bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3891: A phase 1 study to evaluate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer (OC)
Authors: Zhang Jian , Gao Yu Nong , Lou Ge , Yin Ru Tie , Hou Jian Mei , Yan James , Li Jing , Zhang Zhi Yi , Wu Xiao Hua 
Published: August 2019

Abstract
Purposes: To characterize the PK and safety of niraparib as a maintenance therapy in Chinese OC patients.
Methods: Eligible patients were randomized 1:1:1 to 100, 200, or 300 mg once daily cohort. Plasma samples were collected following single and multiple dosing and analyzed using a validated LC/MS/MS method. PK parameters were analyzed by standard non-compartmental approach with WinNonlin. A population PK (Pop PK) model was derived from pooled PK data of current study and two previous PK studies in Caucasian: the dose escalation and expansion study (PN001), and the ENGOT-OV16/NOVA sub-study. Non-linear mixed effect modeling was done with NONEM®.
Results: 36 patients were randomized and included in the PK and safety analysis set. Niraparib was rapidly absorbed after dosing with tmax~3h. The exposure of niraparib was dose proportional, while other PK parameters such as t1/2, accumulation ratio were dose independent (Table 1). The POP-PK analysis model was established using PK data from 144 Caucasians and 39 Chinese. Chinese patients had a slightly higher Cmax than Caucasian patients but similar total exposure (AUC0-∞) after a single dose. Simulation by final Pop PK model indicated comparable total exposure (AUC0-∞) and Cmax between Chinese and Caucasian patients at the steady-state following multiple daily doses. Treatment emergent AEs (TEAEs) occurred in 97.2% of all patients treated with niraparib. The most frequent (&gt;20%) TEAEs were consistent with the known safety profile of PARP inhibitors. TEAEs of Grade 3/4 reported in ≥ 5% patients included decreased platelet count (13.9%), decreased neutrophil count (11.1%), anemia (8.3%) and increased gamma-glutamyl transferase (5.6%).
Conclusions: The PK profile of niraparib in Chinese was consistent with its known profile in Caucasian. Niraparib in Chinese OC patients has a manageable safety profile, similar to that observed in global studies. (NCT03551171)
Citation Format: Jian Zhang, Yu Nong Gao, Ge Lou, Ru Tie Yin, Jian Mei Hou, James Yan, Jing Li, Zhi Yi Zhang, Xiao Hua Wu. A phase 1 study to evaluate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer (OC) [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 3891.
Abstract 3907: Synergistic effect of targeting both CDK4/6 and mTORin sarcoma cell lines
Authors: Wang Xiaochun , Goldstein David , Crowe Philip , Yang Jia-Lin 
Published: August 2019

Abstract
Background: The phosphatidylinositide-3-kinase/Protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling is central for cancer growth, survival and motility. One of the key restraints on cell growth downstream is retinoblastoma (Rb) tumour suppressor, which is negatively regulated by the cyclin-dependent protein kinases (CDK) 4/6 protein. We hypothesize that blocking both the CDK4/6 and the mTOR allows the double brakes to tumour growth.
Aim: Our aim is to investigate whether combination therapy using mTOR and CDK4/6 inhibitors (palbociclib and ridaforolimus) would have a synergistic growth inhibitory effect in sarcoma.
Methods: The effect and mechanism of palbociclib and ridaforolimus was investigated in a panel of twelve sarcoma cell lines by Crystal-violet colorimetric and Western blot assays. HT1080 fibrosarcoma metastatic mouse model was investigated for in vivo therapeutic study.
