tbuckley/cabot-search huggingface dataset:
Abstract 2658: Genome-wide mistargeting of oncogenic SWI/SNF(BAF) complexes in SMARCB1(BAF47)-deficient sarcomas
Authors: Robert Nakayama, Robert T. Williams, Seth H. Cassel, Mingxiang Teng, Rafael A. Irizarry, George D. Demetri, Cigall Kadoch
Journal: Cancer Research (2016)

Abstract SMARCB1/BAF47/INI1 is a core subunit of the mammalian SWI/SNF (BAF) family of ATP-dependent chromatin remodeling complexes, which remodel nucleosome architecture to achieve coordinated regulation of gene expression. Genetic loss of SMARCB1 has been identified in several cancer types, including malignant rhabdoid tumor (MRT, 98%) and epithelioid sarcoma (EpS, 90%), strongly implicating this event as the oncogenic driver in these malignancies. However, the precise mechanism underpinning the tumor suppressive function of BAF47 to date remains unclear. In order to elucidate the underlying mechanism and to identify direct genetic targets of aberrant BAF complexes in this context, we comprehensively evaluated the effects of BAF47 reintroduction in BAF47-deficient sarcomas with respect to complex subunit and associated protein factor composition and stability, global chromatin structure, and gene regulation. Reintroduced BAF47 stably integrated into BAF complexes, and remarkably, stabilized a highly specific set of BAF subunits, resulting in an increased complex molecular weight and stoichiometric nuclear abundance. These biochemical changes inducing the formation of wild-type complexes in MRT and EpS cell settings were directly linked to reproducible changes in BAF complex localization genome-wide, particularly, in the targeting to H3K4me3-marked promoter regions of direct target genes to establish DNA accessibility. Importantly, changes in BAF47-dependent BAF complex targeting between oncogenic and induced wild-type conditions were reproducibly associated with differential chromatin architecture and gene expression signatures hallmark to both MRT and EpS, and uniformly resulted in proliferative senescence of MRT and EpS cell lines in culture. These studies highlight, for the first time, the full spectrum of structural and functional contributions of the BAF47 subunit, implicating its role as a keystone in heteromorphic BAF complex assembly; BAF47 is required for the stable integration of several BAF subunits and novel interacting factors, which we determine govern specific genome-wide targeting mechanisms and chromatin-templated activities. These results reveal the mechanisms underlying the oncogenesis of BAF47-deficient sarcomas and point toward novel therapeutic strategies for this group of human sarcomas. Citation Format: Robert Nakayama, Robert T. Williams, Seth H. Cassel, Mingxiang Teng, Rafael A. Irizarry, George D. Demetri, Cigall Kadoch. Genome-wide mistargeting of oncogenic SWI/SNF(BAF) complexes in SMARCB1(BAF47)-deficient sarcomas. [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 2658.
