tbuckley/cabot-search huggingface dataset:
Abstract IA10: Biomarker selected therapy for pancreas ductal adenocarcinoma: an emerging reality?
Authors: Eileen M. O'Reilly
Journal: Cancer Research (2016)

Abstract Pancreas adenocarcinoma remains a major challenge hallmarked by several notables, including a rising incidence, modest effectiveness of current state-of-the-art therapies and a dearth of validated biomarkers for clinical decision making. With regard to germline genomics, about 5-8% of pancreas adenocarcinoma patients will harbor a mutation in BRCA2, BRCA1 and PALB2. These mutations amongst others lead to impaired DNA repair and are identified to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Genomic instability, a result of deleterious mutations of genes functioning in homologous repair mediated DNA repair pathways, yields an exceptional vulnerability in cancer cells named synthetic lethality. Recent studies have elucidated that platinum agents and Poly-ADP-ribose polymerase (PARP) inhibitors may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. The impact of somatic BRCA mutations on response to DNA targeting agents is currently being investigated. A recent whole genome sequencing study by Waddell et al reported overlapping features in both somatic and germline mutations such as unstable genome along with possible DNA targeting agent sensitivity in both groups. This suggests that gained mutation of DNA repair genes throughout the oncogenesis process may also create synthetic lethality and a larger subset of patients may benefit from these evolving treatment approaches. The characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as novel treatment approaches will be discussed. Citation Format: Eileen M. O’Reilly.{Authors}. Biomarker selected therapy for pancreas ductal adenocarcinoma: an emerging reality? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA10.
The EGFR-Inhibitor Erlotinib Induces Apoptosis in Neoplastic Cells of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), an Effect Determined by the Expression Level of Nucleophosmin (NPM).
Authors: Simone Boehrer, Lionel Ades, Claire Fabre, Pierre Fenaux, Guido Kroemer
Journal: Blood (2006)
Characterization of the anaplastic prostate carcinomas: A prospective two-stage phase II trial of frontline carboplatin and docetaxel (CD) and salvage etoposide and cisplatin (EP).
Authors: A. Aparicio, A. L. Harzstark, E. Lin, P. G. Corn, J. C. Araujo, S. Tu, L. C. Pagliaro, R. E. Millikan, W. Arap, J. Kim, C. J. Ryan, A. J. Zurita, N. M. Tannir, A. M. Lin, E. J. Small, P. Mathew, D. M. Jones, P. Troncoso, P. F. Thall, C. Logothetis
Journal: Journal of Clinical Oncology (2011)

4666 Background: Small cell prostate cancer (SCPC) predicts for resistance to androgen ablation, frequent response to platinum-based chemotherapy, but short survival. We hypothesize that PCa patients who share clinical features with SCPC (Table) but are morphologically heterogeneous share its high responsiveness to chemotherapy and underlying biology. Methods: Men with anaplastic PCa (Table) were treated with frontline CD (C:AUC 5 and D:75mg/m2 Q21days) followed, at disease progression (PD), by salvage EP (E:120mg/m2/day and C:25mg/m2/day x 3 Q21days) to determine the response and clinical course of patients with “anaplastic” PCa and to assemble tissues for biological interrogation. Results: Preliminary data analysis shows 115 of 121 registered were eligible. Six (5%) had primary SCPC. Median (range) Gleason score at diagnosis was 9 (5-10), age at registration 64 (39-80), time from diagnosis 1 (0-20) years, PSA 7ng/mL (0-925) and follow-up 11.9 months. After 2 and 4 cycles of CD, 96 (83.5%) and 76 (66.1%) remained free of PD. After 2 and 4 cycles of EP 45 of 71 (63.4%) and 31 (43.7%) remained free of PD. Median time to PD after CD is 5.1 (95%CI: 4.11-6.12) and after EP 2.92 (95%CI: 1.58-3.32) months. Median overall survival is 15.36 (95%CI: 13.39-19.01) months. Conclusions: Our observations support the hypothesis that a distinct variant of lethal PCa can be identified by clinical features. We estimate the anaplastic Pca contribute to 30% of PCa deaths. These findings serve as the clinical foundation for the efforts to understand the underlying biology. If prospectively confirmed patients with anaplastic PCa must be recognized early and treated aggressively. Clinical features of anaplastic PCa (eligibility criteria). CRPC with at least one of the following: Histologic evidence of SCPC Exclusively visceral metastases Predominantly lytic bone metastases Bulky (≥ 5 cm) lymphadenopathy or pelvic/prostate mass PSA ≤ 10 ng/mL plus ≥ 20 bone metastases Neuroendocrine markers on histology (ChrA or Syn) or serum (ChrA or GRP) plus LDH≥2xULN, CEA≥2xULN or malignant hypercalcemia Response to androgen deprivation therapy ≤ 6 months
Abstract 2190: Oncostatin M reduces SLUG expression in lung adenocarcinoma cells through STAT1-PIAS4-dependent histone deacetylation
Authors: Chih-Ming Pan, Mong-Lien Wang, Cheng-Wen Wu
Journal: Cancer Research (2015)

