tbuckley/cabot-search huggingface dataset:
A phase I study of the CDK4/6 inhibitor, palbociclib plus 5-fluorouracil (5FU) in patients with advanced solid tumor malignancies (NCT01522989).
Authors: Michael J. Pishvaian, Hongkun Wang, Brandon George Smaglo, Jennifer Gao, Laura Macke, Erica Redmond, Eva Camilla Andersson Permaul, Supti Sen, Damian L. McCarthy, Bhaskar Kallakury, Stephen V. Liu, Aiwu Ruth He, Jimmy J. Hwang, Sandra M. Swain, John Marshall, Paula Raffin Pohlmann
Journal: Journal of Clinical Oncology (2016)

2589 Background: We demonstrated in mouse xenografts that CDK4/6 inhibition with palbociclib (P) is synergistic with 5FU in suppressing tumor growth. Based on these preclinical data, we initiated a Phase I trial to evaluate the safety and activity of P plus 5FU. Methods: Eligible patients (pts) had advanced, retinoblastoma (Rb)-positive (as demonstrated by IHC) solid tumors with an adequate performance status and intact organ function. The first stage of the study was a dose escalation to identify the recommended phase II dose (RP2D) of P in this combination (n = 21). The second stage is an ongoing schedule optimization, in which the timing of the P and 5FU are varied to identify the most effective sequence, as demonstrated by Ki67 suppression (n = 8 to date). All pts underwent tumor biopsies prior to treatment (tx), after 7 days of P, and again after the 5FU infusion. Results: Six pts were enrolled at a P dose of 50mg orally daily, Days 1-7, and IV 5FU as a 400mg/m2 bolus Day 8, and 2400mg/m2 continuous infusion Days 8-10, on an every 2 week cycle. However, 5/6 pts experienced significant delays in tx due to persistent myelosuppression, though only 1 met the definition of dose-limiting toxicity (DLT). The protocol was thus amended to remove the 5FU bolus. An additional 23 pts were enrolled. Most pts had colorectal (19) or breast (6) cancer; and pts had received a median 3 prior lines of Tx. 17 pts were DLT evaluable. The most common adverse events (AEs) were neutropenia (10), thrombocytopenia (4), nausea (N) (4), vomiting (V) (3), and mucositis (3). There were 4 DLTs (treatment delay (1), N/V (3)). The RP2D of P in this combination was 100mg orally daily. Efficacy was evaluable in 26/29 pts. One pt experienced a confirmed PR (Breast), and 6 pts had SD for a DCR of 27%. The median PFS in these 7 pts was 10 months, with 3 pts still on study. Tumor assessment of changes in Ki67 and Rb status are ongoing. Conclusions: The combination of P and 5FU is safe at a RP2D of P of 100mg. Accrual to schedule optimization is nearly complete, and the optimal schedule will be presented. This combination demonstrated promising disease control in this highly refractory population and should be tested in disease-specific Phase II trials. Clinical trial information: NCT01522989.
Abstract 5125: Immunomodulatory activity of bitter melon extract in head and neck squamous cell carcinoma
Authors: Sourav Bhattacharya, Robert Steele, Naoshad Muhammad, Guangyong Peng, Ratna B. Ray
Journal: Cancer Research (2016)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and leading cause of cancer related mortality worldwide. Despite the advancement in treatment procedures the overall survival rate of patients has not considerably enhanced in the past few decades. Therefore, new strategies to achieve a favorable response for the improvement in the prognosis of HNSCC are urgently needed. In this study we examined the immune modulatory activity of bitter melon extract (BME) in HNSCC tumor microenvironment. For this, mouse head and neck cancer (SCCVII) cells were subcutaneously injected into the flanks of C3H mice. BME was fed orally, and tumor growth was evaluated. We observed that BME treatment significantly inhibits the tumor growth in BME fed mice as compared to control group. Flow cytometry data showed that BME treatment not only decreases the infiltrating T regulatory (Treg) cells in the tumor but also in splenocytes. Additionally, BME treatment reduces Th17 cell population in the tumor and augments in the spleen. However, BME treatment did not alter Th1 and Th2 populations. Further study suggested that BME inhibits cell proliferation as evident from low expression of PCNA and c-Myc in the tumors of BME fed mice as compared to that of control group. To our knowledge, this is the first report showing BME exerts immunomodulatory effect in regressing HNSCC tumor growth in preclinical model. Citation Format: Sourav Bhattacharya, Robert Steele, Naoshad Muhammad, Guangyong Peng, Ratna B. Ray. Immunomodulatory activity of bitter melon extract in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5125.
