tbuckley/cabot-search huggingface dataset:
Abstract 4401: Role of estrogen signaling in colon microenvironment during obesity
Authors: Amena Archer, Linnea Pettersson, Marcela González-Granillo, Christina Savva, Marion Korach-André, Cecilia Williams
Journal: Cancer Research (2017)

Abstract Recent epidemiological studies highlight the strong association between high body mass index (BMI) and enhanced risk of colon cancer. This association appears stronger in men than in women, indicating a possible protective role of estrogens in this context. The biological action of the estrogens is mediated by specific transcription factors, the estrogen receptors (ERs). ERβ is the main ER in the intestine; and it is expressed in both epithelial cells and immune cells. Anti-inflammatory and anti-tumorigenic effects of ERβ in colitis-associated neoplasia have been demonstrated. Several rodent models for obesity show an impaired intestinal epithelial barrier function and an increase of pro-inflammatory markers in the colon. Moreover, in murine colitis models, high fat diet (HFD) exacerbates colonic inflammation. However, the specific molecular mechanisms linking obesity to increased colon cancer development, where estrogen signaling may be involved, is not clear. We hypothesize that ERβ-selective agonists can oppose the HFD-mediated inflammatory pro-tumorigenic colonic signalling in a gender-specific manner during obesity, and thereby protect against colorectal cancer. Our study is focused on the initiation of colon inflammation during obesity and aims to investigate the impact of ERβ activation in this context. To address this question, male and female mice were fed a HFD for 26 weeks and treated with a ERβ-selective agonist for 3 weeks prior sacrifice. Stool pellets were regularly collected. Animals were sacrificed; colon samples and caecal contents were collected for further analysis. We show that the expression pattern of inflammatory genes in colon is modified by the ERβ-selective agonist in HFD fed mice. Moreover the ERβ-selective agonist appears to induce gender-specific changes of the microbiota of HFD-fed mice. Our results show that an ERβ-selective agonist can modulate the colon microenvironment during obesity in mice and will provide a better comprehension of the molecular mechanisms leading to obesity-associated colonic inflammation. Citation Format: Amena Archer, Linnea Pettersson, Marcela González-Granillo, Christina Savva, Marion Korach-André, Cecilia Williams. Role of estrogen signaling in colon microenvironment during obesity [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 4401. doi:10.1158/1538-7445.AM2017-4401
Abstract 1122: ATR inhibitors synergize with PARP inhibitors in killing glioblastoma stem cells and treating glioblastoma
Authors: Jianfang Ning, Hiroaki Wakimoto, Robert L. Martuza, Samuel D. Rabkin
Journal: Cancer Research (2017)

Abstract PARP inhibitors (PARPi) have been used alone or in combination with other agents for the treatment of tumors with homologous repair (HR) deficiencies. However, challenges remain for the treatment of tumors that are PARPi-resistant or HR-proficient. Glioblastoma (GBM) is an invariably lethal tumor that is not associated with HR deficiencies. GBM stem cells (GSCs), thought to be critical for tumor growth and resistance to therapy, can be isolated from GBM specimens and are representative of the patient's tumors. GSCs exhibit variable PARPi sensitivity, with at least half being resistant. In order to enhance the antitumor efficacy of PARPi for GBM, we examined the combination of PARPi with inhibitors of oncogenic or DNA damage pathways, including inhibitors of PTEN, PI3K, ATM, ATR, and temozolomide, some of which have been reported to sensitize cancer cells to PARPi. Only inhibitors of ATR (VE821, VE822, AZ20) synergized with PARPi in killing GSCs in vitro. VE822 inhibited ATR activity both in vitro and in vivo, and modestly, but significantly, extended survival in mice bearing GSC-derived tumors. However, ATR inhibitor (ATRi) in combination with PARPi further prolonged survival, compared to each drug alone, even in mice bearing PARPi-resistant GSC-derived tumors. This is the first report that ATRi alone or in combination with PARPi is effective in treating GBM and provides a rationale for clinical trials for GBM. Citation Format: Jianfang Ning, Hiroaki Wakimoto, Robert L. Martuza, Samuel D. Rabkin. ATR inhibitors synergize with PARP inhibitors in killing glioblastoma stem cells and treating glioblastoma [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 1122. doi:10.1158/1538-7445.AM2017-1122
Abstract 4027: Developing biophysical platforms to study KRAS membrane interaction in artificial membranes
Authors: Frantz L. Jean-Francois, Andrew G. Stephen
Journal: Cancer Research (2017)

