tbuckley/cabot-search huggingface dataset:
Abstract 3926: RhoB expression is upregulated by androgen in thyroid cancer cells
Authors: Anvita Gupta, Melanie Jones, Augustine Moscatello, Edward Shin, Raj K. Tiwari, Jan Geliebter
Journal: Cancer Research (2015)

Abstract The incidence of thyroid cancer has increased three-fold over the last thirty years and the American Cancer Society estimates that there will be 62,980 new cases and 1,890 deaths due to the disease in the United States in 2014. Papillary Thyroid Cancer (PTC) is the most common endocrine malignancy and develops in premenopausal women, at a four-fold higher incidence, than in men. However, PTC exhibits increased aggressiveness with poor prognosis in men diagnosed with the disease. These observations led us to explore the role of androgen and androgen receptor in this disease. Preliminary data from our lab indicates that androgen receptor (AR) acts as a negative regulator of growth as evidenced by a statistically significant decrease in proliferation upon DHT addition to 8505c anaplastic/PTC cells stably transfected with AR. Transcriptional profiling using RNA-Seq and gene ontology analysis, on a 48 hour DHT treated 8505c-AR transfected clone, 84E7, revealed significant changes in the expression of genes associated with proliferation (474 genes, p = 2.4E-24), cell cycle progression (129 genes, p = 6.54E-6) and migration (301 genes, p = 3.77E-30). Amongst the genes which showed the highest significant differential expression was RhoB, a Rho GTPase, with an approximately 50-fold upregulation. Rho proteins are small molecules belonging to the Ras superfamily, known to regulate cell morphology, actin/microtubule cytoskeleton reorganization along with vesicle trafficking. While RhoA and RhoC promote cancer progression and metastasis, the functions of their structural homolog, RhoB, are largely context dependent. Evidence has emerged that RhoB expression may support malignancy in certain cancers, while exhibiting a tumor-suppressor gene function in others. In our system, addition of DHT to 84E7 cells for short time periods of 1, 3 and 6 hours resulted in rapid RhoB mRNA upregulation by 2.5, 8, and 17 fold, respectively, compared to untreated cells. This quick, time-dependent increase in androgen-responsive RhoB may play an integral protective and reparative role which is possibly lost during neoplasticity of thyrocytes. Investigations into various pathways linking RhoB and effector proteins with carcinogenesis would be crucial in assessing the potential of RhoB as a bio-marker for metastatic PTC and thence opening avenues for development of viable therapies for better management of the disease. Citation Format: Anvita Gupta, Melanie Jones, Augustine Moscatello, Edward Shin, Raj K. Tiwari, Jan Geliebter. RhoB expression is upregulated by androgen in thyroid cancer cells. [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 3926. doi:10.1158/1538-7445.AM2015-3926
Quantitative detection of the T790M EGFR mutation in circulating tumor DNA of lung cancer patients subjected to EGFR-TKI treatment.
Authors: J. Uchida, K. Taniguchi, F. Imamura, K. Nishino, T. Kumagai, Y. Akazawa, T. Okuyama, K. Kato
Journal: Journal of Clinical Oncology (2011)

