tbuckley/cabot-search huggingface dataset:
Abstract 3885: Evaluation of pharmacokinetics of proxalutamide, a novel androgen receptor antagonist, in treatment for mCRPC patients via CTC enumeration and AR biomarker analysis
Authors: Lincy Chu, Phoebe Zhang, Amanda Anderson, Mark Landers, Yipeng Wang, Karl Zhou
Journal: Cancer Research (2019)

Abstract Introduction: Proxalutamide (code name: GT-0918) is a novel androgen receptor (AR) blocker and has shown efficacy in the treatment of castration resistant prostate cancer. Proxalutamide binds to AR and inhibits androgen-induced receptor activation. A Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT02826772) was conducted to identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and PK of GT0918 in pts with mCRPC who have progressed on standard of care and experimental therapies in the United States. To better understand patient responses and pharmacokinetics of GT0918, we sought to examine CTC enumeration, AR-N term expression, and AR-V7 nuclear expression using Epic CTC platform for patients treated with GT0918. Methods: A total of 18 metastatic castrate resistant prostate cancer (mCRPC) patients were recruited under either dose escalation or expansion studies and blood samples were collected at 3 time points: C1D1, C3D1, and C6D1/EOS. Patients with histologically confirmed mCRPC who had progressed after both hormonal therapy (abiraterone or enzalutamide) and chemotherapy (e.g., docetaxel) were eligible. Dosages of 300, 400, and 500 mg were evaluated in this study. CTCs were detected using the Epic Sciences platform and assessed for full length AR status using an AR N-terminus specific antibody and for nuclear localized AR-V7 truncation. AR-V7 nuclear localization was confirmed by trained technician. Results: 18/18 (100%) of patients had detectable CTCs, with 12/18 (67%) patients having AR-N term+ CTCs. 7/12 (58%) of AR-N term+ patients were AR-V7 positive. Reduction of CTC/mL, AR+ CTC/mL and % of AR+ CTC in follow up draws were observed in the whole cohort, with 500mg dose group showing more reduction than others. Sample accrual and patient follow up is ongoing and the correlation of CTC, AR, and AR-V7 status with the clinical outcomes will be investigated once the data becomes mature. Conclusions: In this clinical trial, we evaluated the pharmokinetic effects of GT0918 on CTC enumeration and Androgen Receptor CTC status. GT0918 might serve as a potential alternative for late stage mCRPC patients who have developed resistance to both hormone and chemotherapy treatments. The role of CTC as PK marker or patient selection device is ongoing. Citation Format: Lincy Chu, Phoebe Zhang, Amanda Anderson, Mark Landers, Yipeng Wang, Karl Zhou. Evaluation of pharmacokinetics of proxalutamide, a novel androgen receptor antagonist, in treatment for mCRPC patients via CTC enumeration and AR biomarker analysis [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 3885.
Abstract 5163: Angiocrine induction of colorectal cancer cell HER3 activation and cell survival is independent of CRC mutational status
Authors: Rui Wang, Rajat Bhattacharya, Fan Fan, Xiangcang Ye, Lee M. Ellis
Journal: Cancer Research (2019)

