tbuckley/cabot-search huggingface dataset:
Abstract 2506: Citral reduces breast tumor growth by inhibiting cancer stem cell marker ALDH1A3
Authors: Margaret L. Thomas, Roberto De Antueno, Krysta Coyle, Brianne Cruickshank, Michael Giacomantonio, Roy Duncan, Carman Giacomantonio, Paola Marcato
Journal: Cancer Research (2016)

Abstract Breast cancer stem cells (CSCs) can be identified by increased Aldefluor activity which is primarily due to aldehyde dehydrogenase 1A3 (ALDH1A3) expression. In addition to being a CSC marker, ALDH1A3 regulates genes expression via inducing retinoic acid (RA) signaling and plays an important role in mediating progression of cancers, including breast, melanoma, lung and glioblastoma. Therefore, ALDH1A3 represents a novel druggable anti-cancer target of interest. There are no currently characterized inhibitors of the ALDH1A3 isoform, so twelve general ALDH inhibitors were tested for their effectiveness in targeting ALDH1A3 activity. Ability to directly inhibit ALDH activity was quantified with the Aldefluor assay on a patient tumor xenograft and on breast cancer cell lines with known ALDH isoform activity. Inhibition of RA signaling was quantified by measuring expression of the RA-inducible genes RARRES1 and RARβ. To investigate the anti-cancer properties of these compounds, apoptosis was quantified with the annexin V assay. Citral significantly reduced ALDH1A3- and ALDH2-associated Aldefluor activity in breast cancer cell lines and also reduced Aldefluor activity of a patient-derived xenograft. Citral reduced expression of RA-inducible genes through reducing ALDH1A3 activity. Citral induced apoptosis in vitro in an ALDH-independent manner in breast cancer cell lines and reduced proliferation in the MDA-MB-231 breast cancer cell line. Nanoparticle (NP)-encapsulated citral was generated for in vivo use and administered intravenously to female NOD/SCID mice harbouring MDA-MB-231 ALDH1A3-overexpression tumors. 10mg/kg NP-citral significantly decreased the growth of ALDH1A3-driven MDA-MB-231 tumors. Nanoparticle-encapsulated citral shows promise as an adjuvant therapy for patients with tumors that have a large population of high-ALDH1A3 CSCs. Citation Format: Margaret L. Thomas, Roberto De Antueno, Krysta Coyle, Brianne Cruickshank, Michael Giacomantonio, Roy Duncan, Carman Giacomantonio, Paola Marcato. Citral reduces breast tumor growth by inhibiting cancer stem cell marker ALDH1A3. [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 2506.
Abstract 618: Dual PI3K/mTOR inhibition as a treatment strategy for PIK3CA and APC mutant colorectal cancers
Authors: Susan Payne, Tyler Foley, Cheri Pasch, Alexander Yueh, Demetra Korkos, Dana Van De Hey, Linda Clipson, Dustin Deming
Journal: Cancer Research (2016)