Results: Palbociclib showed anti-proliferation in all cell lines (IC50s: 0.1-1.1µM), while ridaforolimus had growth inhibition in 10/12 cell lines (IC50s: 0.4-26nM). The palbociclib-ridaforolimus combination achieved synergistic effect (CIs: 0.1-0.9) in 9/12 cell lines, including applying the drugs in different sequence (together or pre-treatment with one drug for 24-48 hours) and ratio (1:1, 1:2, 1:4, 2:1 or 4:1). The Western blot demonstrated that the 2-drug combination further blocked both CDK/Rb/E2F and AKT/mTOR pathways, via promoting apoptosis. In the experimental lung metastatic HT1080 mouse model, using palbocilib (10 and 30mg/kg, every other day) and ridaforolimus (0.1 and 0.3mg/kg, daily for 5 days per week) for 4 weeks synergistically (CI = 0.7) inhibited the development of lung metastases (mean number of colonies: 132 in low combination dose and 38 for high combination dose) compared to monotherapy [243 (palbociclib) and 255 (ridaforolimus) in low dose, 113 and 97 for high dose) and vehicle control (286). In the orthotopic fibrosarcoma HT1080 mouse model, the palbociclib-ridaforolimus combination therapies achieved significant (p&lt;0.001) and synergistic (CI=0.00375) growth inhibitory effect compared to monotherapies and control groups.
Conclusions: This study demonstrated that palbociclib-ridaforolimus combination is active in a variety of sarcoma subtypes and worthy of further development towards a clinical trial.
Citation Format: Xiaochun Wang, David Goldstein, Philip Crowe, Jia-Lin Yang. Synergistic effect of targeting both CDK4/6 and mTORin sarcoma cell lines [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 3907.
Abstract 3914: mTOR pathway components dictate cell response to Src inhibitors in prostate cancer cells
Authors: Dai Yao , Siemann Dietmar W. 
Published: August 2019

Abstract
Src inhibitors have been actively evaluated in the clinic for the treatment of advanced prostate cancer however the effects are modest. One interpretation is that oncogenic signaling pathways are redundant and blocking one pathway is not sufficient to yield considerable efficacies. mTOR pathway is commonly hyperactivated in prostate cancer. However, the functional role of mTOR in Src inhibitor-mediated response remains largely unknown. In the current study, we combined mTOR inhibitor rapamycin and Src inhibitor dasatinib to detect functional behaviors in prostate cancer cells. Cell proliferation and clonogenic survival were detected by MTT and colony formation assay, respectively. Wound-healing” scratch assay was conducted to monitor cell migration, and Matrigel-based transwell assay was applied to assess cell invasion. Protein expression was detected by Western blotting. Gene silencing was detected by siRNA transfection. We found that two agents combined together showed greater inhibition on proliferation and clonogenic survival than either agent alone. Such combination effects were additive or synergistic depending on the cell types, as reflected by combination index calculation. In addition, cell migration and invasion were inhibited in a greater extent by rapamycin plus dasatinib, compared to either treatment alone. At the molecular level, co-targeting mTOR and Src lead to clear inhibition of Src and its downstream pathway focal adhesion kinase (FAK), Akt and mTOR downstream components S6RP and 4E-BP1. Interestingly, knockdown 4EBP1, but not S6RP, attenuated dasatinib-mediated functional inhibition. These data indicate that adding mTOR inhibitors to Src-based intervention may achieve better treatment outcomes. Such combination could be evaluated as a novel treatment strategy for prostate cancer patients who are less responsive to Src inhibitors. In addition, 4EBP1 may be used as a candidate predictive biomarker for monitoring clinical effectiveness of Src inhibitors in prostate cancer.
Citation Format: Yao Dai, Dietmar W. Siemann. mTOR pathway components dictate cell response to Src inhibitors in prostate cancer 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 3914.
