tbuckley/cabot-search huggingface dataset:
Adequacy of data provision and analysis in oncology phase III trials over the past 5 years.
Authors: H. K. Gan, B. You, G. R. Pond, E. X. Chen
Journal: Journal of Clinical Oncology (2010)

6122 Background: The CONSORT guidelines (2001) aimed to improve the reporting of RCTs. This study examined the adequacy of data provided in oncology RCTs in selected journals (Ann Oncol/BJC/Breast Can Res Treat/Cancer/EJC/JCO/JNCI/Lancet/Lancet Oncol/NEJM) in 2005-2009. Methods: RCTs were identified through Medline and manual search. Phase II, noninferiority, equivalence, pediatric and non-drug trials were excluded. For each RCT, data on 3 requirements of the CONSORT statement were extracted by two independent reviewers: primary endpoint (PE), sample size calculation, and outcomes. Adequate statistical description required all the following: alpha; beta/power; PE; expected benefit in PE (hazard ratio [HR] or absolute difference); number of patients/events required; and use of interim analyses. Adequate outcomes description required: number of enrolled patients; observed benefit in the specified PE (HR/absolute benefit, depending on stated design); and p-values. Frequency analysis was by X2 or Fisher's exact test. Results: Of 229 trials, 34% failed to provide one required datum and 13% lacked 2+ data items. The commonest statistical omission was regarding interim analyses (utilization was unclear in 28%; even where this was specified, information about methodology was usually poor). A total of 28% and 42% of studies failed to reach their targets for patient recruitment and observed events respectively. The most common omissions in outcomes data were failures to provide p-values (12% of cases) or to provide the protocol-specified HR/absolute difference in the PE (6%). Additionally, data regarding use of blinding was available in only 51% of trials. Interestingly, the proportion of trials with adequate data increase significantly in 2009 (74%) compared to all previous years (42% 2008, 51% 2007, 55% 2006, 48% 2005; p < 0.05 for all comparisons against 2009). The adequacy of data did not differ between industry trials, cooperative group trials, or journal impact factor. Conclusions: Despite wide endorsement of the CONSORT guidelines, reporting of oncology RCTs still suffers from inadequate data provision. The CONSORT statement should be followed more closely by investigators and enforced more rigorously by journals. No significant financial relationships to disclose.
Abstract 4558: PIN1 expression level is maintained by a negative feedback loop through regulation of Myc and miRNAs
Authors: Ka Wai Leong, Chi Wai Cheng, Yok Lam Kwong, Wai Choi Eric Tse.
Journal: Cancer Research (2016)

Abstract Introduction: PIN1 is a peptidyl-prolyl-isomerase (PPIase) that binds specific motifs (serine/threonine preceding a proline) in proteins, thereby catalyzing cis/trans isomerization of the peptide bond between the phosphorylated serine/threonine and proline. As a result of such conformational changes, stability, sub-cellular localization, functional activity as well as protein-protein interactions of the PIN1-bound proteins may be altered. PIN1 has been demonstrated to play an important role in controlling various cellular processes such as cell proliferation, apoptosis and migration. Consequently, its expression has to be tightly controlled. Previously, we found that two miRNAs, miR-296-5p and miR-874-3p, served as negative regulators of PIN1. However, the mechanism regulating these two miRNAs remains to be defined. Methods: The online database-UCSC Genome Bioinformatics (NCBI/hg18) was used to search for the upstream regulator of miR-296-5p and miR-874-3p. Luciferase reporter assay was conducted to examine the effect of the identified regulator on the promoter regions of miR-296 and miR-874-3p. Quantitative polymerase chain reaction (Q-PCR) was used to detect the expression levels of miR-296-5p and miR-874-3p. Protein expression levels of the identified regulator and PIN1 were examined by western immunoblotting. Results: By screening the online database-UCSC, Myc was identified as a potential transcription factor for the miRNAs, miR-296-5p and miR-874-3p. As demonstrated by luciferase reporter assay, expression of Myc activated the promoters of miR-296-5p and miR-874-3p. Myc over-expression also increased the expression levels of these two miRNAs, which in turn led to down-regulation of PIN1. Interestingly, we found that over-expression of PIN1 increased the expression of Myc, miR-296-5p and miR-874-3p. We therefore hypothesized that PIN1 expression is maintained via a negative feedback loop of Myc-miRNAs-PIN1. Consistent with this hypothesis, we demonstrated that over-expression of exogenous EGFP-tagged PIN1 led to the enhancement of Myc, miR-296-5p and miR-874-3p expression, and thereby subsequently decrease the endogenous PIN1 level. Conclusion: Taken together, our results suggested that the expression level of PIN1 is maintained by a negative feedback loop through the regulation of Myc, miR-296-5p and miR-874-3p. Citation Format: Ka Wai Leong, Chi Wai Cheng, Yok Lam Kwong, Wai Choi Eric Tse. PIN1 expression level is maintained by a negative feedback loop through regulation of Myc and miRNAs. [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 4558.
Abstract 2098: Understanding the synergy between temozolomide and PARP inhibition in Ewing sarcoma
Authors: Ruth Carlson, Raushan Kurmasheva
Journal: Cancer Research (2016)

