tbuckley/cabot-search huggingface dataset:
Abstract 4236: Gene expression profiling of prostate tissue identifies biological pathways associated with <i>TMPRSS2:ERG</i> gene fusion
Authors: Ericka Ebot, Masis Isikbay, Travis Gerke, Thomas U. Ahearn, Rachel S. Kelly, Svitlana Tyekucheva, Andreas Pettersson, Kathryn L. Penney, Lorelei A. Mucci
Journal: Cancer Research (2017)

Abstract Background: TMPRSS2:ERG, a hormonally regulated gene fusion present in about half of prostate tumors, is the most common somatic event in prostate cancer. There is intriguing evidence to suggest that TMPRSS2:ERG-positive tumors may define a distinct subgroup of prostate cancer. In this study we compared gene expression profiles according to fusion status to identify genes and biological pathways differential expressed by TMPRSS2:ERG. Methods: The study included men with prostate cancer in the Health Professionals Follow-up Study and the Physicians’ Health Study diagnosed between 1982 and 2004 and followed through 2012. Tumor biomarker data was available for archival tumor tissue from 380 cases, 191 of whom also had gene expression data for adjacent normal tissue. Whole genome mRNA expression profiling (20,254 genes) was performed using the Affymetrix 1.0 ST array. TMPRSS2:ERG tumor status was assessed by a genetically validated IHC assay for ERG. To relate expression of individual genes to ERG we used linear regression. Gene Set Enrichment Analysis (GSEA) was used to identify pathways of genes associated with ERG in both tumor and adjacent normal tissue. Data from The Cancer Genome Atlas (TCGA) was used to validate these findings. Results: Among 380 cases, 186 (49%) of tumors were positive for the gene fusion. Genome-wide differential expression analysis identified 492 genes upregulated and 369 genes downregulated in tumor tissue comparing ERG+ to ERG- tumors (FDR p-value &amp;lt; 0.05). No genes were identified in the adjacent normal tissue at this significance level. 772 of the 861 genes (90%) identified in the HPFS/PHS dataset were confirmed in TCGA (448 upregulated and 324 downregulated). The top ten genes included ERG, WNK2, CACNA1D, HES1, SEPT9, PLA2G7, TDRD1, ANTXR2, SORBS2, and MYO6. Enrichment analysis identified a number of metabolic pathways associated with ERG tumor status including pathways involved in amino acid and fatty acid metabolism. Conclusions: We identified significant differences in gene expression profiles in prostate tumor tissue according to TMPRSS2:ERG status, providing supportive evidence of this fusion as a unique subtype. Citation Format: Ericka Ebot, Masis Isikbay, Travis Gerke, Thomas U. Ahearn, Rachel S. Kelly, Svitlana Tyekucheva, Andreas Pettersson, Kathryn L. Penney, Lorelei A. Mucci. Gene expression profiling of prostate tissue identifies biological pathways associated with TMPRSS2:ERG gene fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4236. doi:10.1158/1538-7445.AM2017-4236
Abstract 4574: Combinatorial strategies of folate receptor-targeted chemotherapy guided by improved understanding of tumor microenvironment and immunomodulation
Authors: Yingjuan Lu, Leroy W. Wheeler, Vicky A. Cross, Elaine M. Westrick, Alex M. Lloyd, Theresa P. Johnson, Nikki L. Parker, Christopher P. Leamon
Journal: Cancer Research (2017)

Abstract Inflammation disorder is a major component of cancer progression and drug resistance. Tumor microenvironment due to its complex nature presents physical and physiological barriers to both chemotherapy and immunotherapy. On the other hand, the folate receptor (FR) family includes two cysteine-rich GPI-anchored membrane glycoproteins (FRα/β) that are capable of bringing folate-linked small-molecule drugs (SMDCs) into the cell cytosol via endocytosis. Consequently, both receptor isoforms have been considered promising therapeutic targets due to frequent overexpression of FRα by cancer cells of epithelial origins and FRβ by tumor-associated macrophages (TAMs). TAMs are strongly immunosuppressive and high TAM frequency has been correlated with poor patient prognosis and treatment outcome. While a folate-targeted chemotherapy can be very powerful for sensitive tumor types, resistance does regularly occur in FR-positive tumors for reasons that are largely unknown. Moreover, there seems to be considerable disconnect between a drug candidate’s in-vitro activity and in-vivo efficacy. Using syngeneic mouse models that represent different tumor immune microenvironments (M109, Renca, 4T1-Cl2), we investigated the immunomodulatory properties of SMDCs and devised combinatorial strategies with standard-of-care (SOC) agents to break the tumor-induced immune tolerance. Our results indicated that a successful treatment goes beyond targeting the cancer cells themselves; instead, it requires a good match between our compound and a “sensitive” tumor microenvironment. We found that within “TAM-rich” solid tumors, an effective SMDC may be one with dual mechanisms of action that affect both FRα-positive tumor cells and FRβ-positive TAMs. Moreover, the process of choosing partner drugs, such as immune checkpoint inhibitors and inhibitors of myeloid-derived suppressor cells, should be guided by the immunomodulatory properties of both SMDCs and SOC agents to overcome the frequently observed chemo- and immuno-resistance. Citation Format: Yingjuan Lu, Leroy W. Wheeler, Vicky A. Cross, Elaine M. Westrick, Alex M. Lloyd, Theresa P. Johnson, Nikki L. Parker, Christopher P. Leamon. Combinatorial strategies of folate receptor-targeted chemotherapy guided by improved understanding of tumor microenvironment and immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4574. doi:10.1158/1538-7445.AM2017-4574
Abstract 3054: Tracing EMT with fluorescent biosensors (chromobodies) in living cancer cells
Authors: Julia Maier, Theresa Plaga, Stefanie Egetemaier, Bjoern Traenkle, Ulrich Rothbauer
Journal: Cancer Research (2017)

