tbuckley/cabot-search huggingface dataset:
Abstract 4359: Systematic approach to methylation biomarker development in chronic lymphocytic leukemia, breast and lung cancers
Authors: Tomasz K. Wojdacz, Iben Daugaard, Tina Kjeldsen, Henrik Hager, Thomasz Kristensen, Louise Kristensen, Michael B. Møller, Lise Lotte Hansen
Journal: Cancer Research (2017)

Abstract There is no doubt that testing for disease specific methylation changes can guide disease risk assessment, facilitate detection of the disease, support prognostication and personalization of treatment as well as guide post treatment patient care (1). Nevertheless, the use of methylation biomarkers in standard patient care is still marginal. Difficulties in implementation of methylation biomarker testing in standard in-vitro diagnostics are mainly attributed to challenges in establishment of the systematic approach allowing for efficient discovery and subsequent validation of clinical utility of potential disease specific methylation biomarkers. We have combined state-of-the-art genome wide methylation screening technologies (including: newest Illumina MethylationEPIC 850k BeadChip) enabling methylation biomarker discovery with the cost and time efficient locus specific technologies to streamline the development, validation and implementation of methylation biomarkers for clinical disease management. With the use of technologies that in an affordable fashion enable screening for genome wide methylation changes in a substantial number of clinical samples, we were able to discover clinically relevant disease specific methylation signatures e.g. in CLL. The high technical complexity of the genome wide screen technologies prevents them for being straightforward applicable in diagnostic settings. Thus we used techniques such as Methylation-Sensitive High Resolution Melting (MS-HRM) (2) to develop assays fulfilling the requirements for diagnostic applications. Subsequently, we evaluated the clinical relevance of the most promising biomarker candidates in chronic lymphocytic leukaemia, breast and lung cancers, using these assays (3, 4). Overall, our workflow allows fast and efficient validation of not only already existing biomarker candidates but also discovery of new disease specific methylation changes that show promise for clinical implementation. References: (1) Wojdacz TK. Expert Rev Mol Diagn. 2012 Jan;12(1):39-47 (2) for BLUEPRINT consortium, Nature Biotechnology, Vol. 34, Nr. 7, s. 726-737. (3) Daugaard I et al., Sci Rep. 2016 Oct 26;6:35807. (4) Wojdacz TK et al.. Breast Cancer Res. 2014 Feb 3;16(1):R17 Note: This abstract was not presented at the meeting. Citation Format: Tomasz K. Wojdacz, Iben Daugaard, Tina Kjeldsen, Henrik Hager, Thomasz Kristensen, Louise Kristensen, Michael B. Møller, Lise Lotte Hansen. Systematic approach to methylation biomarker development in chronic lymphocytic leukemia, breast and lung 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 4359. doi:10.1158/1538-7445.AM2017-4359
Abstract 5767: Ex vivo three-dimensional tumor growth assay: 3DX-TGA
Authors: Praveen Nair, Dileep Nair, Kaede Hinata, Cyrus Mirsaidi, Junjie Wu, Yong Hu, Brett M. Hall
Journal: Cancer Research (2017)