Abstract 392: LKB-inactivated lung cancer cells exhibit dependency on INSL4 signaling
Authors: Yang Rongqiang , Li Steven W. , Chen Zirong , Zhou Xin , Ni Wei , Fu Dongtao A. , Lu Jianrong , Kaye Frederic J. , Wu Lizi 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. The LKB1 (STK11) tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Currently, no effective treatments are available for LKB1-inactivated lung cancer. Elucidation of critical signaling downstream of LKB1-inactivation has the potential to uncover rational therapeutic targets for this unique and prevalent molecular subset of lung cancers. In this study, we identified INSL4 (insulin-like 4), a member of the insulin/IGF/relaxin superfamily, as a novel downstream target of LKB1-deficiency through gene expression profiling analysis. We observed that INSL4 expression was highly induced through aberrant CRTC-CREB activation subsequent to LKB1 inactivation. INSL4 was highly expressed in human LKB1-deficient NSCLC cells and primary tumors while undetectable in all normal tissues except in the placenta. High INSL4 expression was associated with more advanced lung cancer and worse patient survival. INSL4 depletion inhibited the growth and viability of LKB1-null NSCLC cells in vitro and blocked the growth of lung cancer xenografts. Moreover, expression profiling identified an INSL4-regulated gene program that is associated with the regulation of cell cycle, growth, and survival. In conclusion, LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.
Citation Format: Rongqiang Yang, Steven W. Li, Zirong Chen, Xin Zhou, Wei Ni, Dongtao A. Fu, Jianrong Lu, Frederic J. Kaye, Lizi Wu. LKB-inactivated lung cancer cells exhibit dependency on INSL4 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 392.
Abstract 3946: Tumor checkpoint inhibitor profiling for an optimal clinical response
Authors: Maniyar Rachana R. , Chakraborty Sanjukta , Rahoma Ghada Ben , Degliuomini John J. , Wallack Marc , Geliebter Jan , Tiwari Raj K. 
Published: August 2019

Abstract
The last three decades have seen a steady rise in melanoma, the most aggressive form of skin cancer. The discovery of checkpoint inhibitors has revolutionized the treatment landscape for melanoma; anti-CTLA4 and anti-PD1 showing great successes in clinic. While checkpoint molecules and co-stimulatory molecules are traditionally present on cells involved in immune activation, mounting evidence suggests that tumor cells also express these molecules. Our laboratory has characterized five patient-derived melanoma cell lines, MEL-2, MEL-V, 3MM, KFM, and GLM-2 and screened them for the expression of a comprehensive list of 29 co-stimulatory and co-inhibitory molecules compared to normal adult melanocytes. We see a differential mRNA expression of many of these immune-regulatory molecules, including BTLA, HVEM, CD160, CD226 and TIM1. Western blots and immunofluorescence confirmed the presence of these molecules at the protein level. A flow cytometry analysis demonstrated that BTLA, HVEM, CD160, TIM1 and CD226 are present on the membrane of these patient derived melanoma cells; implying that they are capable of engaging their respective ligands and exerting a functional role in immunomodulation. These findings were additionally validated in melanoma tissues, obtained from patients, by immunohistochemistry. Interestingly, treatment of MEL-2, MEL-V, KFM and GLM-2, our BRAFV600E containing patient derived cells, with BRAFV600E inhibitor PLX4032 led to the upregulation of these molecules. This upregulation was coupled with an increase in transcription factor MITF, a binding site for which is present in the promoter region of all the upregulated molecules. Co-culture experiments with immune cells, demonstrate a modulatory role played by the HVEM/BTLA/CD160 axis molecules that are present on tumor cells. The presence of these additional immune-regulatory molecules signify the existence of a robust tolerance mechanism induced by these checkpoint inhibitors. Our studies underscore the importance of characterizing tumor profiles to enable the selection of an optimal treatment regimen combining targeted small molecule inhibitors, and checkpoint inhibitors to maximize T cell killing, and tumor clearance.
Citation Format: Rachana R. Maniyar, Sanjukta Chakraborty, Ghada Ben Rahoma, John J. Degliuomini, Marc Wallack, Jan Geliebter, Raj K. Tiwari. Tumor checkpoint inhibitor profiling for an optimal clinical response [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 3946.
