tbuckley/cabot-search huggingface dataset:
Abstract 1026: PEG-LPrA2 is a non-toxic adjuvant for triple negative breast cancer
Authors: Courtney D. Dill, Adriana Harbuzariu, Antonio Rampoldi, Crystal C. Lipsey, Viola Lanier, Tia Harmon, Danielle Daley-Brown, Cynthia Tchio, Pierre Candelaria, Ruben Rene Gonzalez-Perez
Journal: Cancer Research (2016)

Abstract Background: Triple Negative Breast Cancer (TNBC) is an aggressive cancer with poor prognosis and is difficult to treat. Current standard therapy for the disease includes a combination of chemotherapeutic drugs: doxorubicin (DOX), paclitaxel (TAX), and cyclophosphamide (CTX). These drugs are ineffective as they exhibit shortcomings and several side effects. TNBC patients develop chemoresistance that may be enhanced by leptin, which affects survival, proliferation, and angiogenesis. Our lab developed and tested a novel and specific inhibitor of leptin signaling, LPrA2. A pegylated derivative of LPrA2 (PEG-LPrA2), with enhanced bioavailability, was successfully used in mouse breast cancer models. Preliminary data showed that PEG-LPrA2 was non-toxic in vitro. Therefore, it is hypothesized that PEG-LPrA2 is not toxic in vivo. Methods: To determine potential toxicity of PEG-LPrA2, in vitro and in vivo assays were performed. In vitro toxicity of PEG-LPrA2 was tested in a human non-malignant mammary epithelial cell line (MCF-10A). MCF-10A cells were cultured in 96 well plates (5,000 cells/ well) and grown to 70-80% confluence. Cells were treated with PEG-LPrA2 for 24 hrs and viability was determined via MTT assay. In vivo toxicity studies were performed in obese mice. Fifty-seven, eight week old C57BL/6J mice (Charles River Laboratories) were divided into 6 groups. Control mice were fed a low fat diet (10% Kcal from fat) and the rest of the mice were fed a high fat diet (60% Kcal from fat) for 11 weeks. Obesity was characterized as body weight (BW) ≥ 25% BW of control mice. Obese mice were divided into six groups (n = 7/each). Mice were injected with 50 μL of either Sc-PEG-LPrA2 (scramble control) or active inhibitor, PEG-LPrA2, (0.1 mM, 1 mM, or 5 mM) two times a week, for eight weeks. Blood chemistries were analyzed. Additionally, heart, liver, and kidney tissue were harvested and examined to determine toxicity. The tissues were probed for OB-R via immuno histochemistry. Results: The results showed no changes in BW or food intake. Additionally, no evident changes in blood parameters and organ histology were found. Conclusions: PEG-LPrA2 is non-toxic and could serve as an adjuvant therapy for standard TNBC chemotherapeutics. Citation Format: Courtney D. Dill, Adriana Harbuzariu, Antonio Rampoldi, Crystal C. Lipsey, Viola Lanier, Tia Harmon, Danielle Daley-Brown, Cynthia Tchio, Pierre Candelaria, Ruben Rene Gonzalez-Perez. PEG-LPrA2 is a non-toxic adjuvant for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1026.
Abstract 828: α-Lipoic acid inhibits human hepatoma cell proliferation by Grb2-mediated downregulation of EGFR activity
Authors: Lan Yang, Yuntao Lin, Ya Wen, XiaoJuan Sun
Journal: Cancer Research (2016)