Abstract With a 7% likelihood of regulatory approval, oncology drug registration failure rates lead all therapeutic areas. Further complicating the drug development process, preclinical oncology models poorly reflect tumor tissue biology and produce a high level of false positive data. Yet, monocellular two-dimensional (2D) tissue culture remains the preferred platform for most laboratory preclinical studies. The popularity of 2D tissue culture was driven predominantly by fast and dependable proliferation of human tumor cells rather than alignment to the pathophysiology of human cancer. As a consequence of this artificial selection bias, many registered oncology drugs today are highly toxic with a propensity to attack any dividing cell (i.e., non-targeted). Fortunately, recent advances in genomics, metabolomics and immunology have aided in development of new targeted agents, many of which have achieved regulatory approval. Nevertheless, rational drug combinations and identification of clinically meaningful drug targets persist as major challenges in oncology, and each can be meaningfully addressed using more diverse and biologically relevant preclinical models. Ex vivo tumor tissue transplant models, such as patient-derived xenografts (PDX) offer greater model diversity and more faithfully reflect patient tumor genetics. However, cost and scalability barriers tend to limit widespread and practical model utility. In addition, there remains a strong selection bias for autocrine human tumors that can quickly adapt to a cross-species mouse host. As a practical alternative to PDX models, we established, serially propagated and molecularly characterized 300 ex vivo 3D (3DX) models spanning 15 tumor indications. Given patient tumor seeding success rates of over 95%, the 3DX-TGA model enabled diverse pharmacologic evaluation for the vast majority of cancer patient models attempted. After achieving sufficient tumor biomass, typically within 7 to 8 weeks, thirty-one drugs were screened for proliferation and viability endpoints over a three-log dose range. Resistance and sensitivity profiles mirrored population-based response rates for indication-aligned FDA-registered drugs. Taken together, the 3DX-TGA model represents a powerful preclinical ex vivo model that: (1.) more faithfully recapitulates human tumor biology, (2.) can be scaled at a fraction of time and cost compared to PDX models, and (3.) provide a superior screening platform for novel drugs and drug-drug combinations. Citation Format: Praveen Nair, Dileep Nair, Kaede Hinata, Cyrus Mirsaidi, Junjie Wu, Yong Hu, Brett M. Hall. Ex vivo three-dimensional tumor growth assay: 3DX-TGA [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 5767. doi:10.1158/1538-7445.AM2017-5767
Abstract 3385: Genomic landscapes of pulmonary sclerosing hemangioma
Authors: Seung-Hyun Jung, Min Sung Kim, Sun Shin, Mi-Ryung Han, Yu Jin Cho, So Youn Kim, Sug Hyung Lee, Yeun-Jun Chung
Journal: Cancer Research (2017)

Abstract Pulmonary sclerosing hemangioma (PSH) is a benign tumor that usually presents as a solitary, well-defined mass in the lung. The PSH predominantly affects females with a higher incidence in the Far East. Histologically, the tumor cells in PSH consist of two cell types (cuboidal epithelial and polygonal stromal cells). Immunohistochemical and ultrastructural studies have identified that both cells are derived from undifferentiated respiratory epithelium that is the histologic origin of lung adenocarcinoma as well. Previous studies have shown that PSH and adenocarcinoma in the lung share some immunohistochemical and genetic features. However, as for somatic mutations, whereas many driver genes for lung adenocarcinomas have been identified, there have not been any candidate driver mutations identified in PSHs, except for low frequency mutations in β-catenin and TP53. Frequent somatic mutations identified in lung adenocarcinomas such as KRAS and EGFR have not been detected in PSH, suggesting that genomic alterations of these two lung tumors might be different from each other. Also, there is no evidence of PSH progression to lung cancers. These earlier data indicate that despite the common cellular origin of PSH and lung adenocarcinoma, genetic mechanisms for their development may be different. Based on the established concept that PSH is a true tumor, we hypothesize that it may harbor somatic mutations. In this study, we conducted whole exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and β-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent β-catenin mutations (overall 3/68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Since the AKT1 mutations were not found to co-occur with β-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be a single most common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas including a high rate of AKT1 mutation in PSHs. These genomic features of PSH discovered in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors. Citation Format: Seung-Hyun Jung, Min Sung Kim, Sun Shin, Mi-Ryung Han, Yu Jin Cho, So Youn Kim, Sug Hyung Lee, Yeun-Jun Chung. Genomic landscapes of pulmonary sclerosing hemangioma [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 3385. doi:10.1158/1538-7445.AM2017-3385
US doctor is shot dead after refusing to prescribe opioids
Authors: Owen Dyer
Journal: BMJ (2017)

A man whose wife was denied opioids for her claimed pain condition stalked and murdered the treating physician before killing himself in Mishawaka, Indiana, authorities have said.

