tbuckley/cabot-search huggingface dataset:
Abstract 3343: RNA demethylase alkbh5 supports breast cancer growth and progression
Authors: Vijay Kumar Eedunuri, Panneerdoss Subbarayalu, Subhapriya Rajamanickam, Abdelfattah Nourhan, Benjamin C. Onyeagucha, Santosh Timilsina, Pooja Yadav, Manjeet K. Rao
Journal: Cancer Research (2017)

Abstract N6-methyladenosine (m6A) is one of the most prevalent internal modifications in eukaryotic messenger RNA. This dynamic and reversible modification is installed by methyltransferase complex consisting of three subunits: Methyltransferase-like protein 3 (METTL3), Methyltransferase-like protein 14 (METTL14) and Wilms tumor 1-associating protein (WTAP), and erased by two independent demethylases, Fat mass and obesity associated protein (FTO) and AlkB homolog 5 (ALKBH5). RNA demthylase ALKBH5 has been reported to play vital roles in several biological processes. However, very little is known about the role of ALKBH5 in cancer in general and breast tumorigenesis in particular. In this study, we report that ALKBH5 promotes breast cancer growth and progression. Using in vitro and in vivo models, we show that silencing of ALKBH5 inhibits breast cancer growth and invasion. Importantly, our studies reveal that ALKBH5 mediates its pro-tumorigenic function by regulating several microtubule associated genes including KIF2C, PLK1, MAPRE1 and RCC2 that are critical for spindle formation or assembly during mitotic progression. Interestingly, ALKBH5 target genes KIF2C and MAPRE1 are highly expressed in breast cancer patients and their higher expression is strongly correlated with lower survival of breast cancer patients. We believe that an optimal level of RNA methylation of key target genes is critical for normal cell cycle progression and any alteration in the levels of RNA methylation may alter activity or expression of these genes resulting in unabated cell proliferation. Citation Format: Vijay Kumar Eedunuri, Panneerdoss Subbarayalu, Subhapriya Rajamanickam, Abdelfattah Nourhan, Benjamin C. Onyeagucha, Santosh Timilsina, Pooja Yadav, Manjeet K. Rao. RNA demethylase alkbh5 supports breast cancer growth and 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 3343. doi:10.1158/1538-7445.AM2017-3343
Abstract 3240: Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents
Authors: Emmanuel Yawson, Angel Garcia, Husamuldeen Dhari, Rajendram V. Rajnarayanan
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TBNC) is the only major type of breast cancer for which no specific FDA approved target therapy is available to improve patient outcomes. TNBC lacks the usual breast cancer targets estrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor. Studies have shown that TBNC does express the epidermal growth factor receptor and has recently emerged as one of the potential targets in TBNC. Epidermal growth factor (EGF) mediates several cellular functions and processes such as survival, motility, differentiation, proliferation and death. When it is released by epidermal tissues, EGF binds to cell surface receptors such as the Epidermal growth factor receptor (EGFR) causing a conformational change which facilitates its dimerization. This receptor dimerization triggers its tyrosine kinase-mediated signal transduction activity. Apart from EGF, EGFR is reported to bind to Transforming growth factor alpha (TGF-α), Argos and Potato Carboxypeptidase inhibitor (PCI). All of these proteins have unique structural motifs which targets EGFR. PCI’s structure consisting of three disulfide bridges presents a unique knot like binding motif resembling EGF and is able to compete with EGF for its binding site on EGFR preventing receptor dimerization thereby antagonizing its action. We have used an integrated computational drug discovery approach to generate several PCI derived peptidic ligands targeting EGFR protein-protein interactions. PCI- peptides bind to EGFR in silico and block EGFR-mediated cell growth, proliferation and migration in vitro. We believe these designer peptidic inhibitors will provide structural and mechanistic clues towards novel therapeutics to combat TNBC. Citation Format: Emmanuel Yawson, Angel Garcia, Husamuldeen Dhari, Rajendram V. Rajnarayanan. Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents [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 3240. doi:10.1158/1538-7445.AM2017-3240
Abstract 848: Netropsin blocks EMT of murine BRAF mutated melanoma cells
Authors: Juliano Freitas, Fenfei Leng, Lidia Kos
Journal: Cancer Research (2017)