Abstract INTRODUCTION: Colorectal cancer (CRC) is the second-leading cause of cancer-related death in the United States. A better understanding of the regulation of CRC cell survival pathways is necessary for developing new therapeutic strategies for patients with metastatic CRC (mCRC). We have previously found that endothelial cells (ECs) from the liver, the most common site of CRC metastases, secrete soluble factors in their conditioned medium (CM) that, in turn, increase cell growth and chemoresistance of CRC cells. We also determined that EC-induced CRC cell survival is mediated, in part, by HER3/ERRB3 signaling. OBJECTIVES: In the current study we sought to determine if alterations in driver mutations mediate the role of liver ECs in activating HER3 signaling and promoting cell survival in CRC cells. METHODS: Primary ECs from non-malignant liver parenchyma were isolated as previously described (Wang et al., Mol Cancer Res., 2018). CRC cell lines with distinct molecular profiles (MSI status, and wildtype or mutant KRAS, BRAF, and PIK3CA) were incubated with either their own CM (control) or CM from ECs. The effects of CM on CRC cell growth and response to 5-fluorouracil (5-FU) was determined by MTT and colony formation assays. The effect of angiocrine signaling on chemoresistance was also determined by fluorescence-activated cell sorting (FACS) for apoptosis after treating CRC cells with 5-FU, either in control CM or EC CM. HER3 blockade was accomplished by 1) siRNA knockdown or 2) a HER3 antibody. RESULTS: CM from liver ECs significantly increased cell growth and chemoresistance in CRC cells regardless of the gene alteration profiles in in vitro assays. We confirmed that EC CM activated the HER3-AKT signaling pathway in CRC cells. Furthermore, we found that HER3 blockade attenuated EC CM-induced AKT activation and cell survival in CRC cells independent of the cell mutational profile. CONCLUSIONS: Our results demonstrate that HER3 mediates liver EC-induced cell growth and chemoresistance in CRC cells independent of the driver mutational profiles of the cells. The genetic background of CRC cells is not a mediator of EC CM-induced HER3 activation and cell survival. These findings suggest that effects of HER3 targeting of tumor cells in patients with mCRC should be independent of MSI status, or RAS, BRAF, or PIK3CA mutational status. Citation Format: Rui Wang, Rajat Bhattacharya, Fan Fan, Xiangcang Ye, Lee M. Ellis. Angiocrine induction of colorectal cancer cell HER3 activation and cell survival is independent of CRC mutational status [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 5163.
Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Liver Disease
Authors: So-Ryoung Lee, Hyun-Jung Lee, Eue-Keun Choi, Kyung-Do Han, Jin-Hyung Jung, Myung-Jin Cha, Seil Oh, Gregory Y.H. Lip
Journal: Journal of the American College of Cardiology (2019)
Abstract 2575: EZH2 mediates resistance to cisplatin in small cell lung cancer through nucleotide excision repair
Authors: Allyson E. Koyen
Journal: Cancer Research (2019)

Abstract Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, with a five-year survival rate of 7%. Cisplatin-based chemotherapy is the first line treatment for SCLC; however, many patients develop treatment resistance and experience tumor recurrence. Targeting proteins critical to the repair of cisplatin DNA crosslinks is a strategy for overcoming acquired cisplatin resistance in SCLC, but many proteins that mediate crosslink repair have yet to be identified. To address this issue, we performed a synthetic lethal siRNA screen in cisplatin resistant SCLC cells, and identified EZH2 as one of the strongest mediators of cisplatin resistance. EZH2 localizes to sites of DNA damage which are induced by UVA-crosslinking laser microirradiation and interacts in a complex with DDB1, and DDB2, members of the nucleotide excision repair (NER) pathway. Loss of EZH2 sensitizes SCLC cells to UV damage, and further, loss of EZH2 and DDB1 together are epistatic in the sensitization of SCLC to cisplatin, confirming a role for EZH2 in NER. Specifically, EZH2 promotes the stability of DDB2, which is responsible for the detection NER lesions. This occurs independently of EZH2’s methyltransferase activity on H3K27. Finally, we found EZH2 expression correlates with cisplatin resistance across SCLC cell lines. Together, this data suggests that EZH2 functions as a novel regulator of NER, and that EZH2 is a promising target for cisplatin resistant SCLC. Citation Format: Allyson E. Koyen. EZH2 mediates resistance to cisplatin in small cell lung cancer through nucleotide excision repair [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 2575.
Association Between Caregiver Depression and Emergency Department Use Among Patients With Dementia
Authors: Elan L. Guterman, I. Elaine Allen, S. Andrew Josephson, Jennifer J. Merrilees, Sarah Dulaney, Winston Chiong, Kirby Lee, Stephen J. Bonasera, Bruce L. Miller, Katherine L. Possin
Journal: JAMA Neurology (2019)