Abstract We previously described that mesenchymal stem cells (MSCs) secrete a multifunctional cytokine - Oncostatin M (OSM) which effectively inhibited the metastasis and growth of LAC cells, and reduce the SLUG expression, leading to mesenchymal-epithelial transition (MET). Our data showed that the OSM-dependent inhibition of SLUG is mediated by a STAT1-dependent pathway through a transcriptional control. Previous studies have shown both positive and negative role of STAT1 in transcriptional regulation of its downstream target genes. However, the underlying mechanism of how STAT1 mediates the suppression of SLUG transcription remains elusive. To investigate the associated effector or mediator in OSM-induced STAT1-dependent SLUG suppression, we knocked down PIAS4 (PIAS4-KD), a co-repressor of STAT1, in A549 cells using lentiviral expressed short hairpin RNAs (shRNA). We demonstrated that knockdown of PIAS4 reversed the OSM-suppressed SLUG level and resulted in a higher SLUG mRNA in comparison to scrambled shRNA control. Moreover, we constructed SLUG promoter-driven luciferase expression reporters and test the effect of PIAS4 on SLUG promoter activity. We observed that PIAS4-KD cells expressed higher SLUG promoter activity than control cells, and OSM treatment further augmented this difference. In contrast, reconstitution of PIAS4 expression in PIAS4-KD cells decreased the SLUG promoter activity. Chromatin immuneprecipitation assay (ChIP) revealed the binding of PIAS4 to SLUG promoter region one hour after OSM administration. We also showed OSM-induced tyrosine-phosphorylated STAT1 interacts with PIAS4 and HDAC1 in a co-immunoprecipitation assay. Finally, the level of H3K9 acetylation in SLUG promoter region decreased significantly upon OSM treatment, and the pan HDAC inhibitor, trichostatin A (TSA) rescues OSM-induced suppression of SLUG promoter activity. Our findings demonstrated the underlying mechanism of the tumor-suppressive effect of OSM, and revealed a STAT1-PIAS4-dependent regulation of SLUG promoter through histone deacetylation. Citation Format: Chih-Ming Pan, Mong-Lien Wang, Cheng-Wen Wu. Oncostatin M reduces SLUG expression in lung adenocarcinoma cells through STAT1-PIAS4-dependent histone deacetylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2190. doi:10.1158/1538-7445.AM2015-2190
CALGB 90207: Phase II trial of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma (TCC)
Authors: J. E. Rosenberg, S. Halabi, B. L. Sanford, A. L. Himelstein, J. N. Atkins, R. Hohl, S. L. Seagren, D. F. Bajorin, E. J. Small
Journal: Journal of Clinical Oncology (2006)

4582 Background: No standard 2 nd -line chemotherapy exists for metastatic TCC. Response rates to 2 nd -line chemotherapy for advanced TCC are low and response duration tends to be short. Bortezomib is a proteasome inhibitor with preclinical activity against TCC. Methods: Twenty-five patients with advanced TCC who had been previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Treatment consisted of bortezomib 1.3 mg/m 2 intravenously twice weekly for two consecutive weeks, followed by a 1-week rest period. The primary endpoint was objective response rate by RECIST criteria. Secondary endpoints included safety, toxicity, progression-free survival, and overall survival. Results: The median age was 65.5 yrs (59–7-74.9) and the median number of years since diagnosis was 1.4 (0.9–3.6). 72% of patients were male. 65% of patients had visceral metastases, and 20% of patients had lymph node-only metastases. Prior chemotherapy regimens included gemcitabine/cisplatin (50%), gemcitabine/carboplatin (25%), paclitaxel/carboplatin (5%), single agent paclitaxel (5%), and other multi-agent regimens (15%). Median hemoglobin was 11.4 g/dL (inter-quartile range 10.6–12.3). No objective responses were observed. The median time to progression was 2.1 months (95% CI= 1.4–5.5). Median overall survival was 5.5 months (95% CI= 3.6–8.1). Toxicity was modest. Grade 3/4 drug-related toxicities included thrombocytopenia (6%), sensory neuropathy (6%), hyperglycemia (6%), neuropathic pain (6%), dehydration (6%) and vomiting (6%). There were no treatment-related deaths. Conclusions: Although bortezomib is well tolerated in patients with previously treated advanced TCC, it does not have anti-tumor activity as 2nd-line therapy in TCC. No significant financial relationships to disclose.
A Phase II Trial Evaluating the Safety of Rapid Infusion Ofatumumab (OFA) in Patients (pts) with Previously Treated Chronic Lymphocytic Leukemia (CLL)
Authors: William B. Donnellan, Jesus Berdeja, Dianna Shipley, Edward Arrowsmith, David Wright, Scott Lunin, Richard H. Brown, James Essell, Ian Flinn
Journal: Blood (2014)
Abstract 3004: Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms
Authors: Melissa M. Keenan, Beiyu Liu, Xiaohu Tang, Jianli Wu, Derek Cyr, Robert D. Stevens, Olga Ilkayeva, Joseph Lucas, Deborah M. Muoio, So Young Kim, Jen-Tsan Chi
Journal: Cancer Research (2015)