Abstract Melanoma is the most aggressive and deadliest type of skin cancer due to its high propensity to metastasize. Despite current progress in the identification of promising drugs for treating melanoma, drug resistance has emerged as a serious issue indicating that novel therapeutic strategies may be required. It is well documented that the process of converting the epithelial tumorigenic cell to a mesenchymal phenotype, the epithelial-mesenchymal transition (EMT), is responsible for conferring an invasive phenotype to cancer cells. An EMT-like process has been shown to occur during melanoma progression. High-mobility-protein AT-hook 2 (HMGA2) is a multi-function transcription factor linked to oncogenesis and EMT in a variety of cancers. HMGA2 is a small DNA-binding protein with three “AT-hook” DNA-binding motifs that specifically recognize the minor groove of AT-rich DNA sequences. HMGA2 is significantly upregulated in human primary melanoma and metastases, including those with BRAF mutations. We accessed the potential application of netropsin, a potent inhibitor of HMGA2-DNA interactions, as an EMT blocking agent of BRAF mutated melanoma cells. Three murine melanoma cells lines that carry mutations in the BRAF gene and show resistance to vemurafenib (D4M, YUMM1.1, and YUMM1.7) were used. Cells were treated with EMT Inducing Media Supplement along with Netropsin and the expression of E-cadherin as well as their migratory behavior were evaluated. Netropsin treatment of EMT induced cells was not cytotoxic, prevented changes in cell morphology, maintained high levels of E-cadherin expression and decreased migratory behavior. All three cell lines express HMGA2 which continues to be expressed in the tumors resulting from subcutaneous injections in mice. YUMM1.1 cells showed the highest levels of expression of HMGA2 amongst the three cell lines. Interestingly, in our preliminary study only YUMM1.1-derived tumors generated overt metastasis in the lung 30 days after the injections. Altogether our data showed that Netropsin is capable of blocking EMT of murine BRAF mutated melanoma cells. The results of this study will contribute to the development of strategies to prevent EMT that may result in the implementation of more effective therapies to treat melanoma. Citation Format: Juliano Freitas, Fenfei Leng, Lidia Kos. Netropsin blocks EMT of murine BRAF mutated melanoma 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 848. doi:10.1158/1538-7445.AM2017-848
Abstract 3313: Autophagic ovarian cancer cells exhibit substantially enhanced sensitivity to Crizotinib
Authors: Alicia M. Blessing, Yan Wang, Weiqun Mao, Lan Pang, Zhen Lu, Robert C. Bast
Journal: Cancer Research (2017)

Abstract One of the major factors contributing to poor outcomes for patients with ovarian cancer is the persistence of dormant, drug resistant cancer cells after primary surgery and chemotherapy. Recurrent, progressively growing ovarian cancer metastases are generally well vascularized and may only have a small fraction of cancer cells undergoing autophagy. By contrast, the persistent, drug resistant, dormant cancer cells that remain on the peritoneal cavity after conventional treatment tend to be poorly vascularized. In this nutrient-poor, avascular microenvironment autophagy is widespread and can be found in more than 80% of cases. Drugs that regulate survival in autophagic cancer cells may be much more active when administered as maintenance therapy than when used to treat gross primary or recurrent disease. Using unbiased siRNA screens, we have identified target genes that regulate the survival of ovarian cancer cells that are undergoing autophagy that has been induced by the re-expression of DIRAS3 or by amino acid starvation. Knockdown of the anaplastic lymphoma kinase (ALK) significantly reduced survival of ovarian cancer cells that were undergoing autophagy. Importantly, the FDA-approved ALK inhibitor, Crizotinib, exhibited significantly greater toxicity after induction of autophagy by upregulation of DIRAS3 (ARHI) in OVCAR8, CAOV3, and SKOv3 ovarian cancer cells. Induction of autophagy by upregulation of DIRAS3 in SKOv3 ovarian cancer cells reduced the IC50 of Crizotinib from 7.44µM ± 0.04708 to 2.129µM ± 0.06152 (P&amp;lt;0.05). Conversely, siRNA knockdown of DIRAS3 in CAOV3 cells with endogenously high DIRAS3 expression and baseline autophagy increased the IC50 of Crizotinib from 204 nM ± 0.01265 to 267 nM ± 0.01715 (P&amp;lt;0.05). Our studies in cell culture suggest that Crizotinib might provide an effective agent to eliminate autophagic, dormant drug resistant ovarian cancer cells that remain after conventional cytoreductive surgery and combination chemotherapy. Subsequent studies will evaluate the effect of Crizotinib in xenograft models of DIRAS3-induced ovarian cancer dormancy. Citation Format: Alicia M. Blessing, Yan Wang, Weiqun Mao, Lan Pang, Zhen Lu, Robert C. Bast. Autophagic ovarian cancer cells exhibit substantially enhanced sensitivity to Crizotinib [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 3313. doi:10.1158/1538-7445.AM2017-3313
Abstract 908: A role for MST4 in organelle organization and breast cancer cell vascular invasion
Authors: Eric B. Berens, Mara Gilardi, Matteo Moretti, Anna T. Riegel, Anton Wellstein
Journal: Cancer Research (2017)