Abstract 4739: The upregulation of cyclooxygenase-2 protein expression by receptor tyrosine kinase inhibitors in bladder cancer <i>in vitro</i>
Authors: Jennifer Bourn, Maria Cekanova
Journal: Cancer Research (2016)

Abstract Several types of cancer, including transitional cell carcinoma (TCC) overexpress several receptor tyrosine kinases (RTKs), including the platelet-derived growth factor receptor (PDGFR), c-kit receptor, epidermal growth factor receptor (EGFR), as well as the vascular endothelial growth factor receptor (VEGFR). Receptor tyrosine kinase inhibitors (RTKIs) are used as targeted therapies for patients diagnosed with cancer with high expression of RTKs. Cyclooxygenase-2 (COX-2) is highly expressed in bladder cancer as well other types of cancers and is one of the key proteins during tumorigenesis. In this study, we validated the effects of RTKIs, Masitinib® (AB1010) and Axitinib on cell proliferation of human (UMUC-3 and T24) and canine (K9TCC#1Lillie, K9TCC#2Dakota, and K9TCC#5Lilly) bladder TCC cells. Using WB analysis, tested human and canine TCC cells, except T24 cells, expressed PDGFR and c-kit receptors. There was no detectable EGFR and VEGFR expressions in any of tested cells by WB analysis. The K9TCC#1Lillie and K9TCC#5Lilly cells had a high expression of COX-2, however K9TCC#2Dakota and human T24 had moderate expression of COX-2, and no COX-2 expression was detected in UMUC3 cells by WB analysis. Both RTKIs, Masitinib® and Axitinib inhibited cell proliferation of the tested human and canine bladder TCC cells in a dose-dependent manner by MTS and apoptosis assays. Interestingly, both tested RTKIs, Masitinib® and Axitinib increased COX-2 protein expressions in tested canine TCC cells. Combined treatment of RTKIs with COX-2 inhibitors decreased cell proliferation of tested TCC cells more effectively as either treatments alone. Our results indicate a possible role of COX-2 signaling pathway in developed RTKIs-resistance in bladder cancer cells in vitro. Co-treatment of RTKIs with COX-2 inhibitors might indicate better clinical outcomes in treatments of patients diagnosed with bladder cancer. Citation Format: Jennifer Bourn, Maria Cekanova. The upregulation of cyclooxygenase-2 protein expression by receptor tyrosine kinase inhibitors in bladder cancer in vitro. [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 4739.
1-Year Outcomes of FFRCT-Guided Care in Patients With Suspected Coronary Disease
Authors: Pamela S. Douglas, Bernard De Bruyne, Gianluca Pontone, Manesh R. Patel, Bjarne L. Norgaard, Robert A. Byrne, Nick Curzen, Ian Purcell, Matthias Gutberlet, Gilles Rioufol, Ulrich Hink, Herwig Walter Schuchlenz, Gudrun Feuchtner, Martine Gilard, Daniele Andreini, Jesper M. Jensen, Martin Hadamitzky, Karen Chiswell, Derek Cyr, Alan Wilk, Furong Wang, Campbell Rogers, Mark A. Hlatky
Journal: Journal of the American College of Cardiology (2016)
Abstract 2993: Dichloroacetate inhibits cell proliferation and induces apoptosis in human endometrial cancer cell lines
Authors: Leslie H. Clark, Chunxiao Zhou, Victoria Bae-Jump
Journal: Cancer Research (2016)

Abstract Objective: Dichloroacetate (DCA) is a well-tolerated, oral drug used in the treatment of hereditary lactic acidosis. DCA has been found to have anti-tumorigenic activity in various non-gynecologic cancers through its inhibition of pyruvate dehydrogenase, leading to profound mitochondrial defects in cancer cells. Thus, we sought to assess the effects of DCA on human endometrial cancer cell lines. Methods: Three endometrial cancer cell lines (KLE, Ishikawa, and ECC-1) were treated with varying concentrations of DCA from 0.1uM to 100 uM. Cell proliferation was measured using the MTT assay. Cell cycle progression was assessed by Cellometer. Apoptosis was evaluated by the Annexin V-FITC assay using Cellometer. Western immunoblotting was performed to assess effects of DCA on cell cycle and cellular stress proteins. In addition, cellular stress was measured using a reactive oxygen species assay. All experiments were performed in triplicate. Results: DCA inhibited cell proliferation in a dose-dependent manner in all three endometrial cancer cell lines following 72 hours of exposure. The IC50 was 30 uM for KLE, 78 uM for Ishikawa, and 72 uM for ECC-1. Treatment with DCA resulted in G1 phase cell cycle arrest in all three cell lines. DCA induced apoptosis in all three cell lines. Western blotting analysis demonstrated that DCA increased cyclin D1 expression, decreased CDK4 expression, and increased PERK expression after 24 hours of DCA exposure. A dose dependent increase in reactive oxygen species was seen in all three cell lines. At a maximum dose of 100 uM DCA, ROS production compared to controls for KLE increased 3.2-fold (p = 0.002), Ishikawa increased 1.8-fold (p = 0.003), and ECC-1 increased 2.1-fold (p = 0.002). Conclusions: DCA effectively inhibited cell proliferation via G1 cell cycle arrest and induced apoptosis in human endometrial cancer cell lines. DCA induced significant cellular stress as evidenced by a dose dependent increase in reactive oxygen species. Further evaluation of DCA as a targeted metabolic therapy in endometrial cancer is warranted. Citation Format: Leslie H. Clark, Chunxiao Zhou, Victoria Bae-Jump. Dichloroacetate inhibits cell proliferation and induces apoptosis in human endometrial cancer cell lines. [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 2993.