Abstract In our studies, we leverage the techniques that we believe will allow us to better understand and tackle KRAS membrane interaction. RAS proteins are small GTPases that oscillate between an active GTP-bound and inactive GDP-bound state to function as plasma membrane localized molecular switches in growth factor regulated signaling pathways. Mutation in HRAS, KRAS and NRAS are present in nearly 30% of human tumors. In particular, KRAS is mutated in almost 90% of pancreatic adenocarcinomas. Considering the requirement of the plasma membrane for KRAS activity, we are setting up ‘screenable’ biophysical platforms to understand the importance of lipids and find small molecules that could prevent KRAS membrane association in reconstituted systems. The two main techniques that are being developed are Surface Plasmon Resonance and Confocal Imaging in model membranes. Using these two techniques, we have been able to better understand the main lipids that drive KRAS membrane association and set up platforms that can be screened by small/large molecules. Biophysical techniques are frequently used by pharmaceutical companies as primary or secondary screening platforms. Developing such platforms for KRAS membrane interaction could enable the discovery of anti-cancer tool compounds. Citation Format: Frantz L. Jean-Francois, Andrew G. Stephen. Developing biophysical platforms to study KRAS membrane interaction in artificial membranes [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 4027. doi:10.1158/1538-7445.AM2017-4027
Abstract CT112: Use of targeted sequencing of cancer genome (cancer panel) to develop patient-centered therapeutic target based on molecular alternations: A pilot prospective study for 25 patients with refractory and metastatic cancer and treatment response
Authors: Chae Hwa Kwon, Young Mi Seol, Young Keum Kim, Yuri Choi, Yeo Jin Won, Do Youn Park
Journal: Cancer Research (2017)

Abstract With the advent for technology of next generation sequencing, targeted sequencing is now becoming part of decision of chemotherapeutics in cancer patients, especially in refractory and metastatic cancer. We performed targeted sequencing to develop patient-centered trials to find therapeutic target based on molecular alternations. We used cancer panel for capturing of target region covering 83 cancer-related genes and validated it using 3 cases with ALK-fusion, ERBB2 amplification, or KRAS mutation. A total of 25 refractory metastatic cancer patients enrolled on this study so far. The majority of alterations were identified in ATM, FBXW7, NOTCH1, TP53, STK11, ARID1B, GNAS, FGFR3, SMAD4, and HNF1A. Among 25 patients, 12 had FDA-approved drug responsive or resistant alterations. However, targeted therapy was guided in 3 patients (12 %) on the basis of sequencing results because of lack of access to clinical trials, declining performance status and/or stable disease with previous treatment; crizotinib to ALK-EML4 fusion in malignancy of undefined origin (MUO) patient, pazopanib to FGFR amplification in malignant peripheral nerve sheath tumor (MPNST) patient, and everolimus to AKT3 amplification in uterine endometrial stromal sarcoma patient. All 3 patients showed partial response after targeted therapy. In addition, we identified KRAS codon 146 mutation (A146V), associated with resistance to anti-EGFR, in a cetuximab resistant colon cancer patient with wild-type KRAS exon 2 and 12 and EGFR. Taken together, this study suggests that identifying targets associated with response or resistance to specific targeted therapies using targeted sequencing can show great promise for improving the care of patients with refractory and metastatic cancer patients. Citation Format: Chae Hwa Kwon, Young Mi Seol, Young Keum Kim, Yuri Choi, Yeo Jin Won, Do Youn Park. Use of targeted sequencing of cancer genome (cancer panel) to develop patient-centered therapeutic target based on molecular alternations: A pilot prospective study for 25 patients with refractory and metastatic cancer and treatment response [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 CT112. doi:10.1158/1538-7445.AM2017-CT112
Abstract 3623: Preclinical efficacy of the selective GR antagonist, CORT125134
Authors: Hazel Hunt, Joseph Belanoff, Thad Block, Stacie P. Shepherd
Journal: Cancer Research (2017)