Abstract There exist 5 Mammalian Sterile20-like (MST) kinases that are broadly distributed into two subgroups. While MST1 and MST2 have established roles in the canonical Hippo signaling pathway, MST3, MST4, and YSK1 are known to regulate the actin cytoskeleton and cell polarity. Here we clarify distinct roles for MST3 vs. MST4 in breast cancer cell lines. Stable knockdown of MST4, but not MST3, enhances the ability of breast cancer cells to disrupt an endothelial monolayer as well as invade from an endothelial network formed within a microfluidic device. In addition, depletion of MST4 in MDA-MB-231 cells alters their morphology, induces abnormalities in nuclear structure, and affects the organization of cellular organelles like the Golgi apparatus. We conclude that, despite their relative homology, MST4 versus MST3 uniquely impacts the intracellular organelle status and vascular invasive behavior of breast cancer cells. Citation Format: Eric B. Berens, Mara Gilardi, Matteo Moretti, Anna T. Riegel, Anton Wellstein. A role for MST4 in organelle organization and breast cancer cell vascular invasion [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 908. doi:10.1158/1538-7445.AM2017-908
Review of Peter L. Rosenbaum, Gabriel M. Ronen, Bernard Dan, Jennifer Johannensen, and Eric Racine, eds., Ethics in Child Health: Principles and Cases in Neurodisability
Authors: Sarah L. Bauer Huang
Journal: The American Journal of Bioethics (2017)

"Review of Peter L. Rosenbaum, Gabriel M. Ronen, Bernard Dan, Jennifer Johannensen, and Eric Racine, eds., Ethics in Child Health: Principles and Cases in Neurodisability." The American Journal of Bioethics, 17(8), pp. W5–W6
Abstract 2933: Involvement of CXCL12-CXCR7 axis in adipocyte-induced TNBC metastasis
Authors: Hyeongjwa Choi, Rosa Mistica C. Ignacio, Carla R. Gibbs, Eunsook Lee, Samuel E. Adunyah, Deok-Soo Son
Journal: Cancer Research (2017)

Abstract Breast cancer (BC) is the most frequent tumor in women worldwide. Although its mortality has significantly decreased owing to advanced therapies, triple negative breast cancer (TNBC) is still difficult to treat because of lack of estrogen receptor, progesterone receptor and HER-2. TNBC accounts for 12-24% of total BC and contributes to the aggressiveness and poorer outcomes. The risk of BC increases significantly in obese women. Obesity is also associated with the worse clinical prognosis of BC. But the underlying mechanisms between obesity and BC, particularly TNBC, remain unclear. Therefore, we compare the molecular mechanisms by which human adipocyte conditioned media (CM) affect TNBC cells (BT549) and non-TNBC cells (MCF7A). Adipocyte CM had no effect on the proliferation of both TNBC and non-TNBC cells. However, adipocyte CM enhanced significantly migration in TNBC cells compared to non-TNBC cells. Next, we examined the signaling pathway by which adipocyte CM promote migration of TNBC cell. AKT and ERK were activated in both TNBC cells and non-TNBC cells. However, phospho-STAT3 was significantly increased in TNBC cells. Also, N-cadherin, a marker for epithelial to mesenchymal transition (EMT), was increased at the late time point in TNBC cells. Furthermore, CXCR7 was specifically increased in TNBC cells after treatment with adipocyte CM using a PCR array. CXCR7 is chemoattractive to CXCL12 which is highly expressed in the lung, the bone marrow, and the liver, common sites of BC metastasis. Taken together, the results indicate that adipocyte CM may promote metastasis of TNBC cells through the CXCL12-CXCR7 axis by activating STAT3. Citation Format: Hyeongjwa Choi, Rosa Mistica C. Ignacio, Carla R. Gibbs, Eunsook Lee, Samuel E. Adunyah, Deok-Soo Son. Involvement of CXCL12-CXCR7 axis in adipocyte-induced TNBC metastasis [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 2933. doi:10.1158/1538-7445.AM2017-2933
Abstract 5313: Associations of calcium and dairy product intakes with colorectal cancer risk among older women: the Iowa Women's Health Study
Authors: Caroline Um, Anna Prizment, DeAnn Lazovich, Roberd M. Bostick
Journal: Cancer Research (2017)