Abstract Ewing sarcoma is the fourth most common highly malignant childhood cancer; it is defined by a tumor-specific chromosomal translocation. In approximately 85% of all tumors, the EWSR1 gene on chromosome 22 is fused to a member of E26 transformation-specific sequence family of transcription factors, the FLI1 gene on chromosome 11. DNA damage induced by expression of EWSR1-FLI1 fusion gene is potentiated by PARP1 inhibition in Ewing cells, where EWSR1-FLI1 genes act in a positive feedback loop to maintain the expression of PARP1. As single agents, PARP inhibitors have shown promising activity in vitro, but only modest activity in in vivo models. In our previous work (in PPTP), we showed that low level damage to DNA by temozolomide (TMZ) can be potentiated up to 40-fold through inhibition of PARP by BMN-673, leading to dramatic tumor regressions in 5 of the 10 Ewing sarcoma xenograft models. Therefore, we were aimed to determine the differences between the tumors that respond to treatment with BMN-673 and those intrinsically resistant to it, and to understand the underlying mechanisms of such resistance, with the ultimate goal to develop more effective therapy for Ewing sarcoma. We have used the same cell lines to investigate biochemical differences between those Ewing sarcoma lines where there is synergy in xenograft models in mice, and those where the combination is inactive. Our studies using cell lines show that, 1) in vitro BMN-673 and TMZ are synergistic in all cell lines, irrespective of their response as xenografts; 2) In vivo synergy correlates with intrinsic sensitivity to BMN-673 and TMZ in vitro. For Ewing lines, where there is no in vivo synergy when they are grown as xenografts, they are ∼9-fold resistant to BMN-673, and ∼15-fold resistant to TMZ relative to lines where there is synergy as xenografts. The resistance of the Ewing sarcoma xenografts to the synergy of the combination of BMN-673 and TMZ in mice is a consequence of intrinsic resistance to either or both of the drugs. The combination of BMN-673 and TMZ in Ewing sarcoma xenografts is the most dramatic synergy between two drugs to be reported. The synergy in vivo is restricted to Ewing sarcoma, yet only half of the models respond to combination treatment with the other half completely resistant. Studies proposed in this application will potentially identify biomarkers that will allow identification of patients likely to benefit from such treatment, and spare toxicity for those unlikely to respond. Citation Format: Ruth Carlson, Raushan Kurmasheva. Understanding the synergy between temozolomide and PARP inhibition in Ewing sarcoma. [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 2098.
Abstract CT114: Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results
Authors: Scott Tagawa, Gurkamal S. Chatta, Sumanta K. Pal, Sanjay Goel, Reza Mazhari, Callie Heaton, Ely Benaim, Neeraj Agarwal
Journal: Cancer Research (2016)

