tbuckley/cabot-search huggingface dataset:
Abstract 5707: STAT3 and STAT5a are potential therapeutic targets in castration-resistant prostate cancer
Authors: Sambit K. Mohanty, Kader Yagiz, Luthringer Luthringer, Mahul B. Amin, Serhan Alkan, Bekir Cinar
Journal: Cancer Research (2017)

Abstract Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying mCRPC are not clearly understood, thus hindering rational-based drug design. Evidence suggests that signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b), key components of the JAK/STAT pathway, play a significant role in aggressive PC. However, expression of STAT3/5 in prostate tumor samples have not been studied. Here, we evaluated the possible role of STAT3/5a in aggressive PC. Materials and Methods: Expression of STAT3 and STAT5a in high grade PC (HGPC, n=15) and in benign prostatic hyperplasia (BPH, n=15) tissue sections were evaluated by immunohistochemistry (IHC) according to the protocol approved by Institutional Review Board. Age ranged from 59 to 95 years (median = 81) in the former and 57 years to 86 years (median = 68 years) in the latter category. In addition, the effects of STAT inhibitor, Pimozide, on androgen-sensitive LNCaP and its castration-resistant subline C4-2 PC cell growth were assessed in vitro. Results: A strong nuclear immunoreactivity for STAT3 and STAT5a in 93% (n=14) and 80% (n=12) of HGPC cases, respectively, were observed. Only one BPH case showed strong STAT3 expression. Focal and weak positivity for STAT3 and STAT5a were noted in 47% (n=7) and 67% (n=10) of BPH cases. None of the BPH cases showed strong STAT5a expression. HGPC cases showed significantly higher STAT3 positivity compared with BPH (p=0.01). No significant differences were observed for STAT5a expression between HGPC and BPH group (p=0.4). However, multifocal or diffuse and strong STAT3 (p&amp;lt;0.0001) and STAT5a (p&amp;lt;0.0001) expression was significantly higher in HGRPC than BPH. Pimozide exposure significantly inhibited LNCaP cell proliferation at 10 μM and C4-2 cell proliferation at 20 μM concentration. Conclusion: Our results demonstrate that increased expression of STAT3 and STAT5a may serve as a predictive biomarker for efficacy of the JAK/STAT targeted therapy. Since JAK/STAT and androgen receptor signaling are functionally synergistic in contributing PC progression, the inhibition of JAK/STAT-alone or in combination with AR may lead to a novel treatment modality for mCRPC. Citation Format: Sambit K. Mohanty, Kader Yagiz, Luthringer Luthringer, Mahul B. Amin, Serhan Alkan, Bekir Cinar. STAT3 and STAT5a are potential therapeutic targets in castration-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 5707. doi:10.1158/1538-7445.AM2017-5707
Abstract 4779: Targeting the CCL20-CCR6 axis as a novel opportunity to stimulataneously modulate cancer stem cells and the tumor-immune infiltrate by a dual anti-cancer mechanism
Authors: Lilian E. van Vlerken-Ysla, Jonathan Rios-Doria, James Moynihan, Lu Shan, Robert E. Hollingsworth, Ronald Herbst, Elaine M. Hurt
Journal: Cancer Research (2017)

Abstract Drugs that target cancer stem cells (CSCs) are thought to be a critical component of any successful therapy against cancer. CSCs are responsible for chemoresistance, metastasis, and ultimately relapse of the cancer, even after an initial successful therapeutic intervention. While it is well known that CSCs are driven by some of the same major self-renewal pathways that drive embryonic stem cells, knowledge of other cellular pathways that drive CSC activity is still limited. In this work, we uncover a novel role for chemokine (C-C motif) ligand 20 (CCL20) in CSC growth and activity, expanding the role for this chemoattractant protein. We discovered that CSCs of many tumor types overexpress CCL20, which we show drives CSC self-renewal and proliferation by autocrine signaling through its receptor CCR6. Targeting this axis with a neutralizing monoclonal antibody against CCL20 significantly reduces CSC frequency and tumor initiation and growth, supporting the novel therapeutic potential of targeting the CCL20-CCR6 axis as a strategy to eliminate CSCs. Furthermore, we found that CCL20 secreted by tumor cells also strongly influences the frequencies not only of T-cells, particularly immune-suppressive regulatory T-cells (Treg) and Th17 populations, but also dendritic and neutrophil/gMDSC