Abstract The role of activation of the glucocorticoid receptor (GR) in the response of several solid tumor types to chemotherapy has been reported by several groups. Skor et al1 have demonstrated that the non-selective GR antagonist mifepristone can potentiate the effect of paclitaxel in a mouse xenograft derived from a human triple negative breast cancer (TNBC) cell line. GR activation is thought to play a role in the regulation of pro- and anti-apoptotic genes. Isikbay et al2 have demonstrated the benefits of combining androgen deprivation therapy with GR antagonism in prostate cancer xenograft model. Signaling via GR appears to be able to compensate for lack of androgen receptor signaling, and to contribute to castrate resistance. CORT125134 is a novel, selective GR antagonist being developed for the treatment of a variety of solid tumors, in combination with an appropriate standard of care agent. CORT125134 is currently being studied in a Phase1/2 study in solid tumors, in combination with nab-paclitaxel. The efficacy of CORT125134 in combination with standard of care agents has been investigated in mouse xenograft models of several tumor types. Previous reports of the benefit of adding a GR antagonist to chemotherapy in a TNBC model and an ovarian cancer model have been confirmed. An enhancement of the anti-tumor effect of castration by the addition of a GR antagonist has been confirmed in a model of prostate cancer. In addition, CORT125134 has been shown to provide a significant improvement in the efficacy of paclitaxel in a pancreatic cancer model. In a MIAPaca-2 xenograft model, paclitaxel was given i.v. every 4 days either alone or in combination with CORT125134. The combination provided significantly better tumor group inhibition than paclitaxel alone (p&amp;lt;0.0001). These encouraging results in a pancreatic cancer model extend the potential utility of GR antagonism in a variety of solid tumor types. In the TNBC model, alternative dosing regimens have been investigated, and suggest that stress during dosing is a confounding factor in these studies. 1. Skor MN, Wonder E, Kocherginsky M, et al. Glucocorticoid receptor antagonism as a novel therapy for triple negative breast cancer. Clinical Cancer Res. 2013;19(22):6163-6172. 2. Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer. 2014;5(2):72-89. Citation Format: Hazel Hunt, Joseph Belanoff, Thad Block, Stacie P. Shepherd. Preclinical efficacy of the selective GR antagonist, CORT125134 [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 3623. doi:10.1158/1538-7445.AM2017-3623
The Medicare Access and CHIP Reauthorization Act: Implications for Nephrology
Authors: Eugene Lin, Thomas MaCurdy, Jay Bhattacharya
Journal: Journal of the American Society of Nephrology (2017)

In response to rising Medicare costs, Congress passed the Medicare Access and Children’s Health Insurance Program Reauthorization Act in 2015. The law fundamentally changes the way that health care providers are reimbursed by implementing a pay for performance system that rewards providers for high-value health care. As of the beginning of 2017, providers will be evaluated on quality and in later years, cost as well. High-quality, cost-efficient providers will receive bonuses in reimbursement, and low-quality, expensive providers will be penalized financially. The Centers for Medicare and Medicaid Services will evaluate provider costs through episodes of care, which are currently in development, and alternative payment models. Although dialysis-specific alternative payment models have already been implemented, current models do not address the transition of patients from CKD to ESRD, a particularly vulnerable time for patients. Nephrology providers have an opportunity to develop cost-efficient ways to care for patients during these transitions. Efforts like these, if successful, will help ensure that Medicare remains solvent in coming years.
Abstract 1986: Determining the signaling pathway of epithelial-IKKα deletion-mediated symbiotic bacterial and fungal infection in carcinogenesis
Authors: Na-Young Song, Jami Willette-Brown, Feng Zhu, Yinling Hu
Journal: Cancer Research (2017)