Michael Jarvis, 48, shot and killed Todd Graham, 56, a physical medicine and rehabilitation specialist, hours after accompanying his wife to her first visit as a new patient. Petra Jarvis had asked Graham to prescribe opioids, but he refused, telling her that he did not believe them to be an appropriate treatment for most chronic pain, said Ken Cotter, St Joseph County prosecutor.

“He did what we ask our doctors to do,” said Cotter at a news conference. “Don’t overprescribe opioids.” Police …
Obesity and adverse breast cancer risk and outcome: Mechanistic insights and strategies for intervention
Authors: Manuel Picon‐Ruiz, Cynthia Morata‐Tarifa, Janeiro J. Valle‐Goffin, Eitan R. Friedman, Joyce M. Slingerland
Journal: CA A Cancer Journal for Clinicians (2017)

Abstract Answer questions and earn CME/CNE Recent decades have seen an unprecedented rise in obesity, and the health impact thereof is increasingly evident. In 2014, worldwide, more than 1.9 billion adults were overweight (body mass index [BMI], 25‐29.9 kg/m 2 ), and of these, over 600 million were obese (BMI ≥30 kg/m 2 ). Although the association between obesity and the risk of diabetes and coronary artery disease is widely known, the impact of obesity on cancer incidence, morbidity, and mortality is not fully appreciated. Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. The first part of this review summarizes the relationships between obesity and breast cancer development and outcomes in premenopausal and postmenopausal women and in those with hormone receptor‐positive and ‐negative disease. The second part of this review addresses hypothesized molecular mechanistic insights that may underlie the effects of obesity to increase local and circulating proinflammatory cytokines, promote tumor angiogenesis and stimulate the most malignant cancer stem cell population to drive cancer growth, invasion, and metastasis. Finally, a review of observational studies demonstrates that increased physical activity is associated with lower breast cancer risk and better outcomes. The effects of recent lifestyle interventions to decrease sex steroids, insulin/insulin‐like growth factor‐1 pathway activation, and inflammatory biomarkers associated with worse breast cancer outcomes in obesity also are discussed. Although many observational studies indicate that exercise with weight loss is associated with improved breast cancer outcome, further prospective studies are needed to determine whether weight reduction will lead to improved patient outcomes. It is hoped that several ongoing lifestyle intervention trials, which are reviewed herein, will support the systematic incorporation of weight loss intervention strategies into care for patients with breast cancer. CA Cancer J Clin 2017;67:378–397. © 2017 The Authors. CA A Cancer Journal for Clinicians published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Abstract 2558: MYC-dependent transformation model of triple-negative breast cancer in vivo
Authors: Corey Lourenco, Manpreet Kalkat, Dharmesh Dingar, Jason De Melo, Rosemary Yu, Linda Penn
Journal: Cancer Research (2017)