Abstract 3829: Preclinical development of a combination inhibitor strategy to block K-Ras effector signaling and autophagy for pancreatic cancer treatment
Authors: Kirsten L. Bryant, Tikvah K. Hayes, Daniel Zeitouni, Samuel D. George, Swapnil Kher, Ahmed A. Samatar, Kris C. Wood, Alec C. Kimmelman, Channing J. Der
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is the 4th leading cause of cancer deaths in the US and the 5-year survival rate is a dismal 6%. The KRAS oncogene is mutated in ∼95% of pancreatic ductal adenocarcinoma (PDAC) and targeting KRAS is one of four key priorities for pancreatic cancer research, as outlined by the NCI. We hypothesize that inhibition of K-Ras effector signaling is the most promising approach to achieve this goal, and that concurrent inhibition of mutant KRAS-mediated metabolic reprogramming, in particular upregulated autophagy, is needed to disrupt resistance mechanisms that render PDAC cells unaffected by inhibition of either pathway alone. Our preliminary data show that PDAC cells increase levels of autophagic signaling upon KRAS silencing as a compensatory mechanism for the cell to maintain anabolic processes, particularly due to the loss of upregulated glycolytic signaling and macropincytotic scavenging. Furthermore, we show that ERK inhibitor treatment, just like KRAS silencing, increases autophagic flux in PDAC cells. Additionally, we have demonstrated in vitro that chloroquine (CQ), an inhibitor of autophagy, synergistically enhances the anti-proliferative capacity of two different ERK inhibitors, one of which is under clinical evaluation. Finally, we show that signaling pathways that promote resistance to ERK inhibitor treatment alone are incapable of promoting resistance to the combination treatment with CQ. Overall, our studies support the further clinical evaluation of duel ERK and autophagy inhibition as a treatment for PDAC. Citation Format: Kirsten L. Bryant, Tikvah K. Hayes, Daniel Zeitouni, Samuel D. George, Swapnil Kher, Ahmed A. Samatar, Kris C. Wood, Alec C. Kimmelman, Channing J. Der. Preclinical development of a combination inhibitor strategy to block K-Ras effector signaling and autophagy for pancreatic cancer treatment. [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 3829.
Prognostic markers assessment in invasive upper tract urothelial carcinoma (UTUC).