populations, to promote anti-tumor immunity that leads to immune-mediated inhibition of tumor growth. Strikingly, we discovered that tumor-specific CCL20 impacted not just the immune cell balance within the tumor microenvironment, but had far reaching effects into the peripheral immune system as well. Thus, our overall findings propose that CCL20 plays a dual role in the tumor environment: 1) by driving activity and tumorigenic ability of CSCs, and 2) by promoting an immunosuppressive phenotype. In this work we show that therapeutic neutralization of CCL20 can deliver a one-two punch against cancer, by directly inhibiting CSCs, and by relieving immunosuppression, thereby opening this target up as an exciting novel strategy to treat cancer. Citation Format: Lilian E. van Vlerken-Ysla, Jonathan Rios-Doria, James Moynihan, Lu Shan, Robert E. Hollingsworth, Ronald Herbst, Elaine M. Hurt. Targeting the CCL20-CCR6 axis as a novel opportunity to stimulataneously modulate cancer stem cells and the tumor-immune infiltrate by a dual anti-cancer mechanism [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 4779. doi:10.1158/1538-7445.AM2017-4779
Abstract LB-166: Risk of anal cancer in women with human papillomavirus-related gynecological neoplasm: Puerto Rico 1987-2013
Authors: Adrianna Isabel Acevedo-Fontanez, Erick Suarez, Carlos R. Torres-Cintron, Ana Patricia Ortiz
Journal: Cancer Research (2017)

Abstract Objective: This study aimed to: 1) describe age-adjusted incidences for invasive cervical, vulvar, vaginal, and anal cancer cases reported from 1987 to 2013 in Puerto Rico (PR); 2) to estimate the Standardized Incidence Ratio (SIR) of secondary anal cancer among women with HPV-related gynecological neoplasms (cervical, vulvar or vaginal) during 1987-2013; and 3) to estimate the magnitude of these associations, adjusting for age. Methods: We identified 9,489 women who had been diagnosed with a primary cervical, vaginal or vulvar tumor during 1987-2013 in PR. To describe the trends of cervical, vulvar, vaginal, and anal cancer, the age-standardized incidences were estimated using the direct method (2000 US Std Pop). SIRs (observed/expected) were computed using the indirect standardization method; expected cases were calculated using age-specific rates of anal cancer in women from the general population of PR. The ratio of SIRs was estimated using the Poisson regression model to estimate the magnitude of the association between secondary anal cancer and HPV-related gynecological neoplasms. Results: A significant increase in the incidence trend for anal cancer was observed from 1987 to 2013 (APC=1.1; p-value&amp;lt;0.05), whereas from 2004 to 2013, a significant increase was observed for cervical cancer incidence (APC=3.3; p-value&amp;lt;0.05). Women with HPV-related gynecological cancers had three times the risk of developing anal cancer in comparison with women with non-HPV-related gynecological cancers (RR: 3.27; 95%CI: 1.37, 7.79). Conclusion: Anal cancer is increasing among women in PR. Women with gynecological HPV-related tumors are at increased risk of anal cancer as compared to women from the general population and to those with various other primary tumors. Further investigation on the public health implications of this association is needed, as well as appropriate screening guidelines for anal cancer in these populations. Citation Format: Adrianna Isabel Acevedo-Fontanez, Erick Suarez, Carlos R. Torres-Cintron, Ana Patricia Ortiz. Risk of anal cancer in women with human papillomavirus-related gynecological neoplasm: Puerto Rico 1987-2013 [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 LB-166. doi:10.1158/1538-7445.AM2017-LB-166
Abstract 5358: Comprehensive evaluation of Illumina’s TruSight® Tumor 170 Panel to estimate tumor mutational burden
Authors: Shile Zhang, Alex S. So, Shannon Kaplan, Kristina M. Kruglyak
Journal: Cancer Research (2017)