Abstract Recent comprehensive breast cancer studies examining mutations and genomic alterations have determined that deregulation of MYC and the PI3K pathway occur frequently during breast cancer progression and may be useful targets for therapy. As a result, there have been large efforts to develop PI3K, AKT and mTOR inhibitors (PAM inhibitors) for clinical use, however clinical trial data demonstrates that many patients treated with PAM inhibitors develop resistant disease. An alternative strategy would be to target Myc, though a lack of effective and specific inhibitors makes this difficult. To identify the core vulnerabilities in these cancers we developed an in vivo xenograft model of triple-negative breast cancer driven by deregulated PI3K signaling and MYC. We hypothesize that determining how these pathways co-operate to transform normal human breast cells into breast carcinomas will reveal a tumor progression signature and highlight new therapeutic opportunities. We developed our model using the spontaneously immortalized, basal, triple-negative MCF10A cell line. By expressing the hotspot PIK3caH1047R protein alone in MCF10A cells (MCF10.H) in addition to MYC (MCF10.HM), we can model normal/early breast cancer and invasive ductal carcinoma respectively. This is the first in vivo human model of breast cancer dependent on MYC for transformation. When injected into female NOD-SCID mice, MCF10A.H cells form organized acinar ducts embedded in extracellular matrix. MCF10A.H ducts form with hollow lumen and a single layer of myoepithelial cells, recapitulating normal human breast histology. Alternatively, MCF10A.HM cells grow as high-grade carcinomas indicative of invasive disease. MCF10A.H benign growths and MCF10A.HM tumors remain basal-like and triple-negative by immunohistochemistry. Importantly, MCF10A.HM tumors are sensitive to MYC repression and therefore may be a suitable model to evaluate direct and indirect anti-MYC therapies. Having relevant human xenograft samples representing both normal and IDC tissue, we performed RNA-seq to identify a MYC-signature driving breast cancer transformation. Our current work will involve targeting the resulting MYC-driven pathways identified by RNA-seq to therapeutically target MYC in breast cancer. Citation Format: Corey Lourenco, Manpreet Kalkat, Dharmesh Dingar, Jason De Melo, Rosemary Yu, Linda Penn. MYC-dependent transformation model of triple-negative breast cancer in vivo [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 2558. doi:10.1158/1538-7445.AM2017-2558
Abstract 3145: Mechanisms of resistance to FGFR-targeted therapy in bladder cancer
Authors: Geoffrey A. Pettitt, Helen R. McPherson, Carolyn D. Hurst, Julie E. Burns, Olivia A. Alder, Matthew C. Dunning, Margaret A. Knowles
Journal: Cancer Research (2017)

Abstract Fibroblast growth factor receptor 3 (FGFR3) overexpression, point mutations or gene fusions are found in ~80% of non muscle-invasive and ~15% of muscle-invasive bladder cancer. FGFR inhibitors have entered clinical trials in advanced bladder cancer however, as with other targeted therapies, intrinsic and acquired resistance are expected to limit treatment efficacy. We have used an in vitro model to explore possible mechanisms of resistance. The urothelial cancer cell line RT112 expresses an FGFR3-TACC3 fusion protein and is sensitive to FGFR inhibition. Isogenic resistant cell lines, termed R1, R2 and R3, were derived by long-term culture of RT112 in the presence of the FGFR inhibitor PD173074. Compared to parental RT112, R1 and R2 show reduced proliferation and have a more mesenchymal morphology, decreased expression of FGFR3 and increased expression of N-cadherin. R3 has a faster growth rate, more epithelial morphology and lower N-cadherin expression than R1 and R2. The changes in morphology and gene expression between parental and resistant derivatives R1 and R2 were reversed when the resistant cells were cultured without PD173074 for 4 passages. Despite this, the cells retained their resistance when re-exposed to PD173074. Exome sequencing, RNA microarray analysis and phospho-receptor tyrosine kinase array data on the parental cells and resistant derivatives and will be presented. Our data suggests that diverse mechanisms of resistance occur following prolonged FGFR inhibition. Citation Format: Geoffrey A. Pettitt, Helen R. McPherson, Carolyn D. Hurst, Julie E. Burns, Olivia A. Alder, Matthew C. Dunning, Margaret A. Knowles. Mechanisms of resistance to FGFR-targeted therapy in bladder 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 3145. doi:10.1158/1538-7445.AM2017-3145
Abstract 3407: Side effects of BRAF inhibitors mimic RASopathies
Authors: Alicia Sfecci, Alain Dupuy, Monica Dinulescu, Catherine Droitcourt, Henri Adamski, Smail Hadj-Rabia, Sylvie Odent, Marie-Dominique Galibert, Lise Boussemart
Journal: Cancer Research (2017)