Abstract To become established as a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. While many stress-signaling mechanisms have been well-studied, much remains unknown about how tumor cells survive these stresses during tumor progression. To identify genes that modulate cellular survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that the genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis through both metabolic and transcriptional mechanisms. First, while depleting α-ketoglutarate in control cells, hypoxia unexpectedly increased levels of α-ketoglutarate in the cells depleted of ACC1 or ACLY. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis in a mitochondria-dependent manner. Second, loss of ACLY or ACC1 reduced protein levels and activity of the oncogenic transcription factor ETV4. Silencing of ETV4 protected cells from hypoxia-induced apoptosis and triggered remarkably similar global transcriptional responses as with silenced ACLY or ACC1. Importantly, within tumor expression datasets, ETV4 transcriptional activity was highly correlated with ACLY or ACC1 gene expression signatures. Therefore, ETV4 acted as a key regulator of the transcriptional output of lipogenic activity via ACLY or ACC1. These results reveal a novel interconnectedness between cellular metabolic and transcriptional responses for life or death decisions under stress. Since lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. Citation Format: Melissa M. Keenan, Beiyu Liu, Xiaohu Tang, Jianli Wu, Derek Cyr, Robert D. Stevens, Olga Ilkayeva, Joseph Lucas, Deborah M. Muoio, So Young Kim, Jen-Tsan Chi. Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3004. doi:10.1158/1538-7445.AM2015-3004
The effect of smoking history on response and survival outcomes patients with in esophageal cancer treated with neoadjuvant concurrent chemoradiotherapy followed by surgery.
Authors: K. Salerno May, N. K. Malik, G. Yang, S. Patil, L. Flaherty, N. I. Khushalani, T. Sher, S. S. Yendamuri, H. R. Nava, G. W. Warren
Journal: Journal of Clinical Oncology (2011)

e14601 Background: There is limited information on the impact of current or former smoking status on survival outcomes in esophageal cancer patients treated with trimodality therapy. Methods: Patients with esophageal carcinoma who completed neoadjuvant concurrent chemoradiotherapy and underwent surgical resection between October 2002 and April 2010 at Roswell Park Cancer Institute were analyzed. Smoking history was abstracted from consultation notes at initial presentation. Survival was compared between patients with any self-reported history of smoking (current or former smokers) and patients who denied any prior history of smoking (never smokers). Follow up was calculated from the date of diagnosis to the date of death or last follow up. Unknown disease status was categorized as a recurrence. Unpaired t-tests were used for statistical comparisons. Results: A total of 115 patients were analyzed, of whom 11% were female and 77% of patients reported a current or former history of smoking. There was no difference in histology, mean radiotherapy dose delivered, chemoradiotherapy completion time, pathologic complete response rates, or total follow up time between groups. Never smokers had a much higher proportion of women as compared with current or former smokers (30.8% vs. 5.6%, p=0.0003). With a median follow-up time of 28 months, there was no difference in disease recurrence, disease specific mortality, or overall survival by self-reported smoking status (current or former vs. never smokers). Conclusions: In esophageal cancer patients receiving neoadjuvant concurrent chemoradiotherapy followed by surgery, data suggest that a history of current or former smoking has no impact on pathologic complete response, recurrence, or survival. Analyses may be confounded by a higher proportion of women in the never smoking population.
Abstract A59: Crosstalk of different macrophage populations with pancreatic acinar or PanIN cells and contribution to development of pancreatic cancer
Authors: Geou-Yarh Liou, Heike Doeppler, Ligia Bastea, Peter Storz
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is characterized by an inflammatory environment. Here we delineate the crosstalk between different macrophage populations with pancreatic cells carrying oncogenic Kras mutations. First, we show that pancreatic acinar cells that undergo oncogenic transformation by mutant Kras upregulate chemoattractants that attract inflammatory macrophages. These inflammatory macrophages contribute to acinar cell dedifferentiation to a progenitor-like cell type (acinar-to-ductal metaplasia; ADM). Resulting cells can give rise to PanIN lesions. We then provide insight at which stage of PanIN formation a switch between inflammatory and alternatively-activated macrophages occurs; and define one mechanism by which this can be mediated. Eventually, we provide insight of how alternatively-activated macrophages facilitate the further progression of PanIN lesions to a more aggressive phenotype. Citation Format: Geou-Yarh Liou, Heike Doeppler, Ligia Bastea, Peter Storz.{Authors}. Crosstalk of different macrophage populations with pancreatic acinar or PanIN cells and contribution to development of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A59.
Abstract 4596: Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the Female Lung Cancer Consortium in Asia
Authors: Mitchell J. Machiela, Chao A. Hsiung, Xiao-Ou Shu, Wei J. Seow, Zhaoming Wang, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Chen Wu, H Dean Hosgood, Kexin Chen, Jiu-Cun Wang, Wanqing Wen, Tangchun Wu, Maria P. Wong, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F. Fraumeni, Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman, Qing Lan
Journal: Cancer Research (2015)

