tbuckley/cabot-search huggingface dataset:
Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial.
Authors: Salvatore Siena, Andrea Sartore-Bianchi, Sara Lonardi, Livio Trusolino, Cosimo Martino, Katia Bencardino, Francesco Leone, Vittorina Zagonel, Emanuele Valtorta, Valter Torri, Giulia Siravegna, Alessio Amatu, Erica Francesca Bonazzina, Francesca Rusconi, Silvia Ghezzi, Fortunato Ciardiello, Silvio Veronese, Paolo Maria Comoglio, Alberto Bardelli, Silvia Marsoni
Journal: Journal of Clinical Oncology (2015)

3508 Background: We conducted a phase II of trastuzumab (T) and lapatinib (L) in HER2-amplified, KRAS exon 2 wild-type, mCRC pts resistant to standard therapies (HERACLES Trial EudraCT 2012-002128-33). Methods: Pts progressing after fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab were eligible if tumor was HER2+ [IHC3+ or 2+ and FISH positive (HER2:CEP17 > 2) in > 50% cells]. L was given po qd, T iv qw at standard doses. Response was assessed q 8 wks. The primary end-point was objective response (OR, RECIST v1.1). To consider the study positive 6/27 ORs had to be observed (α = 0.05; β = 85%; H1 = 30%). Serial liquid biopsies for HER2 ctDNA (ddPCR/NGS) and ectodomain (ECD) plasma levels (ELISA) were collected until progression. Results: As of Jan 31 2015, 913 pts were screened, 44 found HER2+ (4.8%), and 23 eligible and evaluable: 2F/21M, median age 63 (r = 40-86), ECOG PS ≤ 1, median prior regimens 5 (r = 3-8). Primary endpoint was met with 8/23 ORs [7 PR, 1 PRunc (too early); ORR = 35% (95% CL 20-55)]; 7/8 ORs were observed in HER2 IHC3+ pts. Responses lasted: 8+, 12+, 14+, 24, 24.5+ 32, 54+ and 55+ weeks. Median time to progression was 5.5 months (95% CL 3.7-9.8). Toxicity was limited to G2 diarrhea, fatigue, and rash (1 G3). HER2+ ctDNA and ECD levels decreased in 2/3 ORs and 0/2 non responders and in 2/2 ORs 0/6 with SD or PD, respectively. Exploratory correlative analyses of HER2 gene dosage will be presented together with exome analysis of index cases. Conclusions: HER2 is amplified in 5% of WT exon 2 KRAS mCRC patients. The HERACLES trial met its primary endpoint with 8/23 objective responses in pts heavily pretreated with standard therapies, including EGFR-targeted agents, indicating that the dual anti HER2 therapy is effective and deserves further clinical assessment in earlier lines of treatment of HER2+ mCRC patients. HERACLES is funded by Associazione Italiana Ricerca Cancro. Clinical trial information: 2012-002128-33.
Abstract 3665: WAC: A candidate tumor suppressor gene in colorectal cancer
Authors: Christopher R. Clark, Caitlin Conboy, Makayla Maile, Callie Janik, Julia Hatler, Robert Cormier, David Largaespada, Timothy K. Starr
Journal: Cancer Research (2016)

Abstract Our lab recently performed a DNA transposon forward genetic screen in mice that was designed to identify low-frequency mutations that contribute to colorectal cancer (CRC) initiation and progression. Results from this screen identified the WW domain-containing adaptor with coiled-coil (WAC) gene as a top DNA transposon insertion site. WAC has previously been implicated in several cellular processes including amino acid starvation-induced autophagy, golgi biogenesis, and transcription associated histone modification but has never before been linked to tumorigenesis. Transposon mutagenesis screens performed by others (Takeda et al. Nature Genetics 2015) have also identified Wac as a common insertion site, a result that further implicates WAC as a candidate CRC driver gene. Analyses of transposon insertion patterns within Wac predict loss of gene function and a role as a tumor suppressor. Soft agar colony formation assays reveal that shRNA mediated silencing of Wac cooperates with Apc mutations in mouse colorectal cells to promote cellular transformation. Additional colony formation assays using immortalized human colonic epithelial cells and the adenoma derived AAC1 cell line also shows that silencing WAC is protumorigenic. Using a zebrafish model we demonstrated that overexpression of wild type but not cancer-associated mutant forms of WAC induce expression of the cell cycle inhibitor p21, which suggests that loss of WAC may lead to uncontrolled cellular proliferation. Finally, using publicly available mutation data we determined that WAC is somatically mutated in both breast and lung cancers; a finding that indicates WAC may serve a critical tumor suppressive role in several tissues. Currently we are developing a conditional knockout mouse to further investigate the role of WAC in CRC tumor formation. Citation Format: Christopher R. Clark, Caitlin Conboy, Makayla Maile, Callie Janik, Julia Hatler, Robert Cormier, David Largaespada, Timothy K. Starr. WAC: A candidate tumor suppressor gene in colorectal cancer. [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 3665.