Abstract Epithelial-mesenchymal transition (EMT) is a complex cellular program, involved in the progression of epithelial cancers to a metastatic stage. During this process characteristic epithelial marker proteins are repressed in favor of mesenchymal biomarkers, such as the intermediate filament protein vimentin. There is an ongoing need for reliable cell-based EMT model systems, which can be adapted to screening campaigns for novel anti-metastatic therapies. Imaging-based screening systems are restricted to endpoint immunofluorescence studies that provide only little information about the dynamics of the process, or to ectopic expression of EMT markers, fused to fluorescent proteins. However, overexpression of EMT marker proteins, particularly vimentin, have been shown to influence the EMT phenotype of the cells. Here we introduce chromobodies as an innovative technology to monitor EMT in living non-small lung cancer cells. Chromobodies are fluorescently-labeled single-domain-antibodies that are functional within in living cells and directly target endogenous proteins. We generated chromobodies against the EMT biomarkers vimentin, actin and β-catenin and stably introduced them into the genome of A549 cells. Upon induction of EMT with transforming growth factor β (TGF- β), we could visualize the dynamic reorganization of endogenous vimentin, actin and β-catenin in the established EMT chromobody models in 2D as well as 3D cell culture. By means of these chromobody cell lines we further developed a 2D high content analysis system to visualize and quantify spatiotemporal changes of the endogenous biomarkers vimentin and actin during the EMT process. In a proof-of-principle screen, using known EMT-affecting reagents (e.g. TGF receptor I inhibitors LY364947 and SB505124) as well as EMT-unrelated agents, we were able to show that this high content analysis system can be applied to select compounds that inhibit TGF-β-induced EMT. In summary, live cell imaging of EMT markers with chromobodies provides a novel versatile approach to study EMT in real time and allows the identification of EMT inhibitors as potential candidates for anti-metastatic therapies by high content screening. Citation Format: Julia Maier, Theresa Plaga, Stefanie Egetemaier, Bjoern Traenkle, Ulrich Rothbauer. Tracing EMT with fluorescent biosensors (chromobodies) in living cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3054. doi:10.1158/1538-7445.AM2017-3054
Abstract 177: Thymidine quinoxaline conjugates as a novel selective and effective photosensitizer for anticancer photodynamic therapy
Authors: Qibing Zhou, Zhiwei Wang, Rong Yang, Ting Qian, Dejun Zhang
Journal: Cancer Research (2017)

Abstract Thymidine quinoxaline conjugates are a new class anticancer agent that exhibits selective anticancer activity by targeting the abnormally high level of thymidine kinase of the thymidine salvage pathway in cancer cells. In addition, the conjugated quinoxaline moiety could also act as a photosensitizer to generate reactive oxygen species that would significantly enhance the anticancer activity. Therefore, a variety of structural derivatives were synthesized and investigated for the potential of combined anticancer activity. We found that the thymidine moiety was critical for the accumulation of compounds in cancer cells and thus their activity. On the other hand, the substitutions and additional conjugation of quinoxaline moiety had significant impact on the effectiveness to generate reactive oxygen species for enhanced potency. Among all the compounds studied, dT-QP exhibited a potent activity against liver cancer cells with IC50 at 20 nM under photo-irradiation at 400 nm wavelength for 20 min. This potent activity of dT-QP was 12 times more effective than that of the clinically used photosensitizer protoporphyrin IX (IC50 at 250 nM) under the same condition and 5 times more potent than anticancer drug doxorubicin (IC50 at 100 nM). In addition, thymidine quinoxaline conjugates were found to form aggregates with an average size of 200 nm. Further optimization of the aggregating condition led to a highly stable suspension of 90 nm size nanoparticles containing a tumor-specific peptide that could be used for in vivo study. Therefore, thymidine quinoxaline analogs could be a selective anticancer agent and effective photosensitizer for potential photodynamic therapy. Citation Format: Qibing Zhou, Zhiwei Wang, Rong Yang, Ting Qian, Dejun Zhang. Thymidine quinoxaline conjugates as a novel selective and effective photosensitizer for anticancer photodynamic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 177. doi:10.1158/1538-7445.AM2017-177
Abstract 5213: Aberrant tumor metabolism enables GR takeover in enzalutamide-resistant prostate cancer
Authors: Jianneng Li
Journal: Cancer Research (2017)