Abstract Background: It has been reported that α-Lipoic acid (α-LA) as a naturally occurring anti-oxidant, suppresses the growth of hepatoma cells, but the mechanisms remains unclear. Aims: To investigated whether α-LA inhibited hepatoma cells proliferation through EGFR-Grb2. Methods and Results: The results showed that Hu7, Bel7402 and HepG2 proliferation were dramatically decreased after α-LA (2 mM) treatment for 24 and 48 hours, which were measured by CCK8 assay. Moreover, phosphorylation levels of EGFR was decreased by α-LA treatment, and its associated with an inhibition in cell-cycle transition. Next, we found that growth factor receptor bound protein 2 (Grb2), which is adaptor protein, was also significantly reduced by RT-PCR and western blot after α-LA treatment at 24 and 48 hours. Consistent with previous report, silenced of Grb2 dramatically blocked cell proliferation. To test whether the downregulation of Grb2 mediates α-LA induced proliferation inhibition, Grb2 was transfected into hepatoma cells to recover the reduction of Grb2 induced by α-LA. It was showed that overexpression of Grb2 also successfully inhibited α-LA induced decrease of cell proliferation. In addition, the data showed that phosphorylation levels of ERK1/2 was decreased by cell treated with α-LA. These results suggested that the Grb2 through binds to phosphorylated site in EGFR medicated α-LA suppress cell proliferation. Conclusion: Our study showed α-LA inhibited cell proliferation through Grb2 suppressed phosphorylation levels of EGFR, ERK1/2 was involved in this pathway. Citation Format: Lan Yang, Yuntao Lin, Ya Wen, XiaoJuan Sun. α-Lipoic acid inhibits human hepatoma cell proliferation by Grb2-mediated downregulation of EGFR activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 828.
Abstract 4481: Phosphorylation regulates EZH2 neoplastic functions in triple-negative breast cancer
Authors: Talha Anwar, Caroline Arellano-Garcia, Boris Burman, Celina G. Kleer
Journal: Cancer Research (2016)

Abstract Background: Triple negative (estrogen receptor, progesterone receptor, HER2-neu negative) breast cancers (TNBC) comprise 15% of all breast cancers but are responsible for a disproportionately high number of deaths. Overexpression of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is an independent prognostic biomarker significantly associated with poorly-differentiated TNBCs and poor patient outcome. We previously identified a novel link between EZH2 and the p38 mitogen-activated protein kinase, an important mediator of progression and metastasis of TNBC. We found that EZH2 binds to p38, and that EZH2 and activated p38 are concordantly expressed in the metastases of breast cancer patients. Based on these data and previous in vitro studies, we hypothesized that p38 MAPK may also regulate EZH2 through phosphorylation in breast cancer. We further hypothesized that this phosphorylation event may be important for EZH2 contribution to malignancy. Methods: In order to test this hypothesis, we performed knockdown rescue experiments in triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-436. Stable knockdown of EZH2 was achieved using shRNA targeting the 3’UTR. Knockdown of EZH2 was rescued by reintroduction of myc-EZH2 (WT) or a T367A-EZH2 phosphorylation-deficient mutant. Cell lines were then used in functional assays of proliferation, migration, and invasion. In order to further interrogate the importance of this phosphorylation event, we developed a phospho-specific EZH2 T367 antibody. Results: p38-mediated phosphorylation of EZH2 at T367 contributes to the migratory and invasive properties of TNBC. Mechanistically, phosphorylation by p38 does not affect binding to other PRC2 members but may affect EZH2 activity. We are currently investigating the relevance of pEZH2 as a biomarker of breast cancer survival with our new antibody. Conclusions: We provide evidence that p38 phosphorylation of EZH2 at T367 contributes to malignancy of triple-negative breast cancers. Our data suggest a new mechanism by which EZH2 is regulated and may offer an additional mechanism by which EZH2 contributes to TNBC progression. Citation Format: Talha Anwar, Caroline Arellano-Garcia, Boris Burman, Celina G. Kleer. Phosphorylation regulates EZH2 neoplastic functions in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4481.
Abstract LB-314: Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation
Authors: Jianrong Lu
Journal: Cancer Research (2016)