Abstract Tumor mutational burden (TMB), or the density of variants in a tumor, is typically assessed by whole exome sequencing (WES) and has been shown to correlate with efficacy of immunotherapy treatment. Targeted cancer gene panels are broadly used to assess mutational status in cancer related genes but have not historically been used to estimate TMB. Recently, two studies have demonstrated that TMB can be accurately estimated using these cancer gene panelsi,ii. Illumina’s TruSight® Tumor 170 (TST170, research use only, RUO) panel is a comprehensive next-generation sequencing (NGS) assay that covers the coding regions of 170 genes associated with solid tumors. TST170 targets DNA and RNA variants from the same FFPE tumor sample in a single sequencing run. Here we evaluate the performance of TMB estimation with TST170. TST170 is an enrichment-based targeted panel designed to capture mutational changes, including single nucleotide variant, indels, amplifications, splice variants and fusions. The TST170 analysis pipeline is able to call variants with frequencies down to 5%. In the current study, TMB was calculated as the number of reported variants per megabase after germline polymorphism filtering. First, we evaluated the performance of TST170 for TMB estimation using 6,000 TCGA samples that had been analyzed by WES. TMB estimated from the TST170 targeted regions showed a high correlation to TMB estimated from WES (R2=0.91). Next, we evaluated the prognostic value of TMB estimated from TST170 by overlapping the TST170 targeted regions with WES data for 202 subjects treated with CTLA-4 or PD-1 from three clinical studies. Higher TMB estimated from the TST170 targeted regions was observed in subjects who responded to checkpoint inhibitors. Finally, we assessed the correlation of TMB estimation using matched samples profiled with both WES and TST170 and again saw high correlation between the two methods. In summary, our analysis indicates that the panel content of TST170 can be used to accurately estimate TMB from tumor samples. i Garofalo A, Sholl L, Reardon B, et al. The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med. 2016;8(1):79. doi:10.1186/s13073-016-0333-9. ii Campesato, L., Barroso-Sousa, R., Jimenez, L., et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget, 2015;6(33), 34221-34227. Citation Format: Shile Zhang, Alex S. So, Shannon Kaplan, Kristina M. Kruglyak. Comprehensive evaluation of Illumina’s TruSight® Tumor 170 Panel to estimate tumor mutational burden [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 5358. doi:10.1158/1538-7445.AM2017-5358
Abstract 1825: Angiopoietin-Tie-2 functional axis in colorectal cancer liver metastasis (CRCLM) provides a new marker for stratification and evaluation of tumor progression
Authors: Nisreen S. Ibrahim
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the third leading cause of cancer in Canadians, with liver metastases being the major cause of death from this disease. Tumors induce angiogenesis, a phenomenon known as the ‘angiogenic switch’, which is an essential step in tumor progression whereby the balance of pro- and anti-angiogenic factors are important for active angiogenesis. Clinical efficacy of targeted VEGF (anti-angiogenic) treatment has been validated as a cancer therapy. Our group, together with others, has identified unique histological growth patterns HGPs (desmoplastic, replacement and pushing) within liver metastases that have different responses to anti-angiogenic therapy. The patients with Desmoplastic HGP (DHGP) that received anti-angiogenic plus chemotherapy prior to resection had a significantly better pathologic response and survival than patients with Replacement HGP (RHGP). The aim of this study was to explore the role of Ang-1, Ang-2, Tie-2 and VEGF in the development and progression of CRCLM tumors with distinct HGPs. Here, human CRCLM tumor samples were analyzed by quantitative real-time PCR (Q-PCR) and immunohistochemistry (IHC) staining. The Q-PCR results demonstrated that the expression of Ang-2 was lower in RHGP tumor samples compared with DHGP tumor samples. This data was validated by IHC, were IHC scoring results showed that the ratio of Ang-2: Ang-1 expression in DHGP tumors was higher compared to RHGP tumors. VEGF and Tie2 proteins were expressed in both tumor patterns. Thus vascular quiescence maintained by constitutive Ang-1/Tie-2 signaling, found in RHGP tumors, prevails over destabilization and pro-inflammatory Ang-2/Tie-2 signaling, which is higher in the DHGP tumor samples. Since vascular remodelling is driven by Ang-2/Tie-2 in DHGP, which is dependent on VEGF we would expect anti-angiogenic therapy to be effective on DHGP. Furthermore, the RHGP had low levels of Ang-2 and high levels of Ang-1, together with the presence of Tie-2, and then one would predict that VEGF is not required for the growth of these tumors and thus would not respond to anti-angiogenic therapy, as has been shown in our patients’ cohort. Taken together, these data suggest that the Angiopoietin/Tie-2 functional axis is an important player in CRCLM tumor progression and can be a potential target for CRCLM cancer therapy with stratification of patients by HGPs. Citation Format: Nisreen S. Ibrahim. Angiopoietin-Tie-2 functional axis in colorectal cancer liver metastasis (CRCLM) provides a new marker for stratification and evaluation of tumor progression [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 1825. doi:10.1158/1538-7445.AM2017-1825