Abstract 4351: A neighborhood-wide association study (NWAS) in prostate cancer: A new methodologic approach
Authors: Shannon Lynch, Nandita Mitra, Michelle Ross, Craig Newcomb, Karl Daily, Tara Jackson, Charnita Zeigler-Johnson, Harold Riethman, Charles Branas, Timothy Rebbeck
Journal: Cancer Research (2016)

Abstract Background: Cancer results from complex interactions of multiple variables at biological, individual and social levels. However, comprehensive, empirical methods to assess social and neighborhood-level effects are limited. We propose a Neighborhood-Wide Association Study(NWAS), analogous to a genome-wide association study(GWAS), to comprehensively identify neighborhood signatures associated with disease. Methods: Pennsylvania State Cancer Registry data from 1995-2005 were linked to the 2000 U.S. Census data. In a successively more stringent multiphase approach, we evaluated the association between neighborhood exposures(n = 14,663, standard deviation adjusted census variables) and prostate cancer aggressiveness (n = 6,416 aggressive Stage&amp;gt;3/Gleason grade &amp;gt;7 cases vs. n = 70,670 non-aggressive Stage&amp;lt;3/Gleason grade&amp;lt;7 controls) in White men. Each phase accounted for age, year of diagnosis, spatial correlation, and multiple testing. We used generalized estimating equations in Phase 1 and Bayesian mixed effects models in Phase 2 to calculate odds ratios(OR) and credible intervals(CI). Variables meeting statistically significant thresholds after Bonferroni adjustment were identified and used in subsequent phases. In Phase 3, principal components analysis grouped correlated variables. Results: From 14,663 census variables, 17 variables that were most significantly associated with prostate cancer aggressiveness were identified. The top two hits related to transportation (OR = 1.05;CI = 1.001-1.09) and poverty (OR = 1.07;CI = 1.01-1.12). Significant associations between prostate cancer and income, housing, employment, and immigration were also found. Conclusions: This NWAS methodology addresses gaps in neighborhood and cancer research by proposing a standardized, agnostic evaluation of neighborhood using readily accessible data from the U.S. Census. This approach has implications for health disparities research and can be applied broadly to large-scale, public health data. Citation Format: Shannon Lynch, Nandita Mitra, Michelle Ross, Craig Newcomb, Karl Daily, Tara Jackson, Charnita Zeigler-Johnson, Harold Riethman, Charles Branas, Timothy Rebbeck. A neighborhood-wide association study (NWAS) in prostate cancer: A new methodologic approach. [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 4351.
Circulating tumor cells (CTC) and HER-2 status on CTC and primary tumor in urothelial cancer (UC) patients refractory to platinum based chemotherapy.