Abstract 1796: Metformin may function as an anti-cancer agent of pancreatic cancer via targeting RET signaling pathway
Authors: Xiang-Lin Tan, Wen Yue, Tao Wang, Darren Carpizo, Yong Lin, Xi Zheng, Chung S. Yang, Lanjing Zhang, Qing Xu, Robert S. DiPaola
Journal: Cancer Research (2016)

Abstract Pancreatic cancer (PaCA) is one of the most lethal human cancers and is the fourth leading cause of cancer-related deaths in the United States. However, there are currently no established recommendations for prevention of PaCA using pharmacological agents. Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its effects on inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the key underlying molecular mechanisms for the inhibitory effects of metformin on PaCA progression remain largely unknown. Using RNA sequencing followed by the confirmation of RT-PCR and Western blotting, we found that metformin significantly decreased the mRNA and protein levels of RET (REarranged during Transfection), a single-pass transmembrane receptor tyrosine kinase (RTK). RET and its ligand, glial cell-derived neurotrophic factor (GDNF), were strongly expressed in PaCA and correlated to invasion and worse survival after surgical resection. GDNF, as a chemoattractant for PaCA cells, can activate RET to induce tumor progression, migration and invasion in vitro and in vivo. We further observed that metformin significantly inhibited GDNF-induced migration and invasion of PANC-1 cells. These data indicate that targeting RET with metformin or the combination of metformin and RET inhibitors may be an attractive and novel strategy for the prevention and treatment of PaCA progression and metastasis. To elucidate the molecular mechanisms for the inhibitory effects of metformin on the growth and spread of PaCA in humans, further in vitro and in vivo studies are warranted to investigate how metformin modulates RET signaling to inhibit the progression and metastasis of PaCA. Such studies have potential clinical significance using metformin as adjuvant preventive and therapeutic options for PaCA prevention and treatment. [This work was supported by grants from the National Cancer Institute at the National Institutes of Health (K07CA190541 and P30CA072720) and the National Natural Science Foundation of China (Grant No.: 81470132)] Citation Format: Xiang-Lin Tan, Wen Yue, Tao Wang, Darren Carpizo, Yong Lin, Xi Zheng, Chung S. Yang, Lanjing Zhang, Qing Xu, Robert S. DiPaola. Metformin may function as an anti-cancer agent of pancreatic cancer via targeting RET signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1796.
High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival
Authors: Daniel T. Utzschneider, Francesca Alfei, Patrick Roelli, David Barras, Vijaykumar Chennupati, Stephanie Darbre, Mauro Delorenzi, Daniel D. Pinschewer, Dietmar Zehn
Journal: The Journal of Experimental Medicine (2016)

Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.