Abstract BACKGROUND: Colorectal cancer (CRC) is understood as a diverse group of cancers calling for the personalization of therapeutics to individual subtypes of CRC. Mutations in PIK3CA, which result in a constitutively active phosphoinositide-3-kinase protein (PI3K), are present in 20-30% of CRCs. Aberrations in the Adenomatous Polyposis Coli (APC) gene are found in 86% of PIK3CA mutant CRCs. The potential for treatment of tumors with this specific profile is of great interest. METHODS: Mice expressing a constitutively active PI3K and loss of APC were generated and spheroid cultures were derived from the resulting cancers. PIK3CA and APC mutant spheroids were treated with GDC0941 (GDC), a pan PI3K inhibitor, NVP-BYL719 (BYL), a PI3K alpha isomer specific inhibitor, or NVP-BEZ235 (BEZ), a dual mTOR/PI3K inhibitor. Proliferation was measured by changes in spheroid diameter over time. BEZ treatment of mice with PIK3CA and APC mutant CRCs was performed over 14 days. Tumor response was measured with serial murine colonoscopy and dual hybrid 18F-FDG PET/CT imaging. RESULTS: Persistent PIK3CA and APC mutant CRC spheroid growth was observed with BYL and GDC treatment, while BEZ treatment resulted in a significant reduction in spheroid size. Immunoblotting determined that this correlated with significant suppression of phosphorylated AKT, RPS6 and 4EBP1 in BEZ-treated spheroids and incomplete PI3K pathway inhibition following BYL and GDC treatment. BEZ treatment was then investigated in mice with PIK3CA and APC mutant CRCs. BEZ elicited a dramatic treatment response in these cancers on endoscopy, with a 53% decrease in median lumen occlusion compared to a 60% increase in controls over the 14 day treatment period. PET/CT imaging results confirmed these findings demonstrating a decrease in tumor size and avidity post BEZ treatment. BEZ resulted in inhibition of the PI3K pathway in these tumors. Reactivation of PI3K signaling was observed within 24 hours of the withdrawal of BEZ. BEZ was well-tolerated in these mice and associated with a decrease in the endoscopic anemia score. CONCLUSIONS: PIK3CA and APC mutant CRCs are a potentially targetable subtype of cancer. These cancers are resistant to proximal inhibition of the PI3K pathway, but are responsive to dual PI3K/mTOR inhibition. These results warrant further investigation in clinical studies. Citation Format: Susan Payne, Tyler Foley, Cheri Pasch, Alexander Yueh, Demetra Korkos, Dana Van De Hey, Linda Clipson, Dustin Deming. Dual PI3K/mTOR inhibition as a treatment strategy for PIK3CA and APC mutant colorectal cancers. [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 618.
Glucose Ceramide Synthase Inhibitors Inhibit Osteoclast Activation Induced by Myeloma-Derived and De Novo Synthesized Glycosphingolipids.
Authors: Ke Xu, Aristotelis Antonopoulos, Emmanouil Spanoudakis, Simon Parry, Aristeidis Chaidos, Ming Hu, Terry Butters, Anne Dell, Amin Rahemtulla, Nikki Horwood, Anastasios Karadimitris
Journal: Blood (2009)
Abstract 5216: Broadening tumor spectrum in Lynch syndrome: increased incidence for 15 distinct cancer types
Authors: Christina Therkildsen, Steen Ladelund, Lars Joachim Lindberg, Lars Smith-Hansen, Mef Nilbert
Journal: Cancer Research (2016)

Abstract Introduction: Lynch syndrome is a multi-tumor syndrome predominantly associated with an increased risk of colorectal cancer, but is indeed linked to a yet uncertain number of extra-colonic tumor types. Methods: In order to determine the risk for extra-colonic tumors in Lynch syndrome, we determined the incidence rates for 21 distinct malignancies in the national Danish Lynch syndrome cohort compared to an age-and sex matched control cohort from the Danish population. Results: Based on data from 1494 Lynch syndrome mutation carriers, significantly increased risks were demonstrated for 15 cancer types. These included Lynch syndrome-related malignancies, such as cancer of the endometrium, the ovary, the small bowel, the urinary tract and brain tumors as well as tumor types with an undefined role in Lynch syndrome, such as breast cancer, gastric cancer, pancreatic cancer, skin cancer, prostate cancer, lung cancer, kidney cancer, and testicular cancer. Distinctive peak ages were defined with the highest incidence rate ratio at age 30-49 years for ovarian cancer and 50-69 years for endometrial cancer, breast cancer, and brain tumors to continuously increasing incidence rate ratios with increasing age for e.g. urothelial cancer, gastric cancer, pancreatic cancer and skin cancer. Conclusion: The broad tumor spectrum in Lynch syndrome is of relevance to consider during genetic counseling, whereas the variable peak incidence ages provide a basis for precision surveillance programs that consider the different risks throughout life. Citation Format: Christina Therkildsen, Steen Ladelund, Lars Joachim Lindberg, Lars Smith-Hansen, Mef Nilbert. Broadening tumor spectrum in Lynch syndrome: increased incidence for 15 distinct cancer types. [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 5216.
Recombination Rate Variation, Hitchhiking, and Demographic History Shape Deleterious Load in Poplar
Authors: M. Zhang, L. Zhou, R. Bawa, H. Suren, J.A. Holliday
Journal: Molecular Biology and Evolution (2016)