7594 Background: About half of the acquired resistance against EGFR-TKI is due to the T790M secondary EGFR mutation. Monitoring with a non-invasive technique may be clinically beneficial. Circulating tumor DNA (ctDNA) is a promising target for non-invasive cancer diagnostics and evaluations, although detection of rare mutation alleles is technically demanding. Methods: BEAMing (beads, emulsion, amplification, magnetics) is currently the most sensitive technique to detect somatic mutations. In addition, the technique can quantitate the abundance of the mutated allele. In BEAMing, amplified products from a single DNA molecule including the mutation site are fixed to a magnetic bead. By counting beads to which the fluorescent probe for the mutation is attached, the mutation allele is quantitated. Currently, we can detect one mutated allele in 10,000 normal alleles. For evaluation of its ability to detect the T790M mutation in ctDNA, we performed BEAMing with plasma DNA from 27 patients with progressive disease during EGFR-TKI, and 10 patients just before start of EGFR-TKI treatment. We also quantitated activating EGFR mutations in nine patients in the first group. Results: The T790M mutation was detected in 10 patients in the first group, and one patient in the second group, corresponding to 0.03 ~ 9.5% of plasma EGFR molecules. Activating mutations were detected in six patients, corresponding to 0.03 ~ 7.4% of plasma EGFR molecules. Both data were obtained in three cases; the T790M mutation appeared in 13, 40 and 65% of alleles with activating mutations. Conclusions: From the incidence, BEAMing could detect T790M in the majority of eligible cases. The major advantage over other techniques is the ability to calculate the fraction of T790M-positive alleles in cancer cells, irrespective of normal cell DNA contamination.
The Outcome in AML Is Predicted by Cytogenetics, NPM1/FLT3 Mutation, Age and Sex, but Not by Treatment Variables.
Authors: Thomas Buchner, Wolfgang E. Berdel, Utz O. Krug, Torsten Haferlach, Claudia Haferlach, Susanne Schnittger, Wolfgang Kern, Carsten Müller-Tidow, Karsten Spiekermann, Jan Braess, Sarah Volpert, Maria Cristina Sauerland, Achim Heinecke, Bernhard Josef Wormann, Wolfgang Hiddemann
Journal: Blood (2007)
Non-Myeloablative Conditioning with Total Lymphoid Irradiation and ATG and Allogeneic Transplantation for Patients with Myelodysplastic Syndrome, Therapy-Related Myeloid Neoplasms, and Myeloproliferative Neoplasms.
Authors: Jonathan Benjamin, Saurabh Chhabra, Holbrook E Kohrt, Ginna G Laport, Sally Arai, Laura Johnston, David B Miklos, Judith A. Shizuru, Wen-Kai Weng, Robert S. Negrin, Robert Lowsky
Journal: Blood (2012)
Effect of renal function on continuation of S-1 adjuvant chemotherapy in gastric cancer patients
Authors: Katsuya Makihara, Azuma Sayaka, Ueno Hiroyuki, Nakata Izumi, Yamamoto Kazuyoshi, Nishikawa Kazuhiro, Hirao Motohiro, Fujitani Kazumasa, Tsujinaka Toshimasa
Journal: Annals of Oncology (2015)
Abstract IA08: Drugging undruggable kras: will myc do the trick?
Authors: Channing J. Der
Journal: Cancer Research (2016)

Abstract KRAS oncogene mutations are found in ~95% of pancreatic ductal adenocarcinoma (PDAC) and are well validated drivers of PDAC initiation and maintenance. Consequently, a major goal for the field is the development of effective anti-KRAS therapies. However, despite more than three decades of intensive effort, no effective pharmacologic inhibitors of the KRAS have reached the clinic, prompting the widely held perception that KRAS is “undruggable”. However, with more advanced knowledge of KRAS function and new technological approaches, there is renewed hope that the time is ripe to revisit targeting KRAS. I will present our studies focused on the RAF-MEK-ERK mitogen-activated protein kinase cascade. This effector signaling network is a well-validated driver of KRAS-dependent cancer growth. Despite this key role, pharmacologic inhibitors of RAF and MEK have been ineffective in inhibiting growth of KRAS-mutated cancers, in large part due to dynamic signal reprogramming leading to ERK reactivation and bypass of inhibitor action. We therefore addressed whether direct ERK inhibition may be a more effective therapeutic approach. We identified a growth suppression mechanism due to pharmacologic inhibition of ERK that involves degradation of the MYC oncoprotein, activation of the p16INK4A-RB1 tumor suppressor pathway and induction of a senescence-like phenotype. We also applied unbiased genetic and chemical functional screens, as well as reverse phase protein array analyses, and identified the PI3K-AKT-mTOR signalling network as a key driver of pancreatic cancer resistance to ERK inhibition. Novel combination inhibitor approaches that synergistically enhanced ERK inhibitor anti-tumor activity were also identified. Finally, we determined that continued expression of KRAS was required for maintenance of MYC protein expression. We determined that previously identified mechanisms of RAS effector signaling alone did not account for MYC protein regulation in PDAC, prompting our search for novel protein kinases that regulate MYC protein degradation. Our efforts are centered defining pharmacologic strategies to accelerate MYC protein degradation as a novel approach for blocking mutant KRAS in PDAC. Citation Format: Channing J. Der.{Authors}. Drugging undruggable kras: will myc do the trick? [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 IA08.
Abstract POSTER-CTRL-1209: Ovarian cancer disparities in a high volume academic medical center
Authors: Hayley Hunt, Noah Rodriguez, Keiji Oda, Robert J. Wagner, Ron E. Swensen
Journal: Clinical Cancer Research (2015)