Abstract Bacteria and fungi, two major components of the microbiota, generally share niches and develop both antagonistic and symbiotic relationships, regulating the pathological impacts on the host. The epithelium is where the bacterial-fungal interaction occurs most abundantly, but the relationship between the epithelium, bacteria, and fungi on the pathogenesis, particularly tumorigenesis, is poorly understood. IKKα is one of the crucial factors regulating the homeostasis of squamous epithelial tissues. Recently, our lab has established a mouse model that develops esophageal squamous cell carcinomas associated with IKKα reduction, inflammation and chronic fungal infection. Cladosporium cladosporioides was a major type of fungi identified in this mouse model. Because IKKα deletion in the keratinocytes causes impaired skin barrier, we hypothesized that loss of epithelial IKKα may control fungal colonization through regulating the barrier integrity and inflammation. We generated IKKαf/f mice with inducible K15.Cre (IKKαf/f/K15.Cre) specifically expressed in keratinocytes in hair follicles which is considered as skin stem cells. After deleting IKKα in K15 cells in oral mucosa and skin, IKKαf/f/K15.Cre mice were orally inoculated with Cladosporium cladosporioides. We found that epithelial IKKα deletion increased bacterial colonization in oral mucosa and skin. Moreover, Cladosporium infection further promoted bacterial and fungal colonization in oral cavity and development of skin tumors. Taken together, our data suggest that loss of epithelial IKKα induces the bacterial-fungal symbiosis in oral mucosa, promoting skin tumors. This study will shed light on the importance of the epithelial-bacterial-fungal interaction in the pathogenesis, proposing epithelial IKKα as a novel regulator of the bacterial-fungal interaction. Citation Format: Na-Young Song, Jami Willette-Brown, Feng Zhu, Yinling Hu. Determining the signaling pathway of epithelial-IKKα deletion-mediated symbiotic bacterial and fungal infection in carcinogenesis [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 1986. doi:10.1158/1538-7445.AM2017-1986
QT interval and drug therapy
Authors: Drug and Therapeutics Bulletin
Journal: BMJ (2016)

The QT interval is measured from the beginning of the QRS complex to the end of the T wave on a surface electrocardiogram and represents the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium.1 The interval varies greatly and is affected by age, sex, sympathetic tone, and diurnal pattern.2 Because it increases as heart rate falls, measurements of QT interval are usually corrected for heart rate (QTc). Several methods have been used (box 1) but, as the relation between QT interval and heart rate varies between individuals, guidelines recommend use of linear regression functions such as the Framingham rather than the Bazett or Fridericia method.4

#### Box 1: Formulae used to correct the QT interval for heart rate3

Measurement of the QT interval is not straightforward and is associated with considerable intraindividual and interindividual variability. There is currently no agreed consensus on how to measure the QT interval in patients with broad complex ventricular conduction abnormalities or paced ventricular rhythm, and measurement in patients with atrial fibrillation requires special consideration. The QT interval also differs between electrocardiograph (ECG) leads, and it is unclear whether normal values—historically derived from single lead measurements—relate directly to those obtained from multi-lead ECG recordings. In addition, details of algorithms used in semi-automated ECG machines are not always readily available. QTc intervals of 450 ms and 460 ms are generally accepted as the upper limits of normal for adult men and women, respectively.4