Deleterious alleles are expected to be purged by purifying selection or maintained at low frequency. However, many additional evolutionary forces may shape the pattern of deleterious mutations across the genome and among populations, including selection, hitchhiking, recombination, and demographic history. We used exome capture data to estimate the genome-wide distribution of deleterious alleles across natural populations of the model tree black cottonwood (Populus trichocarpa). Although deleterious alleles were on average present at low frequency suggesting purifying selection, they were preferentially enriched both within genomic regions of low-recombination and in regions showing evidence of positive selection. The demographic history of this species also appeared to play a role in the distribution of deleterious alleles among populations, with peripheral populations having higher rates of deleterious homozygosity. This be due to less efficient selection arising from smaller effective population sizes at the edges of the range, and possibly also due to recent bottlenecks associated with postglacial recolonization. Finally, correlations between deleterious homozygosity and plant growth suggest a significant effect of deleterious load on fitness. Our results show that both genomic context and historical demography play a role in shaping the distribution of deleterious alleles across the genome and range of P. trichocarpa.
CONKO-008: Oxaliplatin (O)/folinic acid (FA)/5-fluorouracil (5-FU) (24h) in combination with lapatinib as second-line therapy in pancreatic cancer after gemcitabine failure: A phase I trial.
Authors: Jens Stieler, Uwe Pelzer, Marianne Sinn, Jana Kaethe Striefler, Bernd Dörken, Hanno Riess
Journal: Journal of Clinical Oncology (2012)

e14533 Background: ErbB-1 and ErbB-2 as its enhancer are expressed in pancreatic cancer. Based on the results of the 2nd-line chemotherapy (CT) with Oxaliplatin, 5-FU and Folinic acid (OFF) (CONKO-003; ASCO 2008) and the activity of EGFR- tyrosine kinase inhibition in pancreatic cancer (Moore JCO 2007), this trial aims to further improve therapeutic options for patients after Gemcitabine failure by combining OFF with lapatinib, a combined ErbB-1 and ErbB-2 tyrosine kinase inhibitor which showed preclinical synergy with 5-FU (Kim PloS One 2009). Methods: The daily dose of lapatinib combined with oxaliplatin 85 mg/m 2 (2-4 h infusion d 8, 22), 5-FU 2000 mg/m 2 (24 h continuous infusion d1,8,15,22 q d 42) and FA 200 mg/m2 (30 min infusion d1,8,15,22 q d 42). was expected to be between 750 to 1,500 mg, further dose intensification was not planned. Starting dose for lapatinib was set on 1,000 mg/day, with a minimum of 3 pts. on each level and extension to 6 pts. in case of a dose limiting toxicity (DLT). Maximum tolerated dose (MTD) was defined as a dose level (DL) below the level where 2/6 patients would show DLTs during cycle 1. Results: 18 Pts (12m/6w). have been enrolled in the trial.7 pts. were treated on 1,000 mg/d (DL 1), 5 pts. on level 1,250 mg/d (DL 2), and 6 pts. on 1,500 mg (DL 3). DLTs were met on DL 3 with diarrhea CTC grade 4 and concomitant neutropene enterocolitis in one patient and diarrhea CTC grade 3 in another patient. MTD is thus limited to 1,250 mg lapatinib in combination with OFF. Conclusions: With diarrhea as most prominent cumulative toxicity of the regimen, the maximum dose of lapatinib in combination with OFF is 1,250 mg. This dose may find further use in future phase II trials.
Branched Chain RNA <i>In Situ</i> Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer
Authors: Philip J. Saylor, Richard J. Lee, Kshitij S. Arora, Vikram Deshpande, Rong Hu, Kara Olivier, Erika Meneely, Miguel N. Rivera, David T. Ting, Chin-Lee Wu, David T. Miyamoto
Journal: Clinical Cancer Research (2016)

The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues.We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status.We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055).Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363-9. ©2016 AACR.
Quality of informed consent in cancer clinical trials in India: A cross-sectional survey.
Authors: Vikram Gota, Manjunath Nookala, Akanksha Yadav, Sadhna Kannan, Raghib Ali
Journal: Journal of Clinical Oncology (2015)