Abstract Objective: To identify disparities in care and survival in ovarian cancer patients treated at a high volume academic center. Methods: A review of epithelial ovarian cancer cases treated between 01/01/97 and 12/31/07 was conducted. Demographic, clinico-pathologic, insurance carrier, and treatment data were collected. Insurance carrier was categorized into three groups: Commercial, Medicare, and Medicaid. ANOVA or Kruskal-Wallis tests were utilized for continuous variables and chi-square or Fisher’s exact tests for categorical variables. Univariable Cox proportional hazards model was used to estimate hazard ratios for demographic and pathologic variables identified in association with survival. Multivariable Cox regression models were fitted with insurance status as the main exposure. Kaplan-Meier survival curves were generated for race, income, and insurance and compared utilizing log-rank tests. Results: 279 epithelial ovarian cancer cases were identified out of 460 total ovarian cancer cases. 199 (71%) were White and 80 (29%) were non-White. 159 (57%) had commercial insurance followed by 71 (25%) and 49 (18%) with Medicaid and Medicare, respectively. 166 (60%) of the study group had less than $45,000 as an annual median income. 219 (78%) patients underwent primary debulking surgery. Of the three insurance categories, women with commercial insurance had a survival advantage (p= 0.002). Medicaid was associated with worse survival after adjusting for grade, stage, residual disease, and chemotherapy (p= 0.04). Survival rates in advanced stage disease were similar across the 3 insurance carriers. Conclusions: Ovarian cancer survival disparities persist at a high volume center but are largely eliminated in advanced stage. Citation Format: Hayley Hunt, MD, Noah Rodriguez, MD, Keiji Oda, MPH, Robert J. Wagner, MD, Ron E. Swensen, MD. Ovarian cancer disparities in a high volume academic medical center [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1209.
Abstract 4723: Mesenchymal status promotes metastatic colonization via a cancer cell-stroma crosstalk which uncouples EMT and stemness
Authors: Yaiza Del Pozo Martin, Danielle Park, Erik Sahai, Ilaria Malanchi
Journal: Cancer Research (2015)

Abstract During metastatic colonisation tumour cells must establish a favourable microenvironment, or niche, that will sustain their growth. However, both the temporal and molecular details of this process are poorly understood. Here, using breast cancer models, we find that metastatic initiating cells (MICs) in a mesenchymal phenotype exhibit high niche activation ability as a result of Thrombospondin 2 (THBS2) secretion, which prompts lung fibroblasts activation. Importantly, inhibiting the mesenchymal phenotype of MICs, by blocking the epithelial to mesenchymal transition (EMT)-associated kinase AXL during the early stages of cancer cell infiltration, reduces THBS2 secretion, niche activation ability, and consequently metastatic establishment. Subsequently, cancer cells start expanding at the target site and revert to a more epithelial phenotype. Interestingly, the activated fibroblasts of the newly formed metastatic niche trigger the reversion of cancer cell mesenchymal phenotype without compromising self-renewal. Preventing this phenotypic reversion by enhancing AXL expression during colonization block metastasis. In summary, we demonstrate that during metastatic colonization the two events of niche activation and EMT are functionally linked at the target site. However, in this context, EMT becomes uncoupled from the ‘stemness’ required for metastatic growth. Further, once fibroblasts within the niche are activated they promote the mesenchymal to epithelial transition (MET) of tumour cells, leading to the outgrowth of metastases with similar epithelial characteristics and stromal cell networks to their original primary tumours. Citation Format: Yaiza Del Pozo Martin, Danielle Park, Erik Sahai, Ilaria Malanchi. Mesenchymal status promotes metastatic colonization via a cancer cell-stroma crosstalk which uncouples EMT and stemness. [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 4723. doi:10.1158/1538-7445.AM2015-4723
266. In Vivo Rod Photoreceptor Reprogramming Using AAV-Delivered CRISPR/Cas9 Rescues Retinal Degeneration
Authors: Wenhan Yu, Suddhasil Mookherjee, Jung-Woong Kim, Suja Hiriyanna, Yasaman Ataeijannati, Xun Sun, Lijin Dong, Tiansen Li, Anand Swaroop, Zhijian Wu
Journal: Molecular Therapy (2016)