Abstract Calcium has been consistently modestly associated with lower risk of colorectal cancer, which remains the second leading cause of cancer deaths among men and women combined in the United States. Dairy products, a major source of dietary calcium, have also been consistently inversely associated with colorectal cancer, although inconsistencies in relation to high-fat dairy products have been noted. Limited evidence suggests that dairy products may contain components other than calcium and fat, such as insulin-like growth factor 1 (IGF-1), that may be independently directly associated with risk of colorectal and other cancers. Data from the Iowa Women’s Health Study, a prospective cohort study, were used to investigate associations of calcium, dairy products, and the non-calcium component of dairy products with colorectal cancer incidence. Dietary data were collected using a semiquantitative food frequency questionnaire (FFQ) mailed to 55 – 69 year-old women in 1986 who had a valid Iowa driver’s license. Among participants with no history of cancer at baseline and who satisfactorily completed their FFQ (n=35,221), through follow up in 2012, 1,731 incident cases of colorectal cancer were documented via the Iowa SEER registry. To investigate total dairy and total, whole, and non-fat milks independent of their calcium components, we used the residuals from linear regression models of their associations with dietary calcium. Associations of the calcium and dairy product variables with colorectal cancer incidence were estimated using multivariable Cox proportional hazards regression. For those in the highest relative to those in the lowest quintiles of intakes, the adjusted hazards ratios and 95% confidence intervals (CI) were 0.81 (CI 0.67-0.98; P-trend 0.004) for total calcium, 0.85 (CI 0.68-1.03; P-trend 0.07) for dietary calcium, and 0.85 (CI 0.68-1.06; P-trend 0.16) for supplemental calcium. For total dairy and total milk, the corresponding findings were 0.79 (CI 0.66-0.94; P-trend 0.01) and 0.82 (CI 0.69-0.96; P-trend 0.09), respectively. Low-fat dairy products, non-fat milk, and residuals of total dairy products and total and non-fat milk were not associated with colorectal cancer. These results are consistent with previous findings of lower colorectal cancer risk with higher intakes of calcium and dairy products, but provide little support for the hypothesis that the non-calcium, non-fat component of dairy products may be associated with colorectal cancer. Citation Format: Caroline Um, Anna Prizment, DeAnn Lazovich, Roberd M. Bostick. Associations of calcium and dairy product intakes with colorectal cancer risk among older women: the Iowa Women's Health Study [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 5313. doi:10.1158/1538-7445.AM2017-5313
An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers.
Authors: Antoine Hollebecque, Tim Meyer, Kathleen N. Moore, Jean-Pascal H. Machiels, Jacques De Greve, José María López-Picazo, Ana Oaknin, Joseph N. Kerger, Valentina Boni, T.R. Jeffry Evans, Rebecca Sophie Kristeleit, Shangbang Rao, Ibrahima Soumaoro, Z. Alexander Cao, Suzanne Louise Topalian
Journal: Journal of Clinical Oncology (2017)