Authors: Maria De Santis, Thomas Bauernhofer, Franz Stoiber, Lorenz Höltl, Andreas Sommerhuber, Johann Klocker, Johannes Gobertus Meran, Johannes Klikovich, Daniela Colleselli, Christian Dittrich, Klaus Pantel, Sabine Riethdorf
Journal: Journal of Clinical Oncology (2016)

4520 Background: There are no established serum markers to monitor UC progression, response to therapy and to evaluate the risk for metastases. This study was set up to define the percentage of CTC positive UC pts at progression after platinum based combination therapy, potential CTC cut-off levels for drug screening and the HER2 status on CTC in comparison to the primary tumor. Methods: Blood samples from pts who fulfilled the inclusion criteria were analysed with CellSearch- CTC Kit and -Tumor Phenotyping Reagent HER2/neu. Results were reported as number of CTC/7.5 mL whole blood. Paraffin embedded tumor tissue was evaluated for HER2 positivity (FISH) and compared to that on CTC. The correlation between CTC parameters, the HER2 status of the primary tumor, and the Bellmunt prognostic groups (0-3) were investigated using descriptive statistics. The planned sample size of 70 pts should allow for a two-sided 95% confidence interval with a width of +/- 12% for the expected rate of 50% CTC positive pts. Results: 70 pts with platinum refractory UC were enrolled in 8 institutions and 69 pts fulfilled all inclusion criteria and CTC of 63 pts were evaluable. 66/69 pts had measurable metastases (38 visceral metastases of which 23 were in the liver). 21, 29, 14 and 5 pts belonged to Bellmunt prognostic groups 0,1,2,3, respectively. In 42 of 63 evaluable pts (66%) CTC (≥ 1 CTC) were detectable, and 29 (46.0%), 25 (39.7%) and 23 (36.5%) pts had more than 2, 3 and 5 CTC/7.5ml, respectively. In 3 pts HER2-positive CTC were detected; HER2 gene amplification on the primary tumor was found in 6/46 cases (13%). All patients with HER2-positive primary tumors also harboured CTC. HER2-positive CTC were found in 2 pts with HER2 amplified primary tumors and in one patient with a HER2-negative primary tumor. In 3/5 pts with HER2 amplified tumors CTC were HER2 negative. HER2 positive CTC were significantly correlated with the Bellmunt risk group 3 (60%, CI 23.1- 88.2) but not with the HER2 status of the primary tumor. Conclusions: CTC are present in a considerable number of platinum refractory UC patients and might serve as a drug screening biomarker as well as for the detection of targetable molecular alterations. Clinical trial information: EudraCT 2013-000124-34.
Abstract 2475: Bmi1 is a therapeutic target in recurrent medulloblastoma
Authors: Sheila K. Singh, Neha Garg, Branavan Manornajan, David Bakhshinyan, Chitra Venugopal, Robin Hallett, Kevin Xin Wang, Vijay Ramaswamy, Yoon-Jae Cho, Siddhartha Mitra, David Kaplan, Thomas Davis, Michael Taylor
Journal: Cancer Research (2016)

Abstract We describe the epigenetic regulator Bmi1 as a novel therapeutic target for the treatment of recurrent human Group 3 medulloblastoma, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Through comparative profiling of primary and recurrent medulloblastoma, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden and increased mouse survival, without neurotoxicity. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials. Current clinical trials for recurrent medulloblastoma patients who no longer respond to risk-adapted therapy are based on genomic profiles of primary, treatment-naïve tumors. These approaches will provide limited clinical benefit for patients since recurrent metastatic Group 3 medulloblastomas are highly genetically divergent from their primary tumor. Our experimental approach defines a tractable target, the epigenetic regulator Bmi1, which characterizes not only recurrent medulloblastoma, but many other metastatic and treatment-resistant cancers. As future clinical oncology trials will most likely begin with relapsed patients, therapeutic targets from comparative analyses in primary and matched-recurrent tumors offer the greatest clinical yield and may be readily translated to the patient bedside. Citation Format: Sheila K. Singh, Neha Garg, Branavan Manornajan, David Bakhshinyan, Chitra Venugopal, Robin Hallett, Kevin Xin Wang, Vijay Ramaswamy, Yoon-Jae Cho, Siddhartha Mitra, David Kaplan, Thomas Davis, Michael Taylor. Bmi1 is a therapeutic target in recurrent medulloblastoma. [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 2475.