Current attempts to gauge the acute care needs of patients with dementia have not effectively addressed the role of caregivers, despite their extensive involvement in decisions about acute care management.To determine whether caregiver depression is associated with increased use of the emergency department (ED) among patients with dementia.This longitudinal cohort study used data from the Care Ecosystem study, a randomized clinical trial examining telephone-based supportive care for patients with dementia and their caregivers. Patients were 45 years or older with any type of dementia. A total of 780 caregiver-patient dyads were enrolled from March 20, 2015, until February 28, 2017, and 663 dyads contributed baseline and 6-month data and were included in the analysis.Caregiver depression (9-item Patient Health Questionnaire score of ≥10). Secondary analyses examined caregiver burden and self-efficacy.The primary outcome was the number of ED visits in a 6-month period.Among the 663 caregivers (467 women and 196 men; mean [SD] age, 64.9 [11.8] years), 84 caregivers (12.7%) had depression at baseline. The mean incidence rate of ED visits was 0.9 per person-year. Rates of ED presentation were higher among dyads whose caregiver did vs did not have depression (1.5 vs 0.8 ED visits per person-year). In a Poisson regression model adjusting for patient age, sex, severity of dementia, number of comorbidities, and baseline ED use, as well as caregiver age and sex, caregiver depression continued to be associated with ED use, with a 73% increase in rates of ED use among dyads with caregivers with depression (adjusted incident rate ratio, 1.73; 95% CI, 1.30-2.30). Caregiver burden was associated with higher ED use in the unadjusted model, but this association did not reach statistical significance after adjustment (incident rate ratio, 1.19; 95% CI, 0.93-1.52). Caregiver self-efficacy was inversely proportional to the number of ED visits in the unadjusted and adjusted models (adjusted incident rate ratio, 0.96; 95% CI, 0.92-0.99).Among patients with dementia, caregiver depression appears to be significantly associated with increased ED use, revealing a key caregiver vulnerability, which, if addressed with patient- and caregiver-centered dementia care, could improve health outcomes and lower costs for this high-risk population.
Low doses of ketoconazole and prednisone in patients with castration resistant prostate cancer (CRPC): A retrospective study on 73 patients.
Authors: Gloria Amaniera, Valentina Ballatore, Fiorella Ruatta, Veronica Prati, Leonardo D'Urso, Giovanni Muto, Massimo Aglietta, Cinzia Ortega
Journal: Journal of Clinical Oncology (2013)

e16099 Background: The management of rising PSA in metastatic CRPC remains controversial. In Italy, abiraterone and enzalutamide are not at all approved in this setting of patients (pts). Ketoconazole is an inhibitor of adrenal androgen synthesis that has shown anti-tumor activity by interfering with C-17,20-lyase and could be used as secondary hormonal manipulation. In this retrospective study we report our experience with low doses of ketoconazole and prednisone in the treatment for CRPC. Methods: From March 2007 to March 2012, 73 pts with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally 2 times daily, orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Overall, 40/73 (55%) pts had only bone metastases, 13/73 (18%) had nodal metastases, 20/73 (27%) both. Pts were monitored clinically and with serial PSA measurements every month. Partial biochemical response (PR) was defined as a &gt;50% fall in PSA from baseline. Progressive disease (PD) was defined by objective disease progression or PSA increase of &gt;50% above nadir or &gt;25% above baseline. The endpoints of the study were biochemical response (BR), progression free survival (PFS), overall survival (OS) and adverse events assessment. Results: Median age was 74 (70-78) years; median baseline PSA was 33.09 (1.18-1348.8) ng/ml; median duration of the treatment was 5.05 (0-56.8) months. Twenty out 73 pts (27%) showed a decrease in PSA &gt;50%, with a median duration of PSA response of 3.56 (1.17-33.58) months and 3 pts (4%) a PD. Fifty out 73 pts (68%) achieved a SD with an overall disease control (PR+SD) of 85%. PFS was 10 months for pts who achieved PR and 4 months for those with SD. Differences in PFS stratified according to site of metastases showed better prognosis in patients with only lymph nodes disease (p&lt;0.05). Treatment with Ketoconazole was well tolerated and grades 3-4 toxicities occurred in only 3% of patients. Conclusions: Low-dose ketoconazole is an effective and well-tolerated treatment in pts with CRPC and should be considered in the subset of pts with low tumor burden and a rising PSA level despite maximal androgen blockade.
Abstract 1103: The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases
Authors: Owen M. Heath, Eleni Maniati, Chiara Belato, Ganga Gopinathan, Laura Lecker, Anissa Lakhani, Colin Pegrum, Jacqueline McDermott, Michelle Lockley, Desmond P. Barton, Frances Balkwill
Journal: Cancer Research (2019)