Abstract 3879: Comprehensive delineation of stromal proteins implicated in the multistage carcinogenesis and identification of Tenascin-C as stromal marker for metastasis of colon carcinoma
Authors: Yongheng Chen, Maoyu Li
Journal: Cancer Research (2016)

Abstract Colon carcinoma (CC) is one of the most common malignancies threatening the human health. Early diagnosis or effective biomarker for intervention is still a challenge in clinical application for CC. The stroma in human cancer provides the microenvironment for cancer initiation and development, and furthermore, the stroma has been regarded as a therapeutic target for cancer. However, little is known about the dynamics of proteins within the stroma during the carcinogenic process. To discover the involvement of stroma in carcinogenesis and identify the biomarker candidates, the stromal components at the various stages of colonic carcinogenesis were purified by laser capture microdissection (LCM) and iTRAQ-based quantitative proteomic analysis was used for identifying the differentially expressed stromal proteins at different stages. In total, 222 differentially expressed proteins were identified. The expression of two of the top ranked proteins, extracellular matrix protein TNC and S100 family protein S100A9, was further confirmed by immunohistochemical analysis. Further analysis revealed that TNC was highly expressed in the stroma of metastasis and also abundantly secreted by the high metastatic cells. These results suggested that TNC was potential stromal marker for metastasis of colon carcinoma. Our results will contribute to investigating the role of stroma in the colonic carcinogenesis and might provide clues for pathogenesis, early diagnosis, and clinical therapy of CC. Citation Format: Yongheng Chen, Maoyu Li. Comprehensive delineation of stromal proteins implicated in the multistage carcinogenesis and identification of Tenascin-C as stromal marker for metastasis of colon carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3879.
Abstract 1045: Targeting NAMPT in Ewing's sarcoma cells
Authors: Cornelia N. Mutz, Raphaela Schwentner, Eric Bouchard, Edgard M. Mejia, Anna M. Katschnig, Maximilian O. Kauer, Dave N.T. Aryee, Antje Garten, Versha Banerji, Heinrich Kovar
Journal: Cancer Research (2016)

Abstract Ewing Sarcoma (ES) is the second most common bone cancer in children and adolescents with a high metastatic potential. Tumor development is driven by the specific t(11;22)(q24;q12) chromosomal translocation resulting in the generation of the chimeric transcription factor EWS-FLI1. NAD is a key metabolite of energy metabolism being involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability serving as a donor of ADP-ribose. This study describes targeting NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in salvage generation of NAD, by FK866 in ES cells. Using FK866 has been proposed as a treatment option for various inflammatory diseases as well as cancer, rendering ES cells with high NAMPT expression especially susceptible to FK866-induced cytotoxicity. Here we report that NAMPT inhibition in ES cells leads to exhaustive NAD depletion, followed by a delayed reduction of ATP levels and concomitantly to apoptosis-mediated cell death. These effects can be reversed by nicotinic acid, a substrate for the NAD salvage generation. However, the use of a doxycycline-inducible shRNA against EWS-FLI1 revealed that the cytotoxic activity of NAMPT inhibition is significantly lowered in the absence of EWS-FLI1. EWS-FLI1-low ES cells have higher viability and lower rates of apoptosis throughout inhibitor treatment compared to cells with high EWS-FLI1 expression. Additionally, changes in mitochondrial respiration and glycolytic rate can be observed when comparing untreated versus EWS-FLI1 knockdown ES cells after NAMPT inhibition. Interestingly, loss of EWS-FLI1 leads to elevated NAD levels and results in alteration of RNA expression of some enzymes involved in the NAD synthesis pathway. These results might explain the high susceptibility of Ewing Sarcoma cells to FK866 treatment. Taken together, our data reveal evidence of an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of ES cells and suggests NAMPT inhibition as a potential new treatment approach for Ewing Sarcoma in combination with standard therapies. Supported by the Austrian Science fund, grant I1225-B19; and the Research Manitoba and CancerCare Manitoba Foundation. Citation Format: Cornelia N. Mutz, Raphaela Schwentner, Eric Bouchard, Edgard M. Mejia, Anna M. Katschnig, Maximilian O. Kauer, Dave N.T. Aryee, Antje Garten, Versha Banerji, Heinrich Kovar. Targeting NAMPT in Ewing's sarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1045.