Abstract The Warburg effect, which reflects cancer cells’ preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. Cancer cells restrain pyruvate flux into mitochondrial oxidative metabolism in large part by inhibiting the pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential implication of Src in tumor metabolism remained largely unclear. Here we report that active Src enzyme directly tyrosine-phosphorylates the PDH E1α subunit (PDHA1). Conversely, pharmacological Src inhibitors or depletion of Src by shRNA abolish PDHA1 tyrosine phosphorylation in cancer cells, suggesting that Src is the main kinase responsible for PDHA1 tyrosine phosphorylation. This Src-mediated modification inactivates PDH. Consistently, activation of Src attenuates PDH activity and generation of reactive oxygen species (ROS), which are byproducts of mitochondrial respiration. Src inhibitors activate PDH and increase cellular ROS levels. Importantly, expression of a tyrosine non-phosphorable PDHA1 mutant in Src-activated cancer cells restores PDH activity, increases mitochondrial respiration and oxidative stress, decreases experimental metastasis, and sensitizes cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg metabolic phenotype by inactivating PDH through tyrosine phosphorylation, and this metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. As inhibition of Src sensitizes cancer cells to pro-oxidants, combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy. Citation Format: Jianrong Lu. Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-314.
Induction of Vascular Endothelial Growth Factor (VEGF) and Interleukin 6 (IL-6) in Stromal Cells by Plasma Cells from Different Stages of Myeloma.
Authors: Jessica L. Haug, S. Vincent Rajkumar, John A. Lust, Thomas E. Witzig, Teresa K. Kimlinger, Michael M. Timm, Michael P. Kline, Linda Wellik, Shaji Kumar
Journal: Blood (2006)
Abstract 2774: High levels of 5-hydroxymethylcytosine (5hmC) predict biochemical recurrence after prostatectomy in ERG negative prostate cancer
Authors: Siri H. Strand, Soren Hoyer, Anne-Sofie Lynnerup, Christa Haldrup, Tine M. Storebjerg, Michael Borre, Torben F. Orntoft, Karina D. Sorensen
Journal: Cancer Research (2016)

Abstract Background: Prostate cancer (PC) can be stratified into distinct molecular subtypes based on TMPRSS2-ERG gene fusion status, but its potential prognostic value remains controversial. Likewise, routine clinicopathological features cannot clearly distinguish aggressive from indolent tumors at the time of diagnosis, thus new prognostic biomarkers are urgently needed. The DNA methylation variant 5-hydroxymethylcytosine (5hmC, an oxidized derivative of 5-methylcytosine) has recently emerged as a new diagnostic and/or prognostic biomarker candidate for several human malignancies. However, this remains to be systematically investigated for PC. In this study, we determined 5hmC levels in 311 PC (stratified by ERG status) and 228 adjacent non-malignant (NM) prostate tissue specimens by immunohistochemical analysis of a tissue microarray, representing a large radical prostatectomy (RP) cohort with long clinical follow-up. We investigated possible correlations between 5hmC and routine clinicopathological variables and assessed the prognostic potential of 5hmC by Kaplan-Meier, uni- and multivariate Cox regression analyses in ERG+ (n = 178) vs. ERG- (n = 133) PCs using biochemical recurrence (BCR) as endpoint. Results: We observed a borderline significant (p = 0.06) reduction in 5hmC levels in PC compared to NM tissue samples, which was explained by a highly significant (p&amp;lt;0.001) loss of 5hmC in ERG- PCs. ERG status was not predictive of BCR in this cohort (p = 0.73) and no significant association was found between BCR and 5hmC levels in ERG+ PCs (p = 0.98). In contrast, high 5hmC immunoreactivity was a significant adverse predictor of BCR after RP in ERG- PCs, independent of Gleason score, pathological tumor stage, surgical margin status, and pre-operative PSA level (HR (95% CI): 1.62 (1.15-2.28), p = 0.006). Conclusions: This is the first study to demonstrate a prognostic potential for 5hmC in PC. Our findings highlight the importance of ERG stratification in PC biomarker studies, and suggest that epigenetic mechanisms involving 5hmC are important for the development and/or progression of ERG- PC. Citation Format: Siri H. Strand, Soren Hoyer, Anne-Sofie Lynnerup, Christa Haldrup, Tine M. Storebjerg, Michael Borre, Torben F. Orntoft, Karina D. Sorensen. High levels of 5-hydroxymethylcytosine (5hmC) predict biochemical recurrence after prostatectomy in ERG negative prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2774.
Abstract 3396: Purinergic regulation of tumor-mediated angiogenesis: A role for exosomal NM23
Authors: Senny Nordmeier, Suzann Duan, Iain L.O. Buxton.
Journal: Cancer Research (2016)