e17652 Background: An informed consent is an ethical and legal requirement for research involving human subjects. There are serious concerns about the adequacy of such consent in India. We attempted to understand the quality of informed consent in clinical trial participants at our centre. Methods: Subjects were enrolled for this survey if they were aged ≥ 18 years and had consented for a clinical trial at a tertiary care cancer centre in India within the previous week. A questionnaire was developed to capture the level of interest shown by patients to understand the trial; the knowledge of the patient with respect to autonomy, voluntariness, rights, risks and benefits of participation; the people involved in a patient's decision to participate in the trial; and the possible factors that encouraged the patient to consent for the trial. The questionnaire was administered by a trained clinical research coordinator. Bivariate associations with knowledge scores (KS) were assessed with t test or ANOVA. Results: 200 patients participated in this survey (M/F = 120/80). Mean KS was 60.1 (±15.4). More than half were not aware of the true intent of clinical trials and 90% were not aware that non-standard treatments or procedures were being evaluated. None of them reported being coerced into taking part in the trial and almost all of them were aware of their autonomy to withdraw consent anytime during the study. Family played a major role in helping patients with their decision to participate in the trial. Trust in the oncologist was the single most important factor influencing the decision to consent. There was good correlation between KS and level of interest (P < 0.001). KS was significantly higher in pharma sponsored trials as against investigator initiated trials (65.3 vs. 52.2; P < 0.001). All patients anticipated some benefit for themselves by participating in the trial. About 60% were attracted by free treatment being offered in trials. 97% of respondents participated hoping for better care and 70% agreed that they felt the advantages of participating in a trial was too great to be missed. Conclusions: Patients carry several misconceptions about clinical trials which should be carefully addressed while counseling them during the consent process.
Delays in postremission chemotherapy for Philadelphia chromosome negative acute lymphoblastic leukemia are associated with inferior outcomes in patients who undergo allogeneic transplant: An analysis from ECOG 2993/MRC UK ALLXII
Authors: Anita J. Kumar, Phyllis A. Gimotty, Joel Gelfand, Georgina Buck, Jacob M. Rowe, Anthony H. Goldstone, Adele Fielding, David I. Marks, Mark Litzow, Elisabeth Paietta, Hillard M. Lazarus, Martin S. Tallman, Selina M. Luger, Alison W. Loren
Journal: American Journal of Hematology (2016)

Adults with acute lymphoblastic leukemia (ALL) have a poorer prognosis than children due to a high risk of relapse. One explanation may be variable adherence to dose-intense chemotherapy. However, little is known about risk factors for delays in therapy and their impact on survival. We conducted an analysis of ECOG 2993/UKALLXII trial to study delays in postremission chemotherapy in adults with newly diagnosed ALL. Logistic regression was used to identify risk factors for a very long delay (VLD, >4 weeks) in start of intensification therapy. Cox regression was used to evaluate the impact of delays on overall survival (OS) and event-free survival (EFS). We evaluated 1076 Philadelphia chromosome negative (Ph-) patients who completed induction chemotherapy, achieved complete remission, and started intensification. Factors independently associated with VLD included duration of hospitalization (odds ratio [OR] = 1.2, P < 0.001) during Phase I; thrombocytopenia during Phase I (OR = 1.16, P = 0.004) or Phase II (OR 1.13, P = 0.001); chemotherapy dose reductions during Induction Phase I (OR = 1.72, P < 0.014); female sex (OR = 1.53, P = 0.010); Black (OR = 3.24, P = 0.003) and Asian (OR = 2.26, P = 0.021) race; and increasing age (OR = 1.31, P < 0.001). In multivariate Cox regression, patients who underwent allogeneic stem cell transplant (alloHCT) had significantly worse OS (HR 1.4, P = 0.03) and EFS (HR 1.4, P = 0.02) after experiencing a VLD compared to alloHCT patients who experienced ≤4 weeks delay. Specific populations (female, older, Black, and Asian patients) were more likely to experience delays in chemotherapy, as were those with significant toxicity during induction. VLDs in therapy negatively affected outcomes in patients undergoing allografting. Am. J. Hematol. 91:1107-1112, 2016. © 2016 Wiley Periodicals, Inc.
Abstract 2518: Crosstalk between stem and non-stem cells in glioblastoma promotes radioresistance in a CD109-dependent manner
Authors: Mutsuko Minata, Ichiro Nakano, Sunghak Kim, Marat PavliuKov, Jia Wang, Svetlana Komarova, Jun Wang
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is a lethal brain tumor that contains cancer stem cells that are bestowed with tumor initiating and treatment resistant properties. Patient-derived glioma stem-like cells (GSCs) that resemble the clinically relevant MES subtype harbor more aggressive and therapy resistant properties. Here we report that exposure of GSCs to ionizing radiation (IR) provokes inter-cellular signals from therapy-induced senescent non-stem cancer cells to stimulate compensatory growth in cancer stem cells resulting in persistent transcriptomic and phenotypic shift toward a more MES subtype. This IR-induced gain of MES features in GSCs is accompanied by conversion of CD133+ stem cell populations to CD133- /CD109+ cells. In both de novo and IR-induced MES GSCs, CD109+, but not CD109- populations are highly tumorigenic and multipotent in vivo. Inhibition of CD109 attenuates clonogenicity and radioresistance in MES GSCs GBM. Clinically, CD109 expression is significantly associated with the MES GBMs and poorer prognosis of GBM patients. Taken together, our data imply that radiation of GSCs induces direct transformation of cancer stem cells to the MES subtype accompanied by a loss of the widely adopted stem cell marker CD133 and a gain of a novel, tumor propagating, and clinically relevant MES stem cell marker, CD109. Citation Format: Mutsuko Minata, Ichiro Nakano, Sunghak Kim, Marat PavliuKov, Jia Wang, Svetlana Komarova, Jun Wang. Crosstalk between stem and non-stem cells in glioblastoma promotes radioresistance in a CD109-dependent manner. [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 2518.
Primary efficacy analysis of a phase II study of neoadjuvant bevacizumab (BEV), chemotherapy (CT), and trastuzumab (H) in HER2-positive inflammatory breast cancer (IBC): BEVERLY2 study.
Authors: P. Viens, J. Pierga, T. Petit, T. Delozier, J. Ferrero, M. Campone, J. Gligorov, F. Lerebours, H. H. Roche, M. Pavlyuk, T. D. Bachelot, E. Charafe-Jauffret
Journal: Journal of Clinical Oncology (2011)