Abstract Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth in vitro and is in development for the treatment of metastatic clear cell renal carcinoma Methods: The phase Ib/II proof of concept, multicenter, open label study is conducted in 2 phases. The phase Ib was a dose-escalation study of RX-0201 administered in combination with everolimus. RX-0201 was administered as a continuous intravenous infusion for 14 days followed by 7 days of rest; everolimus was administered at a starting dose of 10mg once daily. Subjects were enrolled at increasing doses of RX-0201 in a modified 3+3 design. Plasma concentrations were measured in phase Ib and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. The dose of RX-0201 identified in phase Ib is being studied further in phase II, which is the randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Results: In the Phase Ib, seven males and 3 females, (median age 61 years) were treated with 125 mg/m⁁2/day (n = 3), 200 mg/m⁁2/day (n = 4), and 250 mg/m⁁2/day (n = 3) RX-0201 in combination with 10 mg everolimus. They received 1-3 lines of therapy prior to study entry (median = 1). The most common toxicities attributed to the combination were rash, mouth ulceration, weight loss, thrombocytopenia, facial edema, fatigue, and pruritus. No significant events were attributed to RX-0201 alone. Most events (81%) were mild or moderate in severity. Based on the tolerability, 250 mg/m⁁2/day RX-0201 dose was declared the recommended phase II dose. Three subjects in the phase Ib have experienced stable disease for 383, 191, and 122 days; a tumor burden reduction of 16 and 36% was seen in 2 subjects. RX-0201 PK demonstrated a dose proportional exposure. Conclusions: RX-0201, in combination with everolimus, appears to be safe and well tolerated in patients with metastatic renal cancer at doses up to 250 mg/m⁁2/day. Randomized phase II of this trial is currently ongoing. Citation Format: Scott Tagawa, Gurkamal S. Chatta, Sumanta K. Pal, Sanjay Goel, Reza Mazhari, Callie Heaton, Ely Benaim, Neeraj Agarwal. Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results. [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 CT114.
Beyond HLA: Impact of Immunoreactive Mismatches of Minor Histocompatibility Antigens on Probability of Relapse and Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation from HLA-Matched Unrelated Donors.
Authors: Miroslaw Markiewicz, Urszula Siekiera, Jerzy Wojnar, Agata Wieczorkiewicz, Iwona Wylezol, Sebastian Giebel, Agnieszka Karolczyk, Jerzy Holowiecki
Journal: Blood (2006)
Abstract 3496: TRAF2 protects mammary epithelial and cancer cells from endoplasmic reticulum stress-induced apoptosis
Authors: Hasem Habelhah, Laiqun Zhang, Ainiwaer Xialikaer, Ken Blackwell
Journal: Cancer Research (2016)

Abstract TRAF2 plays a key role in the immune response and cell survival by regulating the NF-κB and JNK pathways in response to most members of the TNF superfamily. TRAF2 has also been shown in cell culture systems to mediate IRE1α-induced activation of the ASK1-JNK pathway to promote apoptosis under conditions of acute endoplasmic reticulum (ER) stress. Gene knockout studies revealed that mice deficient for RANKL or NF-κB display defects in osteoclastogenesis and lactating mammary-gland development. Here, we report that TNFα and TRAF2 double knockout (DKO) mice develop with normal bone morphology and density, but the female mice display a severe lactation defect due to significantly increased apoptosis of cells in the lobuloalveolar tree. Unexpectedly, RANKL-induced activation of the canonical NF-κB pathway is not only normal in DKO mammary epithelial cells (MECs), but the expression of the NF-κB target genes is significantly enhanced due to constitutive activation of the non-canonical NF-κB pathway in the absence of TRAF2. On the other hand, cytotoxicity assays revealed that DKO MECs exhibit significantly increased susceptibility to apoptosis induced by chronic ER stress, but not by death receptor or DNA damage. In addition, siRNA-mediated knockdown of TRAF2 in breast cancer cells significantly sensitized the cells to chronic ER stress-induced apoptosis in a RIP1-dependent manner. These data suggest that the physiological function of TRAF2 is to protect the cells from apoptosis under conditions of pathologically relevant chronic ER stress. Given that the lactating MECs and rapidly growing cancer cells have high demands for protein syntheses and ER stress responses, our findings suggest that inhibition of the IRE1α-TRAF2 pathway could be used as a novel adjuvant therapy to treat rapidly proliferating cancer cells. Citation Format: Hasem Habelhah, Laiqun Zhang, Ainiwaer Xialikaer, Ken Blackwell. TRAF2 protects mammary epithelial and cancer cells from endoplasmic reticulum stress-induced apoptosis. [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 3496.
Abstract 3009: Targeting G-protein coupled receptor-related pathway in mucinous tumors
Authors: Ashok K. Dilly, Yong J. Lee, Herbert J. Zeh, David L. Bartlett, Mohammad Haroon A. Choudry.
Journal: Cancer Research (2016)