Abstract Exogenous nucleoside diphosphate kinase (eNDPK or NM23) has been shown to promote endothelial cell proliferation and migration and tumor-mediated angiogenesis. This is facilitated by its transphosphorylase activity, in which a gamma terminal phosphate group from a triphosphate nucleoside is transferred to a diphosphate nucleoside, resulting in elevated ATP levels. ATP can active purinergic receptors (P2Y1) on adjacent endothelial cells to promote angiogenesis. We previously reported that eNDPK was detected in conditioned media of breast cancer cells and in the serum of breast cancer patients (Yokdang, et al., 2011; Yokdang, et al., 2015). This suggests that eNDPK may have a role in tumorigenesis, but the mechanism by which eNDPK is released into the extracellular environment remains unknown. It is known that all cell types secrete small vesicles called exosomes, 30-100 nm wide vesicles of endocytic origin. We hypothesize that exosomal eNDPK secreted by breast cancer cells targets and promotes endothelial cell tubulogenesis and direct inhibition of eNDPK and P2Y1 activity attenuates angiogenesis. Exosomes were purified from human breast cancer cells, MDA-MB-231 (231) and non-tumorigenic human mammary epithelial cells (HME1) using ExoQuick TC. Transmission electron microscopy, mass spectrometry, and flow cytometry were performed to characterize the exosomes. Purified exosomes labeled with GFP-tagged tetraspanin (CD63) were introduced to human umbilical vein endothelial cells (HUVEC) to detect and measure tubulogenesis formation. We show that 231 secreted exosomes contain eNDPK and HUVEC cells treated with NDPK in the presence of ADP and GTP form tubules. In addition, fluorescently-labeled exosomes are associated with HUVEC tubules. The role of exosomal NDPK released by cancer cells in promoting angiogenesis and tumorigenesis may be used as a potential biomarker and target for treatment in breast cancer management. For future investigations of exosomal eNDPK, this study suggests that breast cancer exosomes promote endothelial tubulogenesis in a P2Y receptor-dependent manner. Citation Format: Senny Nordmeier, Suzann Duan, Iain L.O. Buxton. Purinergic regulation of tumor-mediated angiogenesis: A role for exosomal NM23. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3396.
An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease
Authors: Steve Horvath, Michael Gurven, Morgan E. Levine, Benjamin C. Trumble, Hillard Kaplan, Hooman Allayee, Beate R. Ritz, Brian Chen, Ake T. Lu, Tammy M. Rickabaugh, Beth D. Jamieson, Dianjianyi Sun, Shengxu Li, Wei Chen, Lluis Quintana-Murci, Maud Fagny, Michael S. Kobor, Philip S. Tsao, Alexander P. Reiner, Kerstin L. Edlefsen, Devin Absher, Themistocles L. Assimes
Journal: Genome biology (2016)

Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
The clinical implication of comprehensive geriatric assessment in elderly Korean cancer patients receiving systemic chemotherapy.
Authors: D. Shin, Y. Kim, K. Lee, J. Kim, K. Kim, S. Bang, J. Lee, C. Kim
Journal: Journal of Clinical Oncology (2010)