Abstract 4046: The role of TFPI2 and FGF2 in asbestos-induced mesothelial to fibroblastic transition
Authors: Joyce K. Thompson, Jill Miller, Maximilian B. MacPherson, Arti Shukla
Journal: Cancer Research (2016)

Abstract Mechanisms involved in the tumorigenesis of the devastating cancer, malignant mesothelioma (MM) are poorly understood. We have recently shown that interleukin-1β (IL-1β), an inflammatory cytokine is upregulated by asbestos via the activation of the inflammasome (a molecular platform that assembles for the activation of caspase-1) in mesothelial cells. Furthermore we have demonstrated that IL-1β secretion may lead to the activation of downstream signaling cascades involved in malignant transformation of mesothelial cells. Preliminary data from our lab indicate that in addition to IL-1β, asbestos exposure upregulated the secretion of basic fibroblast growth factor (bFGF/FGF2) and tissue factor pathway inhibitor 2 ((TFPI2) a kunitz type protease inhibitor). These factors were also regulated by the inflammasome and have never before been implicated in asbestos-induced mesothelial to fibroblastic transition (MFT). Based on our preliminary data, we hypothesized that upregulation of IL-1β by asbestos-induced inflammasome activation increases FGF2 secretion and signaling. Furthermore, we hypothesize that FGF2 together with increased TFPI2 secretion induces transition of mesothelial cells to a fibroblastic phenotype that facilitates MM carcinogenesis. In the proposed study we will delineate the role of TFPI2 (siRNA) and FGF2 (pan FGFR inhibitor, BGJ398) in the process of asbestos-induced MFT. Data from this study will provide added insight into the mechanisms involved in the initiation of MM and indicate whether TFPI2 and FGF2 can serve as drugable targets for combination therapy against MM. This work is supported by NIH grant, RO1 ES021110. Citation Format: Joyce K. Thompson, Jill Miller, Maximilian B. MacPherson, Arti Shukla. The role of TFPI2 and FGF2 in asbestos-induced mesothelial to fibroblastic transition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4046.
Infusion of Donor Lymphocytes Genetically Engineered to Express the Herpes Simplex Virus Thymidine Kinase (HSV-TK) Suicide Gene after Haploidentical Hematopoietic Stem Cell Transplantation (HSCT): Preliminary Efficacy Data from the Randomized TK008 Study
Authors: Chiara Bonini, Fabio Ciceri, Arnon Nagler, Evangelia Yannaki, Maria Teresa Lupo Stanghellini, Giacomo Oliveira, Attilio Bondanza, Luca Vago, Raffaella Greco, Jacopo Peccatori, Eduardo Olovarria, Eva M. Mischak-Weissinger, Michael Stadler, Donald Bunjes, Dietger Niederwieser, Lutz Uharek, Wolfgang A. Bethge, John F. DiPersio, Michele L Donato, Andrew L Pecora, Scialini Colombi, Lambiase Antonio, Claudio Bordignon
Journal: Blood (2014)
Abstract 2177: Differential expression of stromal cell-related genes between primary nasopharyngeal carcinoma and distant metastasis
Authors: Liangru Ke, Jinna Chen, Lin Wang, Yahui Yu, Yanfang Ye, Weixiong Xia, Xing Lv, Jing Yang, Xiang Guo, Yanqun Xiang, Xinyuan Guan
Journal: Cancer Research (2015)

Abstract Stromal cells in the tumor microenviroment play an important role in development and progression of nasopharyngeal carcinoma (NPC). Aim of this study is to identify the stromal cell related genes which may promote distant metastasis in NPC. Materials and methods: Differently expressed genes were accessed by comparing nasopharyngeal carcinoma and distant metastasis by microarray. Then stromal cells related genes were analyzed by using statistics tools. Five selected genes were validated in 112 nasopharyngeal carcinoma specimens. Results: We have identified 3360 genes up-regulated (P &amp;lt; .05)and 2327 genes down-regulated(P &amp;lt; .05) in distant metastasis versus primary nasopharyngeal carcinoma, among the differently expressed genes,111 stromal cells related genes were picked up according to previous researches for cluster