Authors: Hamid Emamekhoo, Puneet Dhillon, Dharmesh Gopalakrishnan, Haider Al taii, Hiral D. Parekh, Paul Elson, Jesse McKenney, Cristina Magi-Galluzzi, Holly Lynn Harper, Homi Zargar, Brian I. Rini, Andrew J. Stephenson, Michael C. Gong, Amr Farouk Fergany, Georges-Pascal Haber, Steven C. Campbell, Jihad Kaouk, Ryan Kent Berglund, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2016)

e16034 Background: There is limited data on prognostic factors in UTUC. Methods: A retrospective study of UTUC patients (pts) who had surgery (1995-2014) at Cleveland Clinic (n = 454) was conducted. Univariable (UVA) and multivariable (MVA) analysis (proportional hazards) with a stepwise selection algorithm (p = .10 and .05, as criteria for entry and retention in the model) was used to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS). Results: 286 pts with invasive (pT1-4) UTUC were identified; median age at resection was 72; 66% men, 32% never smokers, 76% had laparoscopic and 15% open nephroureterectomy, 14% had +ve invasive (inv) margins (7% +ve non-inv margins), 22% multifocal tumor. Median tumor size 3.4 cm (range 0.2-25); 70% had tumor < 5 cm; 32% pT1, 18% pT2, 44% pT3, 6% pT4. 36% of pts had lymph node (LN) dissection (21% of them pN+). Most pts had primarily UC (1 sarcomatoid, 2 small cell); 26% mixed UC histology; 36% CIS, 41% confirmed LVI; 10 neoadjuvant, 16 confirmed adjuvant therapy. 51% of pts with follow-up (f/u) recurred; 9% died with no known recurrence. Estimated median RFS was 17.2 months (m) (95%CI 13-39). In UVA, age, +ve inv margins, tumor size, pT stage, LVI, prior/concurrent bladder cancer impacted RFS. In MVA, pT stage (p = .0003), +ve inv margins (p = .03), age > 70 (p = .003) independently correlated with RFS. 37% of pts died with estimated median OS 64.5 m (95%CI 39-107); median f/u was 39.5 m (0.3-186) in pts alive and RF at last f/u. In UVA, LVI, tumor size, age, pT stage, +ve inv margins, tumor location, and mixed histology impacted OS. In MVA, LVI (p = .0009), tumor size (p = .0001), CIS (p = .01), age (p = .005) independently predicted OS. Using these factors, prognostic groups were identified for each outcome (Table). Conclusions: Clinic-pathological parameters can be used as prognostic variables in UTUC and inform clinical trial design; further validation is needed. Group Poor Prognostic Factors N (%) Median (m) % RF (2y) % alive (2y) RFS Favorable 0 45 (26%) 94.1 70 ± 7% Intermediate 1 77 (44%) 34.8 54 ± 6% Unfavorable 2-3 54 (31%) 7.6 26 ± 6% OS Favorable 0 29 (14%) Not reached 94 ± 6% Intermediate 1 71 (36%) 107.4 73 ± 6% Unfavorable 2 62 (31%) 44.6 58 ± 8% Poor 3-4 38 (19%) 9.1 33 ± 9%
Inhibition of Interleukin-6 Signaling with CNTO 328 Sensitizes Plasma Cell Dyscrasias to the Effects of Melphalan in Association with Suppression of Signaling through Protein Kinase B/Akt.
Authors: Sally A. Hunsucker, Valeria Magarotto, Jairo A. Matthews, Michael Wang, Veerabhadran Baladandayuthapani, Peter M. Voorhees, Hong Xie, Mark Cornfeld, Jeffrey A. Nemeth, Robert Z. Orlowski
Journal: Blood (2009)
Stereotactic body radiation therapy (SBRT) on spine metastases from renal cell carcinomas (RCC): Clinical results and impact of upfront vs salvage SBRT.