Abstract 3864: The Jak1/2 inhibitor AZD1480 suppresses tumor growth and metastasis in genetically engineered mouse models of PTEN-deficient prostate cancer
Authors: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Barry R. Davies, Dennis Huszdar, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2016)

Abstract Activation of signal transducer and activator of transcription (STAT) 3 via the interleukin 6 (IL-6)/IL-6R/Janus kinase (JAK) signaling axis is a feature common in patients with advanced human prostate cancer and has been associated with poor prognosis. STAT3 can promote CRPC growth by activating the androgen receptor signaling pathway. It can also promote survival by modulating tumor cell proliferation, epithelial to mesenchymal transition, angiogenesis and immune response. However, recent preclinical data suggests that STAT3 may also act as a tumor suppressor in PTEN-deficient prostate cancer. In this study, we investigated the effectiveness of AZD1480, a potent JAK1/2 inhibitor, in genetically engineered mouse models of prostate cancer driven by the loss of PTEN and PTEN/P53. In vivo pharmacodynamic studies using conditional PTEN-deficient mice demonstrated that AZD1480 strongly inhibited STAT3 phosphorylation. Moreover, AZD1480 monotherapy in PTEN-deficient mice harboring castration-naïve or castration-resistant prostate tumors resulted in tumor growth reductions of 24.8%, P&amp;lt;0.001 and 15.8%, P&amp;lt;0.001, respectively, compared to vehicle treated control mice. Mice treated with AZD1480 also exhibited reduced levels of tumor cell proliferation and microvessel density, and increased apoptosis compared to controls. Clinically relevant outcomes were evaluated in a late-stage model of prostate cancer driven by the conditional inactivation of PTEN and P53. In this model, PTEN/P53 double knockout mice with established tumors were randomized to vehicle or AZD1480 treatment groups. Mice treated with AZD1480 demonstrated a modest but statistically significant improvement in overall survival compared to control mice, median time 20 days vs. 27 days, P = 0.03, respectively. Additionally, the metastatic tumor incidence decreased from 46.6% (7/15) in control mice to 20% (3/15) in AZD1480-treated mice. Our findings provide preclinical evidence supporting the potential use of Jak1/2 inhibitors for the targeted therapy of human prostate cancer. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Barry R. Davies, Dennis Huszdar, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. The Jak1/2 inhibitor AZD1480 suppresses tumor growth and metastasis in genetically engineered mouse models of PTEN-deficient prostate cancer. [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 3864.
Screening for Syphilis Infection in Pregnancy
Authors: Ned Calonge, Diana B. Petitti, Thomas G. DeWitt, Allen Dietrich, Kimberly D. Gregory, David Grossman, George Isham, Michael L. LeFevre, Rosanne Leipzig, Lucy N. Marion, Bernadette Melnyk, Virginia A. Moyer, Judith K. Ockene, George F. Sawaya, J. Sanford Schwartz, Timothy Wilt, US Preventive Serv Task Force
Journal: Annals of Internal Medicine (2009)
Abstract 705: PRL-3/PTP4A3 phosphatase promotes uveal melanoma cell migration through the regulation of integrin â1 in focal adhesion
Authors: Malika Foy, Oceane Anezo, Nathalie Planque, Simon Saule
Journal: Cancer Research (2016)

Abstract Using transcriptomic analysis, we found that Phosphatase of Regenerating Liver-3 (PRL-3) overexpression is highly correlated with metastatic tumors and predicts poor prognosis in patients with uveal melanoma. PRL-3 is a dual specific phosphatase with a carboxy-terminal farnesylation motif, allowing anchorage to the plasma membrane. PRL-3 overexpression in ocular melanoma cell line-1 (OCM1) significantly increases cell migration in vitro and invasiveness in vivo, suggesting a direct role of PRL-3 in metastasis (Laurent et al, Cancer Res 2011; 71:666). Despite its role in the metastatic process of various cancers, its mechanism of action and its intracellular substrates remain largely unknown. It has been shown that the anchorage of PRL-3 to the plasma membrane plays an important role in the metastatic process, suggesting that the phosphatase regulates transmembrane substrates. Among potential targets involved in extracellular matrix adhesion, we focused on integrin â1 which we found overexpressed in the transcriptomic analysis of our uveal melanoma cohort.We showed that FTI-277, a farnesyltransferase inhibitor that prevents PRL-3 anchorage to the plasma membrane, abolishes PRL-3-induced OCM1 cell migration on collagen I in vitro, specifically enhances the spreading of OCM1 cells overexpressing PRL-3, and allows the formation of large focal adhesions involving integrin â1. Knockdown of integrin â1 in OCM1-PRL3 cells partially restores the spreading and migration. Furthermore, in focal adhesions, we observed that PRL-3 specifically regulates the aggregation of integrin â1 but does not affect integrin â3. Our results suggest the involvement of integrin â1 in PRL-3-mediated cell migration. To go further, we are currently investigating the phosphorylation status of specific integrin â1 residues, known to be involved in cell adhesion. The present study highlights the importance of PRL-3 membrane localization in uveal melanoma cell migration, by regulating adhesion to the extracellular matrix through integrin â1. Citation Format: Malika Foy, Oceane Anezo, Nathalie Planque, Simon Saule. PRL-3/PTP4A3 phosphatase promotes uveal melanoma cell migration through the regulation of integrin â1 in focal adhesion. [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 705.