Abstract 3962: Chemotherapy induces alteration of programmed death ligand-1 expression in gastric cancer
Authors: Yamashita Kohei , Iwatsuki Masaaki , Iwagami Shiro , Eto Kojiro , Koga Yuki , Kiyozumi Yuki , Baba Yoshifumi , Yoshida Naoya , Baba Hideo 
Published: August 2019

Abstract
Background Cancer immunotherapy targeting the programmed cell death 1 (PD-1) / programmed death ligand 1 (PD-L1) pathway have been demonstrated favorable therapeutic effect in gastric cancer (GC). However, it remains unclear that PD-L1 expression in GC tissue can be a biomarker to predict the therapeutic effect of immune checkpoint inhibitors. We hypothesize that prior therapy, including chemotherapy and radiation therapy can lead to the alteration of PD-L1 status, resulting in imprecise evaluation of PD-L1 expression. The aim of this study is to clarify the effect of cytotoxic agents on PD-L1 expression in GC cells in time and dose depending manner. Methods PD-L1 expression of GC cell lines were confirmed by quantitative PCR and western blotting. Two gastric cancer cell lines, which have low PD-L1 expression, are selected and used in subsequent in vitro experiment. We evaluated the expression of PD-L1 in these cell lines by quantitative PCR and western blotting after exposure to cytotoxic agents at various concentrations and exposure times. Furthermore, we examined whether the expression of PD-L1 induced by cytotoxic agents was maintained after ceasing the 5-FU exposure. The gene pathway regulating PD-L1 induction was also examined. Results The PD-L1 expression of the selected GC cell lines were upregulated, depending on the concentration and exposure time of cytotoxic agents. Furthermore, the PD-L1 expression induced by cytotoxic agents was maintained even after cessation of exposure. We clarify that the upregulation of PD-L1 expression was induced via p38 MAPK activation. Conclusion We demonstrated that cytotoxic agent can alter the expression of PD-L1 in GC cells through the activation of p38 MAPK pathway in dose and time depending manner. Our findings suggested that the modified administration of immune checkpoint inhibitors can improve the antitumor response, leading to promising new treatment strategy against GC.
Citation Format: Kohei Yamashita, Masaaki Iwatsuki, Shiro Iwagami, Kojiro Eto, Yuki Koga, Yuki Kiyozumi, Yoshifumi Baba, Naoya Yoshida, Hideo Baba. Chemotherapy induces alteration of programmed death ligand-1 expression in gastric 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 3962.
Abstract 3973: Nivolumab-based ELISA revealed increased serum PD-1 levels in advanced RCC patients
Authors: Mizutani Kosuke , Horie Kengo , Kato Taku , Nakane Keita , Kawakami Kyojiro , Fujita Yasunori , Ito Masafumi 
Published: August 2019

Abstract
Introduction: Antibody therapy has been successfully used for several caners, but the efficacy is still limited. To select patients that respond well to the therapy, development of companion diagnostics is essential. Although PD-L1 expression determined by immunohistochemistry has been shown to be a marker to select patients with non-small-cell lung cancer who will benefit from antibody therapy, its potential for Nivolumab treatment in renal cell carcinoma (RCC) patients is unclear. Detection of the soluble form of PD-1 in serum has been reported, but there are few studies demonstrating its clinical role in RCC. Antibody-based assays may rely on characteristics and quality of antibody used. We hypothesized that the use of Nivolumab as a capture antibody in ELISA would give more clinically relevant results to evaluate the serum PD-1 levels in RCC patients.
Materials and Methods: After approval of the study by the Medical Review Board of Gifu University, a total of 71 participants were recruited (22; healthy volunteers, 29; localized RCC and 20; RCC patients with metastasis or recurrence). Serum PD-1 levels were determined using PD-1 Human ELISA Kit (Thermo Fisher Scientific Inc., MA, USA). For Nivolumab-based ELISA, a capture antibody included in the kit was changed to Nivolumab. Nivolumab was coated to 96-well microplates using a commercially available kit.