Authors: Jessica Serrand, Marie-Pierre Sunyach, Sylvie Negrier, Christian Carrie, Ronan Tanguy
Journal: Journal of Clinical Oncology (2016)

e16073 Background: To investigate the results obtained with spine SBRT for metastases from RCC, known as radioresistant tumors, and evaluate the differences observed between upfront and salvage SBRT (failure after a conventional external beam radiotherapy, EBRT). Methods: We reviewed the patients treated in our institution. From November 2010 to December 2015, 48 patients were treated on 70 spine metastases. We collected pain flare-up, local control and neurological symptoms and their evolution after SBRT treatment. Pain recurrence, local evolution or neurological worsening at the last clinical and imaging evaluation were considered as spine recurrence. Results: Median age was 68 years (range: 40–87). There were respectively 35% and 45% of Fuhrman grades 2 and 3. Twenty-five patients (52%) had a metastatic disease at initial diagnosis. Median number of prior systemic therapies was 1 (range: 1-8). Median overall-survival after spine metastases diagnosis was 66 months (CI95% 54–79). Patients were addressed to spine SBRT for pain (82%) with median Visual Analog Scale (VAS) at 5/10, local control (90%) and neurological issue (15%). Fourteen patients treated on 15 spine metastases were addressed to salvage spine SBRT. With a median follow-up of 24 months (CI95% 21.6-26.1), pain control was improved in 72% with median VAS at 2, local control and neurological stability obtained in 81% and 90 % respectively. Overall, 20 lesions (28%) presented a recurrence in a median time of 21 months (CI95% 19–23). Main factor related to spine recurrence was salvage SBRT with 60% recurrences for salvage SBRT vs 20% in upfront SBRT (Fisher test, p = 0.007). A log-rank test on spine recurrence-free survival was also significantly related to salvage SBRT (p = 0.001). This is partly explained by a lower dose delivered in salvage treatments (biological equivalent dose 45GyBED ±11Gy and 55GyBED ± 8Gy for salvage and upfront SBRT respectively, p = 0.001). Conclusions: In this retrospective study, we found satisfying results of spine SBRT for radioresistant RCC metastases on different endpoints. Our statement of a lesser efficiency of salvage SBRT should lead to an early management in expert centers
Abstract SY12-01: PI 3-kinase and cancer metabolism
Authors: Lewis C. Cantley
Journal: Cancer Research (2016)

Abstract In general cancer cells produce higher levels of reactive oxygen species (ROS) than normal cells due to increased rates of metabolism and defective mitochondria. In order to survive under conditions of high ROS, cancer cells typically turn on pathways for generating NADPH and glutathione to bring ROS levels back to homeostasis. Activating mutations in PIK3CA or loss of PTEN or activating mutations in KRAS can stimulate glucose uptake and metabolism and pathways for generating NADPH and glutathione to suppress ROS. A detailed understanding of the biochemical mechanisms by which cancer cells suppress excess ROS may suggest new therapies for inducing synthetic lethality in tumors that evolve in specific mutational backgrounds. Our research using human cancer cell lines and genetically engineered mouse models suggests new approaches for killing cancer cells by targeting metabolic pathways for ROS suppression that allow cancer cells to survive. Citation Format: Lewis C. Cantley. PI 3-kinase and cancer metabolism. [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 SY12-01.
Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study
Authors: Monica Gandhi, David V Glidden, Kenneth Mayer, Mauro Schechter, Susan Buchbinder, Beatriz Grinsztejn, Sybil Hosek, Martin Casapia, Juan Guanira, Linda-Gail Bekker, Alexander Louie, Howard Horng, Leslie Z Benet, Albert Liu, Robert M Grant
Journal: The Lancet HIV (2016)
A first-in-human phase I trial of NKG2D chimeric antigen receptor-T cells in AML/MDS and multiple myeloma.
Authors: Sarah Nikiforow, Joana Murad, Heather Daley, Helene Negre, Jake Reder, Charles L. Sentman, Frederic Lehmann, Sarah Snykers, Rachel Allen, Ilene Galinsky, Nikhil C. Munshi, Richard M. Stone, Robert Soiffer, Jerome Ritz, Susanne H.C. Baumeister
Journal: Journal of Clinical Oncology (2016)