Abstract Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and are associated with poor clinical outcome. We hypothesise that targeting TAMs in high-grade serous ovarian cancer (HGSOC) may improve response to chemotherapy. We have assessed the effects of chemotherapy on TAM populations in human HGSOC obtained pre- and post-chemotherapy as well as in murine HGSOC models harbouring a relevant mutational profile. We find that chemotherapy treatment decreases TAM density within tumour areas. Furthermore, TAMs expressing markers known to associate with disease progression were decreased following chemotherapy. In vivo and in vitro we have demonstrated an up-regulation of inflammasome activation and TLR signalling in live myeloid cells following chemotherapy and have shown that macrophages are killed by chemotherapy at clinically relevant drug concentrations. These observations suggest a mechanism for TAM depletion and highlight chemotherapy induced activation of innate immunity in HGSOC. The majority of HGSOC patients respond well to first line chemotherapy but will relapse and succumb to treatment resistant disease. We have developed a murine model of HGSOC relapse after first-line chemotherapy, which has the potential to extend translational studies into this clinically important area. We have found that TAMs are re-established in tumours at relapse, suggesting a clinically defined window of opportunity to target TAMs in HGSOC following first-line chemotherapy. Overall, our results provide a rationale for targeted re-programming of TAMs in HGSOC after chemotherapy. Citation Format: Owen M. Heath, Eleni Maniati, Chiara Belato, Ganga Gopinathan, Laura Lecker, Anissa Lakhani, Colin Pegrum, Jacqueline McDermott, Michelle Lockley, Desmond P. Barton, Frances Balkwill. The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases [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 1103.
The role of interleukin-8 (IL-8) in predicting the outcome of metastatic colorectal cancer patients treated with aflibercept in combination to FOLFIRI: the FLIBER study
Authors: M. D’Arcangelo, C. Buonerba, A. Avallone, C. Dazzi, G. Frassineti, S. Tamberi, D. Tassinari, G. Aprile, C. Granetto, A. Bonetti, S. Vecchiarelli, F. Cappuzzo
Journal: Annals of Oncology (2019)
Abstract 935: Genetic modification potentiates the antitumor activity of human placental CD34+ cells-derived NK cells
Authors: James Li, Xuan Guo, Hemlata Rana, Andrea DiFiglia, Joseph Gleason, Uri Herzberg, Robert Hariri, Xiaokui Zhang
Journal: Cancer Research (2019)

Abstract Celularity is currently developing a proprietary allogeneic NK cells (PNK) derived from human placental CD34+ progenitors for treatment of a broad spectrum of blood disorders and malignant diseases. To augment the anti-tumor function of CD34-derived PNK-cells, a study was conducted to simultaneous knock-out (KO) CBLB (negative regulator of NK cytotoxicity) and TGFβ receptor II TGFBR2 (tumor microenvironment) genes in PNK-cells using CRISPR/Cas9. In DKCT (Double Knockout CBLB TGFBR2) cells, high efficiency of editing (&amp;gt;80%) was achieved for both genes and did not affect expansion and differentiation of CD34 cells into DKCT PNK-cells. The results showed that knocking-out CBLB (CBLB-KO) in PNK-cells led to an increase (2–4 fold) of cytotoxicity and cytokine secretion against a range of hematological and solid cancer cell lines as well as primary tumor cells. However, these enhanced functions from CBLB-KO PNK-cells were still found to be sensitive to TGFβ-mediated suppression. TGFBR2-KO rendered PNK-cells the ability to maintain high-level expression of NK activating receptors and resist inhibition of cytotoxicity after TGFβ exposure. The improved cytolytic function of DKCT cells in vitro was confirmed using xCELLigence platform. Furthermore, DKCT PNK-cells were insensitive to exogenous TGFβ and exhibited improved (2–4 fold) cytotoxicity. Subsequently, we compared the anti-tumor activity of DKCT to controls in an in vivo model of AML, where conditioned NSG mice were engrafted with HL60-GFP-luc cells 3 days prior to PNK-cell infusion. All four PNK-cell groups exhibited increased survival compared to vehicle. In CBLB-KO and DKCT groups, the tumor burden was similar but significantly reduced compared to Cas9 control or TGFBR2-KO. Future studies will address the benefit of DKCT PNK-cells in TGFβ secreting tumor-bearing animal models to pave the way for genetically modified NK cell therapy. Citation Format: James Li, Xuan Guo, Hemlata Rana, Andrea DiFiglia, Joseph Gleason, Uri Herzberg, Robert Hariri, Xiaokui Zhang. Genetic modification potentiates the antitumor activity of human placental CD34+ cells-derived NK cells [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 935.
Abstract 4951: Obesity-induced changes in baseline immune responses to pre-clinical breast cancer
Authors: Justin Gibson, Prabhakara Nagareddy, Lyse Norian
Journal: Cancer Research (2019)