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy and the leading cause of inherited blindness, due to mutations in any of the over 60 genes/loci identified so far. The disease is characterized by an initial loss of rod photoreceptors and secondary cone cell death. Since cone photoreceptors are responsible for day time vision and visual acuity, preserving cone functions in RP patients is a priority when developing treatment strategies. NRL is a transcription factor that determines the rod photoreceptor cell fate during retinal development. Acute gene knockout of Nrl in mice was shown to reprogram adult rods into cone-like cells, rendering them resistant to effects of mutations in rod-specific genes and consequently preventing secondary cone loss (Montana CL, et al. PNAS, 2013; 110: 1732-7). With a goal to develop this approach for treatment of RP, we used adeno-associated virus (AAV)-delivered CRISPR/Cas9 for Nrl-knockdown in rod photoreceptors. AAV vectors were constructed to carry a photoreceptor-specific Cas9 nuclease expression cassette or a single-guided RNA (sgRNA) targeting Nrl or eGFP gene. The Cas9 and the sgRNA vectors were co-delivered into mice by subretinal administration. Potency of the AAV-CRISPR/Cas9 system was validated by EGFP knockdown in a mouse line with eGFP-labeled rods. Nrl knockdown was conducted in wild-type C57/Bl6 or Crxp-Nrl, a mouse line with rod-only photoreceptors. Molecular, histological and functional alterations were examined by next generation sequencing, immunoblot analysis, immunofluorescence, electron microscopy, and electroretinography (ERG). Our results showed that eGFP and Nrl were efficiently knocked down following AAV-CRISPR/Cas9 treatment. For Nrl knockdown, almost all insertions and deletions were detected in the targeted Nrl locus, and very few mutations were identified in ten potential off-target loci. A majority of the transduced rods acquired characteristics of cone photoreceptors following Nrl-CRISPR/Cas9 vector treatment, as demonstrated by reduced expression of rod-specific genes and enhanced expression of cone-specific genes, loss of the unique rod chromatin pattern, and diminished rod ERG response. Rescue of retinal degeneration was assessed in three mouse models harboring either recessive or dominant rod-specific mutations. In all three models, the Nrl-CRISPR/Cas9 vector treated eyes maintained significantly better photoreceptor viability and cone function than control eyes, as revealed by remarkably thicker photoreceptor layer, higher cone cell number, greater cone ERG amplitude and better optomotor behavior. In conclusion, AAV-CRISPR-mediated Nrl gene knockdown can efficiently reprogram rods into cone-like photoreceptors and prevent secondary cone death in retinal degeneration, which could be developed into a viable treatment for RP in humans.
Abstract 2430: Treatment sequence and molecular biomarker in EGFR mutant lung cancer cells
Authors: Hannah Motes, Emma Borrego-Diaz Reyes, Jared Kevern, Chao H. Huang, Peter J. Van Veldhuizen
Journal: Cancer Research (2015)

Abstract Introduction Lung cancer is the leading cause of cancer related death in the US. A subset of patients with lung cancer has a mutation in the Epidermal Growth Factor Receptor (EGFR) which makes them extremely responsive to EGFR tyrosine kinase inhibitor (TKI) erlotinib. The emergence of EGFR TKI resistance is new challenge in the management of these patients. We conducted a study to determine the best treatment sequence after resistance to EGFR TKI, testing the use of chemotherapy Pemetrexed (P), Afatinib (A), Rociletinib (R) and the combination of these agents in lung cancer cell lines with EGFR mutation that were pretreated with erlotinib. Material and methods Lung cancer cell lines with EGFR mutation CRL-2868 (E746 - A750 deletion) and CRL-2871 (L747 - E749 deletion, A750P) mutation were treated with 5 nM erlotinib for 24h and 72 h. The erlotinib resistance cells were then treated with 10nM of A or 10nM of P, or 21.5 nM of R, or the combination AP or the combination of RP. As control, we used lung cancer HTB-177 which does not have EGFR mutation. MTT proliferation assay was performed after 24, 48, 72 and 144h after the treatment. microRNA profiling was done by real time PCR in all cells after erlotinib treatment to find potential biomarkers as hallmark of erlotinib resistance cells. Results Rociletinib induced the maximum inhibition of cell proliferation at 144h in both cell lines with EGFR mutation. The RP also induced decreased cell proliferation in both cell lines with EGFR mutation. RP combination was more effective then R alone in CRL 2871. The use of A alone, P alone or AP combination was not different in CRL2871 but P had antagonistic effect when combined with A or R in CRL 2868. microRNA 10b, 27a and 27b were upregulated in the erlotinib resistant cells. Conclusion. EGFR resistance arises after treatment with erlotinib in lung cancer cell lines with EGFR mutation. Treatment with R and the combination of RP induced greater inhibition of proliferation compared to A, P alone. The combination of AP was antagonistic. This may have implications in the management of patients resistant to EGFR TKI. microRNA analysis showed up-regulation of several microRNA that should be tested in clinical setting. Citation Format: Hannah Motes, Emma Borrego-Diaz Reyes, Jared Kevern, Chao H. Huang, Peter J. Van Veldhuizen. Treatment sequence and molecular biomarker in EGFR mutant lung cancer cells. [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 2430. doi:10.1158/1538-7445.AM2015-2430
Analysis of Infections In Acute Leukemia According to the Different Phases of Treatment Reveals Marked Differences Potentially Useful for Tailored Prophylactic and Empiric Antimicrobial Treatments
Authors: Chiara Cattaneo, Erika Borlenghi, Francesca Bracchi, Liana Signorini, Alessandro Re, Elisa Cerqui, Liliana Baushi, Roberto Stellini, Giuseppe Rossi
Journal: Blood (2010)
Abstract 2922: Development of Bcl2 BH4 antagonist for cancer therapy
Authors: Bingshe Han, Dongkyoo Park, Rui Li, Maohua Xie, Taofeek Owonikoko, Gabriel Sica, Chunyong Ding, Jia Zhou, Andrew Magis, Suresh Ramalingam, Fadlo Khuri, Walter Curran, Xingming Deng
Journal: Cancer Research (2015)