Results: Medians of the serum PD-1 levels measured by conventional ELISA were 31.8, 29.8 and 34.3 pg/ml in healthy volunteers, localized RCC patients and those with metastasis or recurrence, respectively, which showed no statistically significant difference. When the same set of patients were analyzed by Nivolumab-based ELISA, medians were 24.6, 23.7 and 46.4 pg/ml and the serum PD-1 levels were significantly elevated in patients with metastasis or recurrence (P = 0.013) compared to controls and localized patients. Of the 29 localized patients, 3 patients with relatively higher serum PD-1 levels at initial diagnosis relapsed later. Among 6 patients with metastasis who were treated with Nivolumab, well responders showed relatively lower serum PD-1 levels before treatment.
Conclusion: The serum PD-1 levels determined using Nivolumab were increased in advanced RCC patients. Our results suggest that the detection of target molecules using a therapeutic antibody may yield more clinically relevant information, thus providing a novel approach to develop companion diagnostics.
Citation Format: Kosuke Mizutani, Kengo Horie, Taku Kato, Keita Nakane, Kyojiro Kawakami, Yasunori Fujita, Masafumi Ito. Nivolumab-based ELISA revealed increased serum PD-1 levels in advanced RCC 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 3973.
Abstract 3981: Exosomal microRNA profiles in peritoneal fluids as a therapeutic biomarker for peritoneal metastasis of gastric cancer
Authors: Ohzawa Hideyuki , Saito Akira , Kumagai Yuko , Yamaguchi Hironori , Hosoya Yoshinori , Sata Naohiro , Kitayama Joji 
Published: August 2019

Abstract
Objectives: Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer and has poor prognosis even with systemic chemotherapy. Intraperitoneal chemotherapy (IPC) using paclitaxel (PTX) combined with systemic chemotherapy has demonstrated a remarkable clinical efficacy for gastric cancer with PM. However, there is no reliable biomarker to reflect the response of peritoneal lesions as well as to predict the outcome of the patients receiving IPC. Although peritoneal fluids are considered to contain many factors derived from disseminated tumor cells in peritoneal cavity, little information is available so far. In this study, we examined exosomal miRNA profiles derived from peritoneal fluids in patients with gastric cancer and explored possible biomarkers useful for IPC of the patients with PM.
Methods: Peritoneal fluids were collected from 2 groups; with or without PM. Peritoneal fluids were obtained either laparoscopically, during open surgery or from subcutaneous infusion port connected to an intraperitoneal catheter. Exosomal fractions were isolated using ultracentrifuge method (150,000 xg, 70 min, 4°C) and the presence of exosome was confirmed with nanotracking analysis. Total RNA including small RNA was extracted from exosomal fractions and expression analyses of miRNAs were performed using RT-PCR.
Results: At first, we comprehensively analyzed the expression of miRNAs between 11 samples with PM and 14 samples without PM and identified 11 miRNAs which showed particularly different expression pattern between the 2 groups. Among them, 4 miRNAs (miR-21-5p,miR-223-3p, miR-342-3p and miR-92a-3p) were selected and further analysed using 51 samples derived from the peritoneal fluids of gastric cancer. Expression of these 4 miRNAs were significantly up-regulated in samples with PM which was consistent with formeranalysis. Moreover, expression of miR-21-5p was significantly upregulated in in samples fromT4 tumor (invaded serosa or adjacent structure) as compared with those from T1 to T3 tumor.
Conclusion: We identified several dysregulated exsosomal miRNAs derived from peritoneal fluids of the patients with PM from gastric cancer, which were supposed to reflect the tumor burden on peritoneum. Exosomal miRNA profiles might be useful biomarkers to determine the presence of PM as well as the response to IPC.
Citation Format: Hideyuki Ohzawa, Akira Saito, Yuko Kumagai, Hironori Yamaguchi, Yoshinori Hosoya, Naohiro Sata, Joji Kitayama. Exosomal microRNA profiles in peritoneal fluids as a therapeutic biomarker for peritoneal metastasis of gastric 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 3981.