Although QT prolongation is associated with torsades de pointes (TdP) and sudden cardiac death,5 it is an imperfect predictor. Many patients with prolonged QT never experience TdP, whereas many who experience TdP have a normal QT before the episode. Similarly, some drugs (eg amiodarone) can markedly prolong QT but …
Abstract 336: PIK3CB/p110B is a survival factor in glioblastoma
Authors: Kevin J. Pridham, Sujuan Guo, Zhi Sheng
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) is lethal even after surgical removal of the tumor, radiation, and chemotherapy. Residual tumor cells form an intractable tumor in nearly all patients within two years. Recurrent GBM is incurable due to resistance to current therapies. Inhibitors of PI3K (phosphatidylinositol-4,5-biphosphate 3-kinase)-a signaling pathway that causally contributes to tumor formation/recurrence-have been used to treat recurrent GBMs and achieved modest clinical effect. This is perhaps attributed to non-selective inhibition of PI3K isoforms, which yields intolerable toxicity. Class IA PI3K isoforms include three catalytic subunits (PIK3CA, B, or D that encodes p110α, β, or δ) and three regulatory subunits (PIK3R1-3 that encodes p85 isoforms). Our recent work indicates that PIK3CB levels positively correlate with the chances/risk of GBM recurrence, while being inversely associated with patient prognosis. This suggests that PIK3CB/p110β is important for GBM cell survival. To test this hypothesis, we first measured the expression of PI3K isoforms in a panel of 9 GBM cell lines. We found that U87MG, SF295, and U251 expressed much higher levels of p110β, coinciding with the levels of phosphorylated AKT. We then knocked down PIK3CA, B, and D in human U87MG cells and found that only depletion of PIK3CB/p110β resulted in an inactivation of downstream AKT. Moreover, knockdown of PIK3CB/p110β, but not other isoforms, induced substantial growth inhibition in U87MG, SF295 and U251 cells. This is congruent with the result that inhibition of PIK3CB/p110β activated apoptosis in U87MG cells. We also report that treatment of p110βhigh GBM cells with isoform specific inhibitors selectively represses the viability of these cells. Finally, we report that ectopic expression of p110β, but not p110α or δ, partially rescued U87MG cells from growth inhibition induced by TGX-221, a p110β-selective inhibitor. Collectively, our results demonstrate that PIK3CB/p110β is an important selective survival factor in GBM, underscoring the divergent roles of PI3K isoforms in GBM disease progression/recurrence and future therapeutic intervention. Citation Format: Kevin J. Pridham, Sujuan Guo, Zhi Sheng. PIK3CB/p110B is a survival factor in glioblastoma [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 336. doi:10.1158/1538-7445.AM2017-336
Abstract 3606: RBP2 promotes tamoxifen resistance by altering ER function and activating IGF1R and EGFR/HER2 signaling in histone methylation-dependent and -independent manners in breast cancer
Authors: Hee-Joo Choi, Taekwon Son, Hyung-Yong Kim, Kyueng-Whan Min, Young-Ha Oh, Jeong-Yeon Lee, Gu Kong
Journal: Cancer Research (2017)

Abstract Retinoblastoma binding protein 2 (RBP2, also known as JARID1A), a member of the JARID1 family of histone H3 lysine K4 demethylases, has been considered to have an oncogenic potential in several types of human cancers including breast cancer. Although physical interaction between RBP2 and estrogen receptor (ER), a crucial factor for hormone-dependent breast cancer, has been implied, the role of RBP2 in ER-positive (ER+) breast cancer remains largely unknown. Here, we demonstrate that RBP2 is a novel therapeutic target for tamoxifen resistance in ER+ breast cancer as an ER co-regulator and an activator of receptor tyrosine kinase (RTK) signaling. In large cohorts of breast cancer patients including METABRIC, high expression of RBP2 was associated with poor response to tamoxifen therapy in ER+ breast cancer. Consistently, RBP2 induced tamoxifen resistance in ER+ breast cancer both in vitro and in vivo. Using RNA-sequencing analysis, we identified that many RBP2 target genes are overlapped with ER-dependent- and tamoxifen resistance-associated genes. Mechanistically, RBP2 induced not only hyperactivation of ER-dependent transcription but also estrogen agonist activity of tamoxifen-bound ER via the interaction with ER, thus increasing the expression of NRIP1, a co-repressor of ER. RBP2 also formed a transcriptional repressive complex with ER, NRIP1, and HDAC1 to induce H3K4 demethylation-mediated epigenetic gene silencing of IGFBP4 and IGFBP5, leading to the activation of IGF1R and its downstream, PI3K/AKT pathway. Furthermore, enhanced AKT phosphorylation by RBP2 was mediated by not only IGF1R but also EGFR/HER2 signaling via increasing the stability of EGFR and HER2 proteins in a demethylase activity-independent manner. We further confirmed that combinational treatment with tamoxifen and PI3K inhibitor BKM120 restored tamoxifen sensitivity in RBP2-overexpressing breast cancer. Taken together, these findings suggest that RBP2 mediates tamoxifen resistance in ER+ breast cancer by altering ER activity and activating IGF1R and EGFR/HER2 signal pathways in both a histone methylation-dependent and -independent manner. Therefore, RBP2 may be a promising prognostic marker and therapeutic target for endocrine therapy-resistant breast cancer. Citation Format: Hee-Joo Choi, Taekwon Son, Hyung-Yong Kim, Kyueng-Whan Min, Young-Ha Oh, Jeong-Yeon Lee, Gu Kong. RBP2 promotes tamoxifen resistance by altering ER function and activating IGF1R and EGFR/HER2 signaling in histone methylation-dependent and -independent manners in breast 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 3606. doi:10.1158/1538-7445.AM2017-3606