Abstract 5635: Vitamin D supplementation decreases serum 27-hydroxycholesterol and expression of CYP27A1 in tumors of breast cancer patients
Authors: Catherine Going, Ludmila Alexandrova, Ken Lau, Christine Yeh, Melinda Telli, Kristin Jensen, David Feldman, Sharon Pitteri
Journal: Cancer Research (2017)

Abstract The goal of this study was to investigate whether vitamin D regulates the conversion of cholesterol to 27-hydroxycholesterol (27HC), an endogenous selective estrogen receptor modulator (SERM) that can act as a driver of estrogen receptor positive (ER+) breast cancer, particularly in post-menopausal women with low circulating estrogen levels. The hypothesis of this study was that the active metabolite of vitamin D, calcitriol, can inhibit expression of CYP27A1, the synthesizing enzyme for 27HC, thereby decreasing the concentration of 27HC in the blood. Both 27HC and 25-hydroxyvitamin D (25OHD) were quantified by LC-MS/MS in the serum of 29 breast cancer patients, 26 of which had ER+ cancer, pre- and post-treatment with either a low dose (control) of 400 IU vitamin D or a high dose of 10,000 IU vitamin D per day during the neoadjuvant period, which ranged between 7 and 37 days. In addition to these blood samples, tissue biopsies pre-treatment and the excised tumor collected post-treatment were tested for gene expression by microarray analysis. A significant increase (p = 4.3E-5) was observed in serum 25OHD for patients who received the high dose vitamin D compared to those who received the low dose, whose 25OHD values remained stable. A greater decrease (p = 1.7E-1) was observed in serum 27HC for the high dose group compared to the low dose group, with greater decreases in 27HC on average for those with larger increases in 25OHD concentration. Gene expression measurements showed a decrease in CYP27A1 expression (p = 4.5E-1) in breast cancer tissue for the high dose group compared to the low dose group, with greater decreases in expression observed for patients on high dose vitamin D treatment for longer times. These preliminary data show good evidence that high dose vitamin D supplementation can decrease 27HC levels in the body by inhibiting expression of CYP27A1 and that the longer this treatment, the greater the effect. While larger scale studies are needed, the data in this study point to vitamin D supplementation as a possible simple method for inhibiting ER+ breast cancer growth and suggests this reduction in CYP27A1 expression as an additional pathway by which vitamin D can mitigate risk and improve outcomes for ER+ breast cancer patients. Citation Format: Catherine Going, Ludmila Alexandrova, Ken Lau, Christine Yeh, Melinda Telli, Kristin Jensen, David Feldman, Sharon Pitteri. Vitamin D supplementation decreases serum 27-hydroxycholesterol and expression of CYP27A1 in tumors of breast cancer patients [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 5635. doi:10.1158/1538-7445.AM2017-5635
Abstract 4: Inhibitory effects of aprotinin on survival and local invasion of human breast cancer cell lines
Authors: Saeed Soleyman-Jahi, Kazem Zendehdel, Fatemeh Sadeghi, Ziba Afshari, Tahereh Barati, Samad Mohammadnezhad, Sevil Ghasemi, Saeed Amanpour
Journal: Cancer Research (2017)