Abstract Introduction: Pseudomyxoma peritonei (PMP) is an indolent malignancy characterized by excessive production of Mucin 2 (MUC2; a gel-forming secreted mucin). We have previously demonstrated mucinous tumor growth inhibition in a patient-derived murine xenograft model of PMP using the cyclooxygenase-2 (COX-2) inhibitor celecoxib. We evaluated the downstream mechanism for celecoxib-mediated MUC2-inhibition. Methods: In vitro and in vivo studies were conducted using MUC2-secreting LS174T cells, PMP explant tissue and a unique intraperitoneal patient-derived murine xenograft model of PMP (PDX model of PMP). Results: LS174T cells treated with COX-2 inhibitor celecoxib (5-20 μM) for 24 hours demonstrated a significant reduction in MUC2 protein expression measured by flow cytometric analysis. Similarly, in the PDX model of PMP chronic oral therapy with celecoxib (20 mg/kg/d) for 28 days significantly inhibited MUC2 protein expression in harvested tumor tissue. In the LS174T cells, PGE2 (a COX-2 product) induced MUC2 mRNA (real-time PCR) and protein expression (flow cytometry) and this was inhibited by the G-protein coupled-EP4 receptor inhibitor AH23848 as well as siRNA for CREB (cAMP response element-binding protein). Using chromatin immunoprecipitation assay in LS174T cells, we found that treatment with celecoxib or protein kinase A inhibitor (fragment 6-22 amide) significantly decreased CREB-transcription factor binding to the MUC2 promoter. Conclusions: These data suggest that celecoxib inhibits MUC2 expression via the G-protein coupled receptor/ cAMP/ Protein kinase A/ CREB pathway. Since activating G-protein (GNAS) mutations are commonly found in PMP and may be responsible for its unique mucinous phenotype, our data provide a rationale for targeting this pathway to control mucin production in this malignancy. Citation Format: Ashok K. Dilly, Yong J. Lee, Herbert J. Zeh, David L. Bartlett, Mohammad Haroon A. Choudry. Targeting G-protein coupled receptor-related pathway in mucinous tumors. [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 3009.
Crosstalk of HNF4 α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids
Authors: Hong Lu
Journal: Acta Pharmaceutica Sinica B (2016)

The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver. There have been a few reviews on the regulation of drug metabolism, lipid metabolism, cell proliferation, and inflammation by HNF4α. However, the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered. Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α, and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.
Safety of cabazitaxel (Cbz) in patients (pt) with metastatic transitional-cell carcinoma (mTCC) progressing to cisplatin-based chemotherapy: Results from the JEVTCC-SOGUG Study.
Authors: Ignacio Duran, Xavier Garcia del Muro, Sergio Vazquez-Estevez, Begoña Perez-Valderrama, Miguel Angel Climent, Nuria Laínez, Nuria Sala, M Isabel Sáez, José Pablo Maroto Rey, Esther Noguerón, Albert Font, Enrique Gallardo Diaz, Alvaro Pinto, María José Méndez-Vidal, Martin Lázaro Quintela, M. Pilar Lopez Criado, Carmen Santander, Aranzazu Gonzalez del Alba, Raquel Luque, Jose Angel Arranz
Journal: Journal of Clinical Oncology (2015)