Abstract The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a novel small molecule Bcl2-BH4 domain-antagonist (BDA-366) that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival to a cell death inducer. BDA-366 induces regression of lung cancer xenografts derived from cell line and patient without significant normal tissue toxicity at effective doses. mTOR inhibition up-regulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a novel strategy to improve lung cancer outcome. Citation Format: Bingshe Han, Dongkyoo Park, Rui Li, Maohua Xie, Taofeek Owonikoko, Gabriel Sica, Chunyong Ding, Jia Zhou, Andrew Magis, Suresh Ramalingam, Fadlo Khuri, Walter Curran, Xingming Deng. Development of Bcl2 BH4 antagonist for cancer therapy. [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 2922. doi:10.1158/1538-7445.AM2015-2922
Relationship between plasma BRCA1 mRNA expression and sensitivity to docetaxel and cisplatin in gastric cancer.
Authors: Jie Shen, Jia Wei, Wen xian Guan, Hao Wang, Yi tao Ding, Xiaoping Qian, Lixia Yu, Zhengyun Zou, Li Xie, Miquel Taron, Rafael Rosell, Baorui Liu
Journal: Journal of Clinical Oncology (2012)

e14509 Background: Tumor-derived RNA species successfully detected in plasma may have potential for use in disease and treatment assessment. Although BRCA1 mRNA expression levels in tumor are associated with cisplatin sensitivity but docetaxel resistance, the role of plasma BRCA1 mRNA as a predictive biomarker remains to be known. The aim of this study was to investigate the association between plasma BRCA1 mRNA expression and in vitro chemosensitivity to docetaxel and cisplatin in gastric cancer. Methods: 150 freshly-removed gastric tumor specimens and corresponding blood samples before surgery were collected. Docetaxel and cisplatin sensitivity was determined by histoculture drug response assay (HDRA) procedures. Plasma and tumor BRCA1 mRNA expression levels were determined by quantitative RT-PCR. Results: A significant correlation was observed between plasma and tumor BRCA1 mRNA expression levels (rho=0.558, P&lt;0.001). Plasma BRCA1 mRNA expression level was positively correlated with in vitro sensitivity to docetaxel (docetaxel-sensitive sub-group: 1.25, 95% CI: 1.04-1.47; docetaxel-resistant sub-group: 0.50, 95% CI: 0.23-0.78; p&lt;0.001) but negatively correlated with sensitivity to cisplatin in gastric cancer (cisplatin-sensitive sub-group: 0.84, 95% CI: 0.61-1.08; cisplatin-resistant sub-group:1.20, 95% CI: 0.84-1.56; p=0.083). There was no significant association between clinical characteristics and plasma BRCA1 mRNA levels or in vitro chemosensitivity. Conclusions: It was demonstrated for the first time that plasma BRCA1 mRNA expression was associated with in vitro chemosensitivity to docetaxel and cisplatin, which provided preliminary evidence for using plasma mRNA expression as an approach to predict response to docetaxel or cisplatin based chemotherapy in the clinic.