Abstract It is well known that castration resistant prostate cancer (CRPC) is still driven by the androgen axis. Therefore, the advent of new AR-targeting drugs, such as Enzalutamide (ENZ), has been beneficial for many patients with CRPC. ENZ is a potent FDA-approved AR antagonist which prolongs survival for patients with CRPC, even after docetaxel chemotherapy. Unfortunately, although ENZ has proven effective clinically, treatment resistance eventually arises in nearly all patients with CRPC. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. Hence, we hypothesize that similar to metabolic mechanisms that elicit dihydrotestosterone (DHT) synthesis, which in turn stimulate AR in CRPC, a role for GR in ENZ resistance would be accompanied by a tumor metabolic switch that provides sustained tissue cortisol concentrations which enable GR activation. Here, we found that long-term ENZ treatment sustains tumor cortisol concentrations in models of prostate cancer and patient tissues by using [3H]-cortisol and high performance liquid chromatography. Further investigations with immunoblot, co-immunoprecipitation as well as in vitro ubiquitination assays in ENZ resistant prostate cancer models demonstrated that autocrine motility factor receptor (AMFR), an ubiquitin E3-ligase, and one of its adaptors, Erlin-2, mediate loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which sustains tumor cortisol concentrations, resulting in the continuous stimulation of GR and ENZ resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses ENZ resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of ENZ resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation. Citation Format: Jianneng Li. Aberrant tumor metabolism enables GR takeover in enzalutamide-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5213. doi:10.1158/1538-7445.AM2017-5213
Abstract 4826: Maternal high butter fat intake heightens mammary cancer risk in offsprings gestationally exposed to bisphenol A at environmentally relevant dose
Authors: Yuet-Kin Leung, Vinothini Govindarajah, Ana Cheong, Dan Song, Xuegong Zhu, Jun Ying, Ady Kendler, Mario Medvedovic, Scott Belcher, Shuk-Mei Ho
Journal: Cancer Research (2017)

Abstract In utero exposure to bisphenol A (BPA) at 250ug/kg BW was shown to augment mammary cancer risk in rodent models. High fat diet is widely believed to be a major risk of breast cancer (BCa). It is therefore important to investigate whether maternal high fat intake could potentially heighten mammary cancer risk associated to gestational BPA exposure. In this study, we exposed Sprague Dawley rats with different doses of BPA (2.5-2500ug/kg BW) mixed with high butter-based diet (HBF) in the period from preconception to birth. DMBA-PND50 protocol was followed. In the presence of HBF, we observed non-monotonic effects of BPA in cancer incidence as well as in the number of terminal end buds of PND21 mammary glands. Both results were peaked at a dosage of 25ug/kg BW BPA and the effects were significant when compared with HBF alone group. We further analyzed transcriptomic data of microdissected epithelia of PND21 mammary glands from BPA (25ug/kg BW) group as well as HBF group and revealed that two specific cancer networks involving ERK and androgen receptor signaling were dysregulated. DNA methylation is one of the key mechanisms to dysregulate and impair the transcription of two selected top genes, Car7 and Kcnv2, as supported by our bisulfite-sequencing data. These data suggest that in utero BPA exposure could epigenetically modify gene expression and predispose cancer risk during early development. More importantly, some BPA genes are of high human relevance because seven selected BPA genes could dichotomize patients into two groups with significant difference in overall survival in a TCGA cancer cohort. The prognostic power of the genes was further enhanced in the survival analysis of Caucasian with ER positive patients. In conclusion, our data strongly suggest that BPA predisposes higher cancer risk by dysregulating gene expression during early mammary gland development in the presence of HBF, which could facilitate cancer development later in life. Citation Format: Yuet-Kin Leung, Vinothini Govindarajah, Ana Cheong, Dan Song, Xuegong Zhu, Jun Ying, Ady Kendler, Mario Medvedovic, Scott Belcher, Shuk-Mei Ho. Maternal high butter fat intake heightens mammary cancer risk in offsprings gestationally exposed to bisphenol A at environmentally relevant dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4826. doi:10.1158/1538-7445.AM2017-4826
Identification of changing melanocytic lesions in patients on BRAF inhibitor therapy.
Authors: Sarah Yagerman, Eileen Flores, Ashfaq A. Marghoob, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2013)