Abstract Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, P-value = 4.54×10−14) even after removing rs2736100 (P-value = 4.81×10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk. Citation Format: Mitchell J. Machiela, Chao A. Hsiung, Xiao-Ou Shu, Wei J. Seow, Zhaoming Wang, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Chen Wu, H Dean Hosgood, Kexin Chen, Jiu-Cun Wang, Wanqing Wen, Tangchun Wu, Maria P. Wong, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F. Fraumeni, Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman, Qing Lan. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the Female Lung Cancer Consortium in Asia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4596. doi:10.1158/1538-7445.AM2015-4596
Abstract 2706: Inhibition of PFKFB3/glycolysis overcomes chemoresistance in ovarian cancers
Authors: Susmita Mondal, Debarshi Roy, Eleftheria Kalogera, Ashwani Khurana, Gilles H. Tapolsky, Sucheta Telang, Jason Chesney, Viji Shridhar
Journal: Cancer Research (2015)

Abstract Metabolic alterations in cancer are increasingly being recognized as important novel targets. Among different regulators of altered metabolism, 6-PhosphoFructo-2-Kinase/Fructose-2,6-Bisphosphatases 3 (PFKFB3) a glycolytic enzyme required for tumorigenic growth, and produces fructose-2,6-bisphosphate (F2,6BP), is recognized as important regulator of glycolysis. We determined that the active form of PFKFB3ser471 was overexpressed in chemo-resistant ovarian cancer (OVCA) cell lines and resistant patient derived xenograft (PDX) models compared to their isogenic chemo-sensitive cell lines and sensitive PDX models. These results suggest that targeting PFKFB3 will have beneficial effects in patients with OVCA. PFK-158 is a potent and selective inhibitor of PFKFB3 that is currently being investigated in a Phase 1 study in patients with advanced solid malignancies. Here we report for the first time, PFK-158 dose-dependently inhibits cell proliferation and colony formation ability in both carboplatin and paclitaxel (PTX) resistant cell lines. PFK-158 markedly suppresses glycolysis by reducing glucose uptake, ATP production, lactate dehydrogenase activity and lactate secretion. Interestingly, both Chou-Talalay synergy analysis and apoptosis assay by annexin V-PI staining showed PFK-158 strongly synergies with both PTX and carboplatin in PTX and cisplatin resistant cell lines respectively. PFK-158 induced apoptosis through a significant increase in caspase-3/7 activation and PARP cleavage. Moreover, in a highly metastatic PTX-resistant in vivo model, combination of PFK-158 with carboplatin and PTX significantly reduced tumor weight, ascites and metastasis compared to untreated and PFK-158, carboplatin or PTX alone treated mice. Since the majority of OVCA patients recur with chemo-resistant disease, our results suggest that PFK-158 in combination with standard chemotherapy may have clinical utility in late stage ovarian cancer patients. Citation Format: Susmita Mondal, Debarshi Roy, Eleftheria Kalogera, Ashwani Khurana, Gilles H. Tapolsky, Sucheta Telang, Jason Chesney, Viji Shridhar. Inhibition of PFKFB3/glycolysis overcomes chemoresistance in ovarian cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2706. doi:10.1158/1538-7445.AM2015-2706
Rituximab Infusion Two Months after Nonmyeloablative Transplantation Maintains B-Cell Disease Control with Minimal GVHD.
Authors: Sally Arai, B. Sahaf, C. Jones, James Zehnder, Robert Lowsky, S. Strober, Judith Shizuru, Robert Negrin, Laura Johnston, Ginna Laport, Keith Goldstein, Janice (Wes) Brown, David Miklos
Journal: Blood (2006)