Targeting CBLB as a potential therapeutic approach for disseminated candidiasis
Authors: Yun Xiao, Juan Tang, Hui Guo, Yixia Zhao, Rong Tang, Song Ouyang, Qiuming Zeng, Chad A Rappleye, Murugesan V S Rajaram, Larry S Schlesinger, Lijian Tao, Gordon D Brown, Wallace Y Langdon, Belinda T Li, Jian Zhang
Journal: Nature Medicine (2016)
T-cell inflamed phenotype and PDL1 expression in malignant mesothelioma.
Authors: Hedy Lee Kindler, Zhixiang Zuo, Arun Khattri, Michaela K. Keck, Wickii Vigneswaran, Aliya Noor Husain, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2014)

7589 Background: Malignant mesothelioma (MM), a universally lethal disease caused principally by asbestos exposure, develops in the pleura, peritoneum, pericardium and tunica vaginalis. MM is commonly associated with a prominent inflammatory reaction, though it remains unknown whether this relates primarily to asbestos-induced chronic inflammation or an anti-tumor immune response. We therefore evaluated markers of an anti-tumor immune response established for melanoma in MM. Methods: We analyzed gene expression data on 44 MM (Gordon et al 2005), applied a melanoma-derived signature of T-cell inflammation (Harlin 2009), and analyzed other immune response related genes. We also evaluated 8 MM tumors (7 epithelioid, 1 biphasic; 7 pleural, 1 peritoneal) by multi-color immunohistochemistry (IHC), staining for CD68 (macrophages), CD8 (tumor infiltrating lymphocytes), and PDL1 (immune checkpoint). Results: 14/44 (32%) of MM showed high CD8 gene expression; 11% demonstrated a T-cell inflamed phenotype similar to that observed for melanoma. IHC revealed prominent CD68 infiltration in all tumors. CD8 tumor infiltrating lymphocytes (TILs) were present in all epithelial tumors; the biphasic tumor was negative. Germinal centers surrounding and within the tumor were rich in CD8+ cells; 1 tumor showed accumulation of CD8+ lymphocytes along the tumor invasive front. Two patterns of PDL1 expression were observed: 1) PDL1 expression occurred in 6 MM tumor samples, which was 2-3+ in 3 tumors, and 1+ in 3 tumors; 2) Patchy higher level PDL1 expression was observed in stromal or CD68 cells located close to CD8+ cells in the germinal center or the invasive tumor front in 6 tumor samples (2+ in 4 samples; 1+ in 2 samples). Conclusions: Mesothelioma is an ‘inflammatory’ tumor, with prominent infiltration with CD68+ cells (macrophages). We describe the presence CD8+ tumor infiltrating lymphocytes and a T-cell inflamed expression pattern in a fraction of MM, characteristic of the T-cell inflamed phenotype found in other tumors such as melanoma that benefit from immune checkpoint blockade. These preliminary data suggest that agents that target PDL1 may be appropriate to evaluate in MM. Ongoing work will further characterize immune checkpoints in MM.