9018 Background: Patients treated with BRAF inhibitors (BRAFi) have been observed to develop new primary melanomas. In addition, these patients often develop new nevi and involuting nevi. It remains a challenge to detect clinically subtle and histopathologically early melanomas in a background of such increased nevus volatility. In this study, we sought to quantify and describe the new, changing, and involuting melanocytic lesions observed in these patients. Methods: A retrospective chart and image analysis was conducted for all BRAFi treated patients referred to the Dermatology service at Memorial Sloan-Kettering Cancer Center. Initial overview and follow-up images were compared in MIRROR Body Mapping image system, DermaGraphiX software (Canfield Imaging Systems, Fairfield, NJ). A total count of new, changing, and involuting melanocytic lesions was determined in four anatomic areas: upper back, lower back, chest, and abdomen. Dermoscopy images of all changing lesions that were biopsied were evaluated for dermoscopic pattern and for the presence or absence of any melanoma specific features. Results: Average photography follow-up was 261 days (n=21). The average number of combined new and changing melanocytic lesions was 13.1, 16.4, 9.5, and 6.1 for the upper back, lower back, chest, and abdomen respectively. The average number of involuting melanocytic lesions was 8.0, 4.0, 4.3, and 3.4 for the upper back, lower back, chest, and abdomen respectively. Of all new and changed lesions, 38 were biopsied revealing 31 benign melanocytic lesions and 7 melanomas (18% of lesions biopsied). All 7 melanomas revealed at least one melanoma specific structure, with the most significant dermoscopic discriminate being negative network. Conclusions: Given the setting of highly volatile melanocytic changes in BRAFi treated patients and that 18% of biopsied lesions were melanomas; we propose the use of total body photography and dermoscopy as a method for the identification and monitoring of secondary atypical pigmented lesions.
Abstract 2141: Development of a novel miR-129 mimic with enhanced therapeutic potential for treatment of resistant colorectal cancer
Authors: Andrew T. Fesler, Ning Wu, Hua Liu, Jingfang Ju
Journal: Cancer Research (2017)

Abstract Treatment of advanced stage colorectal cancer remains a clinical challenge associated with resistance to fluoropyrimidine based chemotherapy. There is an urgent need to discover and develop new strategies to enhance treatment efficacy in order to improve outcomes for these patients. Non-coding microRNAs (miRNAs) have important functions as oncogenes or tumor suppressor genes in the regulation of cancer development and progression. Recently, miRNAs have emerged as potential therapeutic options. We have previously identified miR-129 as a tumor suppressor miRNA and potential therapeutic candidate in colorectal cancer. The expression of miR-129 is progressively lost in colorectal cancer patients and is an important regulator of apoptosis through the targeting of genes such as BCL-2. miR-129 was also found to enhance 5-flurouracil (5-FU) cytotoxicity in vitro and in vivo. To further developing miR-129 based novel therapeutics in colorectal cancer, we have designed a modified version of miR-129 to enhance stability and efficacy. The miR-129 mimic is significantly more potent in inhibiting proliferation of a panel of colon cancer cell lines than the native miR-129 precursor, with 79% reduction by miR-129 mimic compared to 38% for native precursor. The miR-129 mimic induces profound cell cycle arrest at the G1/S checkpoint. The G1/S ratio increased 3.8 fold compared to control when cells were transfected with miR-129 mimic. We also demonstrated that the miR-129 mimic retains its target specificity to BCL-2, TS and E2F3. The therapeutic potential of miR-129 mimic was demonstrated in vivo mouse colon tumor models as a potent inhibitor of tumor growth and metastasis. As a result, miR-129 mimic has a great potential to be further developed as a novel therapeutic drug for treatment of advanced colorectal cancer. Citation Format: Andrew T. Fesler, Ning Wu, Hua Liu, Jingfang Ju. Development of a novel miR-129 mimic with enhanced therapeutic potential for treatment of resistant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2141. doi:10.1158/1538-7445.AM2017-2141
Uneven double-lumen cannula for rescue guidewire technique in endoscopic ultrasonography-guided hepaticogastrostomy
Authors: Hiroshi Kawakami, Yoshimasa Kubota, Hiroaki Makiyama, Shinji Sato, Tesshin Ban
Journal: Endoscopy (2017)

Endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) is used after failed endoscopic retrograde cholangiopancreatography (ERCP) [1]. Manipulation of the guidewire is one of the most challenging techniques in EUS-HGS. We present a successful case of rescue guidewire technique using a multilumen catheter [2], namely an uneven double-lumen cannula (Piolax Medical Devices, Yokohama, Kanagawa, Japan) ([Fig. 1]), for EUS-HGS.