5504 Background: Treatment options for cervical, vaginal, and vulvar (GYN) cancers are limited after first-line therapy. Human papillomavirus (HPV) infection is associated with squamous cell carcinomas of the cervix (≥90%) and vulva/vagina (40–70%), and may elicit an immune reaction. Programmed death (PD)-1 and its major ligand PD-L1 are expressed in GYN cancers and inhibit immune responses. Nivolumab disrupts PD-1–mediated signaling, restoring antitumor immunity. Methods: In CheckMate 358 (NCT02488759), an ongoing multicohort study of 5 virus-associated cancers, PD-L1–unselected adults with R/M GYN cancers, ECOG PS 0–1, and ≤2 prior systemic therapies for R/M disease were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated patients (pts), 19 had cervical and 5 had vaginal or vulvar cancer; median age was 51 y. At a median follow-up of 31 wks (range: 6–38), ORR was 20.8% (Table), and disease control rate (ORR + SD) was 70.8%. All responses were in pts with cervical cancer (ORR, 26.3%) and were observed regardless of PD-L1 or HPV status or number of prior R/M therapies. Median PFS was 5.5 mo (95% CI: 3.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated encouraging clinical activity in pts with cervical cancer and a manageable safety profile in virus-associated GYN cancers, supporting further evaluation in these pts. Updated clinical and biomarker data to be presented. Clinical trial information: NCT02488759. [Table: see text]
Abstract 2086: Dominant role of receptor tyrosine kinase in the activation of MAPK signaling in BRAF non-V600 mutant cancers
Authors: Hiromichi Ebi, Hiroshi Kotani, Hidenori Kitai, Yuta Adachi, Seiji Yano
Journal: Cancer Research (2017)

Abstract BRAF mutations are found in ~8% of all cancers. In addition to the commonest mutation in kinase domain at the V600, a wide range of other missense mutations (non-V600) have been reported. Non-V600 mutant BRAF protein was also shown to enhance MAPK signaling, suggesting the effectiveness of MEK inhibitors. However, the existence of feedback mechanism in MAPK singling and the roles of receptor tyrosine kinases (RTKs) in these cells are not fully understood. To interrogate this, BRAF non-V600 cell lines with intermediate/impaired kinase activity were treated with MEK inhibitor. RTKs involved in the upregulation of P-MEK following MEK inhibition in BRAF non-V600E mutant cell lines were determined by phosphor-RTK arrays. The effect of combinatorial inhibition of RTKs and MEK in BRAF non-V600 cancer was assessed in vitro and in vivo. By analyzing drug screen data, we first found cells with BRAF non-V600E mutation were less sensitive to MEK inhibition compared with BRAF V600E mutant cell lines and almost comparable to RAS/RAF wild-type cell lines. MEK inhibition did not induce P-MEK suppression and it resulted in significant upregulation of p-MEK compared to BRAF V600E mutant cell lines. Phospho-RTK arrays in the presence or absence of trametinib displayed basal phosphorylation of RTKs including EGFR, MET, and IGF1R, although the phosphorylation level was not consistently changed following MEK inhibition. Among these RTKs, treatment with the EGFR inhibitor erlotinib led to more complete suppression of P-ERK upon trametinib treatment. Furthermore, we found that erlotinib monotherapy downregulated P-ERK in BRAF non-V600 mutant cell lines in contrast that inhibition of RTKs had no effect on MAPK signaling in BRAF V600 mutant cells. While erlotinib treatment led to MAPK inhibition both in intermediate active and impaired kinase active BRAF mutant cells, p-MEK and p-ERK were more strongly suppressed in impaired type BRAF non-V600 mutant cells. The combination of EGFR inhibitor and MEK inhibitor suppressed cell growth and achieved tumor shrinkage in mice xenograft. These results suggest that RTKs, especially EGFR, are dominantly involved in the regulation of MAPK signaling in BRAF non-V600 cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Hiromichi Ebi, Hiroshi Kotani, Hidenori Kitai, Yuta Adachi, Seiji Yano. Dominant role of receptor tyrosine kinase in the activation of MAPK signaling in BRAF non-V600 mutant cancers [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 2086. doi:10.1158/1538-7445.AM2017-2086
Quality of Life Outcomes after Primary Treatment for Clinically Localised Prostate Cancer: A Systematic Review
Authors: Michael Lardas, Matthew Liew, Roderick C. van den Bergh, Maria De Santis, Joaquim Bellmunt, Thomas Van den Broeck, Philip Cornford, Marcus G. Cumberbatch, Nicola Fossati, Tobias Gross, Ann M. Henry, Michel Bolla, Erik Briers, Steven Joniau, Thomas B. Lam, Malcolm D. Mason, Nicolas Mottet, Henk G. van der Poel, Olivier Rouvière, Ivo G. Schoots, Thomas Wiegel, Peter-Paul M. Willemse, Cathy Yuhong Yuan, Liam Bourke
Journal: European Urology (2017)