analysis and pathway analysis. Upon validating 5 selected genes (BIRC3,FRAS1,NPNT,POSTN,PCSK6) in 112 additional NPC cases, the authors found that expression of POSTN was negative correlated significantly with lymph node involvement (p = 0.006)and clinical stage(p = 0.035) at the moment of diagnosis and FRAS1 was negative correlated with disease-free survival (p = 0.002) and distant metastasis survival (p = 0.02).Conclusion: Increasing knowledge of metastasis promotion of stromal cells related genes may provide feasible explanations underlying NPC progression and metastasis along with the development of biomarkers for screening high-risk populations. Citation Format: Liangru Ke, Jinna Chen, Lin Wang, Yahui Yu, Yanfang Ye, Weixiong Xia, Xing Lv, Jing Yang, Xiang Guo, Yanqun Xiang, Xinyuan Guan. Differential expression of stromal cell-related genes between primary nasopharyngeal carcinoma and distant metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2177. doi:10.1158/1538-7445.AM2015-2177
Abstract 1685: Identification and characterization of EMT/MET signatures in circulating tumor cells isolated from patients with metastatic breast cancer using graphene oxide nano-chip
Authors: Tae Hyun Kim, Hyeun Joong Yoon, Sunitha Nagrath
Journal: Cancer Research (2016)

Abstract Disseminated cancer cells identified in the circulatory system of cancer patients has implied to be the key drivers of tumor metastasis. These cells known as circulating tumor cells (CTCs) are emerging as an alternative to tissue biopsies to predict prognostic values, and to monitor evolving tumor heterogeneity through serial drug treatments. Recent technological advances have enabled the detection of CTCs in patient blood samples. However, the enumeration alone seems to be insufficient to obtain information that could benefit any clinical decisions. The limited sensitivity as well as the specificity of current approaches struggle from realizing the full promise of CTCs. We developed a sensitive microfluidic chip using functionalized graphene oxide (GO) nano-sheets to isolate CTCs with improved sensitivity and purity. Blood samples collected from metastatic breast cancer patients were processed through the chip within 6 hours of sampling and the CTCs were identified by the presence of cytokeratin with the absence of CD45 expression. EMT/MET signatures were characterized in the isolated CTCs to investigate its role by assessing gene expression profiles. Protein markers known to be up regulated during the EMT such as Vimentin and N-cadherin was examined along with HER2. mRNA expression of EMT markers were studied simultaneously using a multiplex TaqMan-based qRT-PCR method and compared to healthy controls. CTCs were successfully detected in &amp;gt;95% of patients examined in this study. Cell-to-cell intrapatient heteroheneity was observed in the isolated CTCs. Markers of EMT/MET phenotypes including Vimentin, EpCAM, HER2, CDH1, CDH2 and cytokeratin in the CTC samples were differentially expressed. These studies demonstrate the feasibility of utilizing the GO nano-chip in CTC isolation and characterization from metastatic breast cancer patients. Given the high sensitivity and the reproducibility to measure protein/gene expression levels of CTC biomarkers, we envision that our GO nano-chip may provide potential tool for real-time monitoring of cancer patients on clinical trials. Citation Format: Tae Hyun Kim, Hyeun Joong Yoon, Sunitha Nagrath. Identification and characterization of EMT/MET signatures in circulating tumor cells isolated from patients with metastatic breast cancer using graphene oxide nano-chip. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1685.
Prevalence of Anti-Heparin Platelet Factor 4 Antibodies in Patients with Disseminated Intravascular Coagulation.
Authors: Jawed Fareed, He Zhu, Josephine Cunanan, Walter Jeske, Debra Hoppensteadt, Hussain Arif, Messmore Harry, Jeanine M. Walenga
Journal: Blood (2009)