Abstract Obesity is known to increase morbidity and mortality in breast cancer patients; however, the immunological contributions to such changes remain incompletely understood. Our long-term goal is to investigate the broad impact of obesity on anti-tumor immunity, with a particular focus on understanding the mechanisms underlying obesity-induced immune alterations and how these alterations may influence the use of immunotherapeutics in breast cancer patients. For our studies, we utilized a diet-induced model of obesity (DIO) in which mice were fed either a high-fat or low-fat diet to generate DIO or age-matched lean controls, respectively. Animals were then challenged with the syngeneic E0771 mammary carcinoma cell line. Tumor outgrowth was quantified by caliper measurements, bioluminescent imaging (BLI) via firefly luciferase-expressing E0771 (E0771-fLUC) cells, and endpoint tumor weights. Whole tumor immunogenetic gene expression profiles were evaluated using nanoString and immune populations were assessed via multi-parameter flow cytometry. All measures of tumor outgrowth reveal that obesity significantly increases primary tumor outgrowth and induces a variety of alterations to the immunogenetic profile. Additionally, obesity significantly alters the frequency of intra-tumoral immune populations, including decreases in CD4+ and CD8+ T cells, increases in granulocytic myeloid-derived suppressor cells (G-MDSCs) and myeloid dendritic cells (mDCs), and a trending decrease in total CD45+ tumor infiltrating leukocytes. These alterations are specific to the tumor environment, as they are not present in the spleens of tumor-bearing mice. Collectively these data implicate obesity as a causal agent in impairing anti-tumor immune responses to murine mammary tumors. Furthermore, they suggest several cellular candidates for future mechanistic investigations into obesity-induced alterations in breast cancer immunity. Citation Format: Justin Gibson, Prabhakara Nagareddy, Lyse Norian. Obesity-induced changes in baseline immune responses to pre-clinical 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 4951.
Abstract 1824: Long noncoding RNA NR_027340 promotes head and neck cancer cell proliferation and glycolysis via PFKP
Authors: Yifan Yang, Ru Wang, Ling Feng, Qian Shi, Chen Tan, Jugao Fang
Journal: Cancer Research (2019)

Abstract Introduction: Long noncoding RNAs (lncRNAs) play crucial roles in various cancers. Recent study has indicated that lncRNA NR_027340 was significantly upregulated in head and neck cancer (HNC). However, its multifaceted roles in HNC are unclear. Here we demonstrate the role of lncRNA NR_027340 in HNC cell proliferation and glycolysis. Methods: qRT-PCR was used to detect lncRNA NR_027340 expression in HNC tissues, and the correlations between lncRNA NR_027340 and clinicopathologic features were then analyzed. RNA pull-down and mass spectrometry analysis were carried out to explore the lncRNA NR_027340-bound proteins. RNA immunoprecipitation (RIP) was used to confirm the association between lncRNA and relevant proteins. lncRNA NR_027340 knockout cell lines were generated using the CRISPR/Cas9. Colony formation, cell cycle analysis and flow cytometry were used to measure the proliferation of HNC cells. The production of lactate was observed to evaluate the glycolysis of HNC cells. Results: We found lncRNA NR_027340 was significantly up-regulated in HNCs and the elevated lncRNA NR_027340 was correlated with poor clinical prognosis. Mechanistically, we identified PFKP as the protein partner of lncRNA NR_027340 in the cytoplasm. In addition, we found that both lncRNA NR_027340 and PFKP depletion reduced the cell proliferation and glycolysis in vitro. The ingenuity pathway analysis and Western blot assay indicated that lncRNA NR_027340 targeted PFKP to regulate cell proliferation and glycolysis in HNC. Conclusion: These findings reveal a functional role for lncRNA NR_027340 in altering glycolysis and promoting proliferation in HNC cells, suggesting that lncRNA NR_027340 might serve as a prognostic and diagnostic indicator as well as a potential therapeutic target. Citation Format: Yifan Yang, Ru Wang, Ling Feng, Qian Shi, Chen Tan, Jugao Fang. Long noncoding RNA NR_027340 promotes head and neck cancer cell proliferation and glycolysis via PFKP [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 1824.