TPS3102 Background: Canonical CAR-T cell constructs encode a single chain antibody variable fragment, costimulatory domain, and signaling domain of CD3 zeta. This restricts recognition to 1 tumor antigen and a limited set of cancers. This study employs a novel CAR fusing full-length human Natural Killer Group 2D (NKG2D) gene with the human CD3 zeta signaling domain. NKG2D CAR receives costimulation via naturally-expressed DAP10 and activates T cells directly to kill and secrete cytokines upon recognition of MIC-A, MIC-B, and UL-16 binding proteins. These NKG2D-ligands are upregulated in many solid tumors and hematologic malignancies but absent or poorly expressed on healthy tissues. In multiple murine cancer models, NKG2D CAR-T cells induced complete remissions, T-cell memory, and altered tumor microenvironment via cytokines. We demonstrated manufacture of autologous NKG2D CAR-T cells in a GMP-environment from healthy adults and patients with AML and myeloma was feasible. Following isolation of mononuclear cells, T cells are activated with anti-CD3 mAb and IL-2, undergo 2 transductions with SFG retroviral vector containing NKG2D CAR construct, and expand in media containing IL-2. Validation studies yielded consistent viability, robust cell expansion, high vector-driven NKG2D expression on T cells, potent IFN-g production during tumor cell co-culture, viral copy number/cell < 5, and no replication-competent retrovirus in NKG2D CAR-T (CM-CS1) cells. Methods: A phase 1 dose-escalation study to establish safety and feasibility of a single infusion of CM-CS1 T cells without lymphodepleting conditioning is currently enrolling subjects with AML/MDS-RAEB or relapsed/refractory progressive multiple myeloma without standard therapy options (ClinicalTrials.gov NCT02203825). Dose-escalation will proceed in 4 cohorts [1x106 to 3x107 CM-CS1 T cells] according to a 3+3 design followed by expansion cohorts at the MTDs in AML/MDS and myeloma for an anticipated 24 subjects. As of February, 2016, 6 subjects have been treated. Cohort 1 was completed without DLTs. Additional studies may include lymphodepletion, multiple infusions, and cytoreductive chemotherapy in both hematologic and solid tumor malignancies. Clinical trial information: NCT02203825.
Abstract 1036: Cellular phenotypes of a novel series of 3-phosphoglycerate dehydrogenase inhibitors
Authors: Nello Mainolfi, Adam Friedman, Mikel P. Moyer, Vipin Suri, Mark Manfredi
Journal: Cancer Research (2016)

Abstract PHGDH (3-phosphoglycerate dehydrogenase) is the first enzyme branching from glycolysis into the serine synthetic pathway and it oxidizes 3-phosphoglycerate into phospho-hydroxypyruvate using nicotinamide adenine dinucleotide (NAD) as cofactor.[1] Increases in PHGDH expression at both mRNA and protein levels have been observed in nearly 70% of estrogen receptor-negative breast cancers; in addition a fraction of malignant breast and melanoma cells are dependent on elevated expression of 3-phosphoglycerate dehydrogenase (PHGDH).[2] Furthermore, serine starvation has been shown to have a dramatic effect on tumor growth during in vivo mouse xenograft experiments.[3] PHGDH has been a target of interest in the pharma/biotech industry for several years since the initial reports in early 2012 of its relevance in cancer2 where PHGDH amplified and overexpressing cancer cell lines have been shown to possess unique sensitivity to PHGDH knockdown that cannot be rescued by nutritional serine. The mechanisms underlying these studies have been subject to intense investigation but remain unclear. We have been able to successfully identify first in class small molecule inhibitors of this target with nanomolar cellular potency, high degree of selectivity and oral bioavailability. In several cancer cell lines, these compounds inhibited glucose derived serine flux with nanomolar median inhibitory concentrations without significantly affecting glucose derived lactate. These compounds also inhibited glucose derived serine in animal studies and have the potential to be highly useful tools for understanding the role of PHGDH in tumor progression. The data presented here will provide unexpected insights on the role of PHGDH in serine biosynthesis and the dependency of cancer cells on PHGDH catalytic function. References [1] Snell, K. Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Advances in enzyme regulation. 1984; 22:325-400. [2] Cantor, J.R.; Sabatini, D. M. Cancer Cell Metabolism: One Hallmark, Many Faces, Cancer Discovery. 2012; 2(10):881-898. [3] Maddocks et al., Serine starvation induces stress and p53-dependent metabolic remodeling in cancer cells Nature, 2013, 493(7433):542-6 Citation Format: Nello Mainolfi, Adam Friedman, Mikel P. Moyer, Vipin Suri, Mark Manfredi. Cellular phenotypes of a novel series of 3-phosphoglycerate dehydrogenase inhibitors. [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 1036.