531 Background: In HER2-negative metastatic breast cancer, BEV significantly improves the efficacy of first-line CT, as shown in three phase III trials. The role of H in HER2-positive breast cancer is established but there is less information on BEV in this setting. Methods: The primary objective of this single-arm, open-label, phase II study is to determine the rate of pathologic complete response (pCR; Sataloff classification) by central review in patients (pts) receiving neoadjuvant CT, BEV, and H for IBC. Secondary endpoints include pCR rate by investigator assessment, disease-free survival, overall survival, safety (CTCAE v3), and potential predictive markers. Pts with HER2-positive IBC (IHC 3+ or FISH/CISH+, T4d, any N) received 4 cycles of FEC100+ BEV 15 mg/kg, d1 q21d, followed by 4 cycles of docetaxel 100 mg/m2 + BEV 15 mg/kg + H 8→6 mg/kg q21d. Pts underwent surgery 4–6 weeks after the last dose, followed by radiotherapy. H was continued during surgery and radiotherapy and as adjuvant therapy. BEV was re-introduced as adjuvant therapy for 10 cycles, giving a total of 18 cycles each of BEV and H. Results: Between Oct 2008 and Oct 2009, 52 pts were included (median age 52 years; Scarff-Bloom–Richardson grade 2 in 40% of pts and 3 in 50%). All 8 cycles of neoadjuvant therapy were completed as planned by 42 pts (81%); 45 (87%) received 8 cycles of BEV and 50 (96%) received ≥4 preoperative cycles of H. The pCR rate was 63.5% by central review (95% CI 49.4–77.5%). Investigator-assessed pCR rate was 67.3% (95% CI 53.6–81.0%). The clinical response rate was 98% in 45 pts with data available. Grade ≥3 adverse events (AEs) in >5% of pts were: neutropenia (48% of pts); febrile neutropenia (17%); alopecia (10%); hand-foot syndrome, leukopenia, febrile bone marrow aplasia, increased 𝛄-glutamyltransferase (each 8%); anemia and mucositis (each 6%). There was only 1 grade ≥3 AE of special interest for BEV (hypertension in 1 pt). Three pts (6%) experienced cardiac failure (all grade 2, resolved). There were no treatment-related deaths. Conclusions: Neoadjuvant BEV, H, and CT is highly active in IBC (pCR rate 63.5%) with an acceptable safety profile.
Death Receptor 3 (DR3) Is Expressed By Innate Lymphoid Cells (ILC) and Ligation By Tumor Like Antigen-1 (TL1A) Leads To Costimulation and Significant ILC Expansion
Authors: Michael R. Verneris, Yong-Oon Ahn, Matthew A Weeres, Bruce R Blazar, Jeffrey S. Miller
Journal: Blood (2013)