e15537 Background: No standard regimen exists for second line treatment of mTCC patients. Taxanes have shown some activity in this setting. Cbz, is a novel semi-synthetic taxane never tested before in mTCC. Methods: A phase II study of Cbz 25 mg/m2/3w in pts with mTCC after progression to a platinum-based regimen. Patients were stratified by prognosis in one of the following 3 subgroups: very good, good or poor prognosis (VGP, GP, PP), defined by 0, 1 or > 1 of the Bellmunt’s criteria. Toxicity was evaluated as a secondary endpoint. Adverse events (AE) were coded according to MedDRA and graded using NCI-CTCAE v.4.0. Results: All 71 pts received at least one dose of study drug (Safety population). Pts in VGP, GP and PP subgroup received a median of 3 Cbz cycles each. Overall incidence of any treatment-related AEs was similar in the 3 subgroups (21/21 VGP; 31/34 GP; 14/16 PP). The most common (> 10%) treatment-related grade ≥ 3 AEs were neutropenia, anemia, diarrhea and asthenia. Table 1 displays most relevant treatment-related AEs by prognostic subgroup. No grade ≥ 3 peripheral neuropathy was reported. There was one toxic death due to septic shock (GP subgroup). Cbz dose was discontinued due to related AEs in 8 (11.3%) pts. Cbz dose delay/reduction was necessary in 14 and 17 pts due to related AEs. Primary prophylaxis with G-CSF was administered in 24 pts (5 VGP; 14 GP; 5 PP). A pharmacogenomic study was conducted to identify potential predictors of toxicity and has been presented elsewhere. Conclusions: Cabazitaxel was overall well tolerated with less hematological toxicity than previously reported in other tumors, except for febrile neutropenia. Tolerability was similar regardless the prognostic subgroup. Funding: Sanofi. Clinical trial information: EudraCT: 2011-003498-27. VGP (n = 21) GP (n = 34) PP (n = 16) All grades grade ≥3 All grades grade ≥3 All grades grade ≥3 Hematological Neutropenia 13 (61.9) 12 (57.1) 8 (23.5) 7 (20.6) 1 (6.3) - Febrile neutropenia ---- 2 (9.5) ---- 6 (17.7) --- 3 (18.8) Anemia 9 (42.9) 2 (9.5) 6 (17.7) 3 (8.8) 3 (18.8) 2 (12.5) Non-Hematological Asthenia 15 (71.4) - 21(61.8) 5 (14.7) 5 (31.3) 1 (6.3) Diarrhea 7 (33.3) 3 (14.3) 10 (29.4) 1 (2.9) 3 (18.8) - Nausea 5 (23.8) - 9 (26.5) 1 (2.9) 6 (37.5) 1 (6.3)
Abstract 2445: Cytoplasmic mislocalization of p27 promotes metastasis and its autoantibody correlates with prognosis in osteosarcoma
Authors: Manjula Nakka, Yiting Li, Aaron J. Kelly, Ching C. Lau, Mark Krailo, Donald A. Barkauskas, John Hicks, Tsz-Kwong Man
Journal: Cancer Research (2016)

Abstract Development of metastasis is the major cause of death in osteosarcoma, which is the most common malignant bone tumor in children and young adults. However, detection of metastasis relies solely on imaging techniques and targeted treatments of metastatic patients are still not available to improve the dismal outcome. Using an immunoproteomic approach, we identified that p27 autoantibody was significantly elevated in the plasma of high-risk osteosarcoma patients. Results of immunohistochemistry showed that cytoplasmic mislocalization of p27 occurred in a majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 and shRNA-mediated gene silencing promoted and inhibited, respectively, the migration and invasion of osteosarcoma cells. Additionally, a mutation in S10 or T198, but not T157, phosphosite abolished the pro-migration and invasion phenotypes of cytoplasmic p27, possibly through a RhoA-related mechanism. Furthermore, mice injected with cells carrying cytoplasmic p27 increased the development of pulmonary metastasis when compared to an empty vector control. Lastly, using a large cohort of serum samples (n = 233), we showed that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival of osteosarcoma (p &amp;lt; 0.05). Together, our results suggest that the circulating p27 autoantibody can be used as a prognostic biomarker at diagnosis and cytoplasmic mislocalization of p27 is a frequent event in osteosarcoma, which can promote tumor cell motility and invasiveness as well as metastasis formation. Targeting specific p27 phosphorylations may provide a novel therapeutic approach for osteosarcoma patients with metastasis. Citation Format: Manjula Nakka, Yiting Li, Aaron J. Kelly, Ching C. Lau, Mark Krailo, Donald A. Barkauskas, John Hicks, Tsz-Kwong Man. Cytoplasmic mislocalization of p27 promotes metastasis and its autoantibody correlates with prognosis in osteosarcoma. [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 2445.