Abstract Recent advances in targeted anticancer therapies have substantially improved the prognosis of several cancers but they are not free of side effects. These side effects are, however, clearly distinct from those induced by classical cytotoxic chemotherapies, likely because targeted therapies are designed to interfere with specific oncogenic signaling pathways and not to inhibit cell proliferation in general. We, therefore, evaluated whether specific side effects of BRAF inhibitor therapies would resemble symptoms seen in patients with RASopathies, in which the MAPK pathway is affected and which includes Costello, Noonan and Cardio-Facio-Cutaneous syndromes. To this end, we collected a cohort of 18 patients with genetically confirmed RASopathies that were followed between 2012 and 2016 at the University Hospital of Rennes, France and that were evaluated based on their personal medical history and a clinical examination. Strikingly, RASopathy patients, particularly those with Cardio-Facio-Cutaneous syndrome, showed symptoms resembling those that we and others have previously seen in genetically characterized patients undergoing BRAF inhibitor treatment. These symptoms included keratosis pilaris, wavy hair, sparse eyelashes/eyebrows, poor hair growth, palmo-plantar hyperkeratosis in areas of pressure, verrucous papillomas, nevi efflorescence, and increased cancer risk. Nevertheless, BRAF-inhibitor treatment can also lead to side effects not typically found in patients with RASopathies, including acneiform dermatitis and vemurafenib-specific phototoxicity, which may even increase under a combined BRAF/MEK inhibition. These results suggest that the side effects of BRAF inhibition that are similar to symptoms in patients with RASopathies are due to direct targeting of the MAPK pathway in BRAF-non-mutated (wild type) cells while those that are dissimilar represent off-target effects that do not affect the MAPK pathway. We hope that this type of comparative analysis may lead to a better understanding of the multiple effects of targeted therapies and perhaps prompt modifications in the targeted therapy approach to minimize these side effects. Citation Format: Alicia Sfecci, Alain Dupuy, Monica Dinulescu, Catherine Droitcourt, Henri Adamski, Smail Hadj-Rabia, Sylvie Odent, Marie-Dominique Galibert, Lise Boussemart. Side effects of BRAF inhibitors mimic RASopathies [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 3407. doi:10.1158/1538-7445.AM2017-3407
Abstract 2171: Multi-CDK inhibition efficiently suppresses AR function and cell growth in prostate cancer
Authors: Brian W. Simons, Maria Ybanez, Emmanuel S. Antonarakis, Jun Luo, Barry D. Nelkin
Journal: Cancer Research (2017)

Abstract Metastatic castration resistant prostate cancer (CRPC) continues to result in over 26,000 deaths per year in the United States. For 70 years, therapy for advanced prostate cancer has relied on AR-directed therapies. Unfortunately, even with the second generation androgen deprivation compounds, treated cancers commonly progress to castration resistance and lethality. This progression to castration resistance remains the central therapeutic roadblock for advanced prostate cancer. Importantly, in the vast majority of CRPC cases, the tumor still depends on AR signaling, but this signaling becomes androgen independent. The most common mechanisms, including mutation, protein truncation, and alternative splicing, affect the C-terminal domain, suggesting that antagonism of AR function via the N-terminal domain may be a promising target for CRPC therapy. Several groups have shown that CDKs 1, 5 and 9 activate AR by phosphorylation of the N-terminal domain. Here, we show that the multi-CDK inhibitor roniciclib (BAY1000394) inhibits activation of AR in a panel of prostate cancer cell lines, including several cell lines which exhibit androgen-independent AR signaling via AR-V7 alternative splicing. In vivo, roniciclib inhibited growth of prostate cancer xenografts. Since AR inhibition in prostate cancer has been shown to induce compensatory PI3K signaling, we also treated xenografts with a combination of roniciclib and the PI3K inhibitor copanlisib (BAY 80-6946). This combination was especially effective, and was well tolerated by the mice. Our results suggest that a combination of a multi-CDK inhibitor and a PI3K inhibitor may be promising for CRPC therapy. Citation Format: Brian W. Simons, Maria Ybanez, Emmanuel S. Antonarakis, Jun Luo, Barry D. Nelkin. Multi-CDK inhibition efficiently suppresses AR function and cell growth in 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 2171. doi:10.1158/1538-7445.AM2017-2171