Abstract Background: Aprotinin is a nonspecific serine protease inhibitor, which can inhibit kallikrein and many downstream extracellular matrix degrading enzymes. In this study, we assessed inhibitory effects of aprotinin on local invasion of human breast cancer cell lines. Methods: We assessed effects of aprotinin on local invasion and survival of human breast cancer cell lines MDA-MB231 and SK-BR-3 in vitro. CHEMICON Cell Invasion Assay Kit was used to assess local invasion of tumoral cells. MTT assay was used to determine the anti-proliferative activity of aprotinin on different cancer cell lines. Mean optical densities of duplicate experiments were calculated for both assays. HDF-1 human fibroblast cell line was used as control normal cell. In addition, local invasion and survival of tumor cell lines treated with aprotinin were compared with untreated experiments. Results: Cancer cell lines showed more invasion compared to HDF-1. Aprotinin significantly decreased the invasiveness of MDA-MB231 in concentration of 1 TIU/ml, 1.3 TIU/ml, and 1.7 TIU/ml in comparison with untreated group (ANOVA P &amp;lt;0.001). Treatment of SK-BR-3 with 1.3 TIU/ml aprotinin trended towards reduction of invasion optical density (P = 0.06). Treatment with different concentrations of aprotinin significantly decreased the surviving fraction and significantly inhibited the growth of all cell lines tested in this study (ANOVA P &amp;lt;0.001). Conclusion: Aprotinin inhibited the survival and local invasion of human breast cancer cell lines MDA-MB231 and SK-BR-3. Although the growth inhibitory effect was significant in both cell lines, inhibition of local invasion was more pronounced in case of MDA-MB231. Future molecular studies could shed further lights on mechanisms underlying anti-neoplastic effects of aprotinin and its potential therapeutic effects. Citation Format: Saeed Soleyman-Jahi, Kazem Zendehdel, Fatemeh Sadeghi, Ziba Afshari, Tahereh Barati, Samad Mohammadnezhad, Sevil Ghasemi, Saeed Amanpour. Inhibitory effects of aprotinin on survival and local invasion of human breast cancer cell lines [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 4. doi:10.1158/1538-7445.AM2017-4
Abstract 267: GeoSurveillance of invasive cervical cancer incidence by counties in the state of Maryland
Authors: Sally Peprah, Frank Curriero, Amber D'Souza
Journal: Cancer Research (2017)

Abstract Background: Invasive cervical cancer (ICC) is a highly preventable cancer whose rates have dramatically declined over the past few decades. In spite of the progress made, new ICC cases are recorded annually in Maryland and in other parts of the United Sates. We assessed if ICC incidence varied significantly 2005-2012 and across counties within the state of Maryland. Methods: Using a discrete Poisson model we evaluated significant space-time clusters of both high and low ICC incidence rates over a retrospective 10-year period. All analyses were conducted at the county level, using 2-year aggregates of time. We adjusted for age, percent minority, cervical cancer screening rates, median income, obesity as well as smoking rates within each county in our final cluster detection analysis. Results: ICC was 13.1 per 100,000 female population and did vary by county and over the 10-year period assessed. We identified five significant space-time clusters of ICC incidence, three of which were clusters of higher than expected rates. The most likely cluster identified was a cluster of low ICC incidence [aRR=0.08, p-value&amp;lt;0.01] observed for the period 2009-2012 and comprised six high-income suburban counties. The other cluster of low rate [aRR=0.41, p-value&amp;lt;0.01], which was a secondary cluster, was observed for the same time period, 2009-2012 in three high to moderate-income suburban counties. There were two clusters of high ICC incidence, observed for recent time periods. One cluster [aRR=1.74, p-value&amp;lt;0.01], which was made up of a single moderate to low-income urban county was identified for the period 2009-2012. The other cluster of elevated rates [aRR=2.47, p-value&amp;lt;0.01] was identified in a suburban moderate-income county for the period 2011-2012. Additionally, for the period 2005-2008 we identified a historical cluster of elevated incidence [aRR=2.53, p-value&amp;lt;0.01]. Conclusion: Overtime some counties in Maryland have experienced significantly lower rates of disease than expected. However there are more recent clusters of higher than expected rates of disease, which are not explained by the county level variables adjusted for. These clusters of high rates need to be further examined and addressed. Citation Format: Sally Peprah, Frank Curriero, Amber D'Souza. GeoSurveillance of invasive cervical cancer incidence by counties in the state of Maryland [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 267. doi:10.1158/1538-7445.AM2017-267