e19562 Background: There are few prospective evaluation of toxicity and functional consequence of systemic chemotherapy in the elderly cancer patients, especially in Asian population. Methods: We prospectively enrolled elderly cancer patients aged ≥ 65 yrs, receiving systemic chemotherapy between July 2006 and February 2008 at a community-based university hospital. We conducted the baseline and follow-up CGA at the time of first response evaluation (after 2∼3months), and analyzed the changes in ECOG performance status, activities of daily living (ADL), Instrumental Activities of Daily Living (IADL), Mini-Mental State Examination (MMSE), Short form Geriatric Depression Scale (SGDS), and Mini-Nutritional Assessment (MNA). Frequency of significant toxicity, defined as grade 4 hematologic toxicity, febrile neutropenia, early treatment withdrawal and hospitalization ≥ 7 days due to toxicity, were assessed and association between significant toxicity and each CGA parameter was analyzed by ANCOVA. Results: Out of 65 patients enrolled, 38 patients (median age: 69.5, 65-80) completed both assessments. The median number of cycles given was 6 (range 1-12), and chemotherapy was for adjuvant (7), curative (3) and palliative intent (28; 20 first-line, 8 ≥second-line). The relative dose intensity of chemotherapy was 0.8 (0.52–1.11). Significant decline was observed in ECOG performance status (p = 0.01), ADL and IADL (p<0.001 and p = 0.003), mental health status (MMSE; p<0.001), and nutritional status (MNA; p<0.001) after chemotherapy. Significant toxicity occurred in 9 patients (23.7%). Decline in MNA was the only CGA profile associated with occurrence of significant toxicity (p = 0.006). Conclusions: Our pilot study suggested that Asian elderly patients can tolerate systemic chemotherapy with low frequency of significant toxicity. Significant decline of physical, mental, and nutritional function was observed after chemotherapy and decline in nutritional status was the only predictor of significant toxicity.The careful follow-up of CGA parameters, especially nutritional status could be used to predict tolerance in elderly cancer patients receiving systemic chemotherapy. No significant financial relationships to disclose.
Mocetinostat (MGCD0103), An Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, Produces Clinical Responses In Relapsed/Refractory Hodgkin Lymphoma (HL): Update From a Phase II Clinical Study
Authors: Anas Younes, R. Gregory Bociek, John Kuruvilla, Pierre Laneuville, Henry C. Fung, Michel Drouin, Tracy Patterson, Jeffrey Besterman, Robert E. Martell
Journal: Blood (2010)
A Report On a Phase 2 Trial Of Combination Therapy With Lenalidomide and Azacitidine In Patients With Non-Del 5q, Low Risk MDS
Authors: Jamile M. Shammo, Kent W. Christopherson, Reem Karmali, Melissa L. Larson, Michelle Balla, Parameswaran Venugopal
Journal: Blood (2013)
Abstract 3207: Influence of tumor mutation burden on response to anti-PD-1 treatment in murine models of melanoma
Authors: Elena Galvani, Kate Hogan, Gabriela Gremel, Amaya Viros, Amit K. Mandal, Matthew Smith, Jacqueline Swan, Antonia Banyard, Garry Ashton, Nathalie Dhomen, Richard Marais
Journal: Cancer Research (2016)

Abstract Therapeutic antibodies directed against immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), have recently shown remarkable clinical benefits, particularly in metastatic melanoma and non-small cell lung cancer (NSCLC), cancers largely caused by chronic exposure to mutagenic agents. Recent studies have focused on identifying genomic and immune predictors of response, but consistent, robust biomarkers have yet to be fully characterized. However, some data suggests a high non-synonymous tumour mutation burden is associated with clinical benefit in melanoma patients who received anti-CTLA-4 therapy. A similar correlation was also found in NSCLC patients treated with anti-PD-1. Using mouse models of BRAFV600E-driven melanoma, we examined the relationship between tumour mutation burden and response to the immune checkpoint inhibitor anti-PD-1. Chronic exposure to ultraviolet radiation (UVR) was used to increase the number of tumour non-synonymous single nucleotide variants (SNVs), and thus mutational load. Responses to PD-1 blockade were compared between tumours having low (∼10 SNVs) and high (&amp;gt;100 SNVs) mutation burden and tumours were subsequently subjected to comprehensive molecular and immune profiling using whole exome sequencing, immunohistochemistry, and flow cytometry. Our initial data suggest there is no significant correlation between tumour mutation burden and response in our model of BRAFV600E-driven melanoma, and we will present a detailed analysis of low- and high-mutation burden tumours in light of their response to PD-1 blockade. Consistent with previous studies, our results highlight that integrated molecular characterization of tumour tissue and associated microenvironment in larger cohorts is needed to identify robust determinants of response to immune checkpoint inhibitors. Citation Format: Elena Galvani, Kate Hogan, Gabriela Gremel, Amaya Viros, Amit K. Mandal, Matthew Smith, Jacqueline Swan, Antonia Banyard, Garry Ashton, Nathalie Dhomen, Richard Marais. Influence of tumor mutation burden on response to anti-PD-1 treatment in murine models of melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3207.