metastatic melanoma patient-derived preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-130. doi:10.1158/1538-7445.AM2017-LB-130
Abstract LB-226: Dual inhibition of CD47 and HER2 to radiosensitize breast cancer cells
Authors: Demet Candas, Lu Zhang, Cheikh Menaa, Ming Fan, Yanhong Zhang, Lin Liu, Weibing Zhou, Soheila Azghadi, Colleen Sweeney, Rulong Shen, Tzu-yin Lin, Chong-xian Pan, Andrew T. Vaughan, Ji Ming Wang, Hong-Wu Chen, Kit Lam, Lun-Quan Sun, Arta M. Monjazeb, William J. Murphy, Jian Jian Li
Journal: Cancer Research (2017)

Abstract Accumulating studies are aimed to combine immunoregulation with the standard of treatment such as radiotherapy in anti-cancer therapy. A potential cross resistance of tumor cells will be a barrier in furthering the long-term control by such combined treatment. CD47, an immunoglobulin-like transmembrane protein, enables cancer cells to escape the immune surveillance by flagging them with a ‘don’t eat me’ signal, which is recognized by the signal regulatory protein α (SIRPα) on macrophages. Here, we report that CD47 expression is enhanced by radiation in breast cancer cells and in vivo irradiated xenograft tumors via NF-κB regulation. In addition, CD47 and HER2 are co-induced by radiation and CD47 expression is specially enhanced by radiation in HER2-expressing cells. Contrasted with primary tumors, co-expression of CD47 and HER2 is elevated in the recurrent breast tumors. Anti-HER2 treatment inhibits CD47 transcription and protein expression with increased macrophage phagocytosis. Likewise, anti-CD47 not only augments macrophage phagocytosis but also reduces the capacity of tumorsphere formation. Radiation with anti-CD47 synergistically suppresses clonogenic survival and the maximal inhibition was achieved by dual inhibition of CD47 and HER2 with radiation. The synergy of in vivo tumor inhibition is established in mouse breast tumor model via local tumor radiotherapy combined with anti-CD47 treatment. These results demonstrate that the HER2-NF-κB-CD47 loop is responsible the cross-resistance of breast tumor against immune surveillance and radiation. Thus dual inhibition of CD47 and HER2 is a potential target to enhance tumor response to immune-radiotherapy. Funding: This study was partially supported by National Cancer Institute RO1 grant R01CA213830-01 (JJL). Note: This abstract was not presented at the meeting. Citation Format: Demet Candas, Lu Zhang, Cheikh Menaa, Ming Fan, Yanhong Zhang, Lin Liu, Weibing Zhou, Soheila Azghadi, Colleen Sweeney, Rulong Shen, Tzu-yin Lin, Chong-xian Pan, Andrew T. Vaughan, Ji Ming Wang, Hong-Wu Chen, Kit Lam, Lun-Quan Sun, Arta M. Monjazeb, William J. Murphy, Jian Jian Li. Dual inhibition of CD47 and HER2 to radiosensitize breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-226. doi:10.1158/1538-7445.AM2017-LB-226
Metabolic tumor burden predicts prognosis of ovarian cancer patients who receive platinum-based adjuvant chemotherapy after cytoreductive surgery outcome.
Authors: Makoto Yamamoto, Tetuya Tujikawa, Hidehiko Okazawa, Yasushi Kiyono, Yoshio Yoshida
Journal: Journal of Clinical Oncology (2016)

e17100 Background: Volumetric parameters of positron emission tomography-computed tomography using 18F-fludeoxyglucose (18F-FDG PET/CT) that comprehensively reflect both metabolic activity and tumor burden are capable of predicting survival in several cancers. The aim of this study was to investigate the predictive performance of metabolic tumor burden measured by 18F-FDG PET/CT in ovarian cancer patients who received platinum-based adjuvant chemotherapy after cytoreductive surgery. Methods: Included in this study were 37 epithelial ovarian cancer patients. Metabolic tumor burden in terms of metabolic tumor volume (MTV) and total lesion glycolysis (TLG), clinical stage, histological type, residual tumor after primary cytoreductive surgery, baseline serum carbohydrate antigen 125 (CA125) level, and the maximum standardized uptake value (SUVmax ) were determined, and compared for their performance in predicting progression-free survival (PFS). Results: MTV correlated with CA125 (r = 0.547, P< 0.001), and TLG correlated with SUVmax and CA125 (SUVmax : r = 0.437, P= 0.007; CA125: r = 0.593, P< 0.001). Kaplan-Meier analysis showed a significant difference in PFS between the groups categorized by TLG (P= 0.043; log-rank test). Univariate analysis indicated that TLG was a statistically significant risk factor for poor PFS. Multivariate analysis adjusted according to the clinicopathological features was performed for MTV, TLG, SUVmax , tumor size and CA125. Only TLG showed a significant difference (P= 0.038), and a 3.915-fold increase in the hazard ratio of PFS. Conclusions: MTV and TLG (especially TLG) could serve as potential surrogate biomarkers for recurrence in patients who undergo primary cytoreductive surgery followed by platinum-based chemotherapy, and could identify patients at high risk of recurrence who need more aggressive treatment.
Abstract 3124: Expression and therapeutic implications of cyclin dependent kinase 4 (CDK4) in osteosarcoma
Authors: Yubing Zhou, Francis Hornicke, Zhenfeng Duan
Journal: Cancer Research (2017)

Abstract Overexpression and/or hyperactivation of cyclin-dependent kinase 4 (CDK4) has been found in many types of human cancers, and a CDK4 specific inhibitor, palbociclib, has been recently approved by the FDA for the treatment of breast cancer. However, the expression and the therapeutic potential of CDK4 in osteosarcoma remain unclear. In the present study, CDK4 was found to be highly expressed in human osteosarcoma tissues and cell lines as compared with normal human osteoblasts. Elevated CDK4 expression correlated with metastasis potential and poor prognosis in osteosarcoma patients as determined by immunohistochemical analysis in a human osteosarcoma tissue microarray (TMA). CDK4 inhibition by either palbociclib or specific small interference RNA (siRNA) exhibited dose-dependent inhibition of osteosarcoma cell proliferation and growth, accompanied by suppression of the CDK4/6-cyclinD-Rb signaling pathway. Flow cytometry analysis showed that CDK4 knockdown arrested osteosarcoma cells in the G1 phase of the cell cycle and induced cell apoptosis. Furthermore, inhibition of CDK4 significantly decreased osteosarcoma cell migration in vitro determined by the wound healing assay. These data highlight that CDK4 may be a potential promising therapeutic target in the treatment of human osteosarcoma. Citation Format: Yubing Zhou, Francis Hornicke, Zhenfeng Duan. Expression and therapeutic implications of cyclin dependent kinase 4 (CDK4) in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3124. doi:10.1158/1538-7445.AM2017-3124