tbuckley/cabot-search huggingface dataset:
Abstract 3328: Protochadherin 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis
Authors: Xiaorong Zhou, Barrett L. Updegraff, Yabin Guo, Michael Peyton, Luc Girard, Jill E. Larsen, Xian-Jin Xie, Yunyun Zhou, Tae Hyun Hwang, Yang Xie, Jaime Rodriguez-Canales, Pamela Villalobos, Carmen Behrens, Wistuba I. Ignacio, John D. Minna, Kathryn A. O'Donnell
Journal: Cancer Research (2017)

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the efficacy of membrane proteins as therapeutic targets in human malignancies, we examined cell-surface receptors that may act as drivers of lung tumorigenesis. Here we report that Protocadherin 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in NSCLC tumors, and high expression of PCDH7 is associated with poor clinical outcome. PCDH7 overexpression synergizes with KRAS and EGFR to induce MAPK signaling and tumorigenesis. Conversely, PCDH7 depletion suppresses ERK activation, sensitizes cells to MEK inhibitors, and reduces tumor growth. PCDH7 potentiates ERK signaling by facilitating interaction of protein phosphatase PP2A with its potent inhibitor, the SET oncoprotein. By establishing a previously unanticipated oncogenic role for PCDH7 in lung tumorigenesis, these results provide proof-of-concept support for the development of novel therapies that target PCDH7 at the cell surface of NSCLC cells. Experiments to evaluate the role of Pcdh7 in Kras-mediated lung tumorigenesis in vivo using autochthonous mouse models, which we expect to lend further support for therapeutic targeting of this protein, are in progress. Citation Format: Xiaorong Zhou, Barrett L. Updegraff, Yabin Guo, Michael Peyton, Luc Girard, Jill E. Larsen, Xian-Jin Xie, Yunyun Zhou, Tae Hyun Hwang, Yang Xie, Jaime Rodriguez-Canales, Pamela Villalobos, Carmen Behrens, Wistuba I. Ignacio, John D. Minna, Kathryn A. O'Donnell. Protochadherin 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis [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 3328. doi:10.1158/1538-7445.AM2017-3328
Abstract SY32-04: About Chomsky, patterns, and noncoding RNAs cancer therapeutics
Authors: George A. Calin
Journal: Cancer Research (2017)

Abstract Resistance to therapy is an important issue in the treatment of cancer, responsible for many cancer-related deaths. Despites decades of research into overcoming this resistance, only modest advances have been made and the resistance mechanisms remain poorly understood. Although to date the most studied noncoding RNAs (ncRNAs) are miRNAs, the importance of long noncoding RNAs (lncRNAs) in cancer is increasingly being recognized. Here we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges. We are further presenting a novel strategy to identify new therapeutic ncRNA targets by using Chomsky-type grammars based on combinatorial use of coding and noncoding RNAs. Citation Format: George A. Calin. About Chomsky, patterns, and noncoding RNAs cancer therapeutics [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 SY32-04. doi:10.1158/1538-7445.AM2017-SY32-04
Abstract 2954: The role of hedgehog signaling in breast cancer progression through macrophage polarization
Authors: Ann Hanna, Lalita A. Shevde
Journal: Cancer Research (2017)

Abstract The tumor microenvironment is comprised of stromal cells that constantly crosstalk with the cancer cells. Stromal cells, specifically tumor infiltrating immune cells, secrete cytokines and chemokines that regulate host responses to cancer through tumor-suppressing or tumor-promoting mechanisms. Macrophages within the tumor microenvironment are very plastic and can modulate different functions that promote tumor growth or tumor suppression, depending on their phenotype. Classically activated macrophages (M1) suppress tumor growth by mounting a pro-inflammatory immune response; while alternatively activated macrophages (M2) promote tumor progression by inducing an anti-inflammatory response which suppresses immune system function. Hedgehog (Hh) signaling is essential for normal mammalian embryonic development by modulating vital functions such as cell proliferation, differentiation, and angiogenesis. Although the Hh signaling pathway is tightly controlled, it often is deregulated, thus promoting tumorigenesis and tumor progression. Aberrant Hh signaling has particularly been implicated in breast cancer progression and metastasis. In this project, we investigate the role of Hh signaling in polarizing cancer associated macrophages toward the tumor-promoting M2 phenotype in a breast cancer model. We have discovered that using small molecule inhibitors to inhibit Hh signaling attenuates the cytokine profile associated with M2 macrophages, while adding recombinant Hh ligand potentiates it. Our data thus far supports a role for Hh signaling in alternatively polarizing macrophages. We hypothesize that Hh inhibitors will reduce the abundance of M2 macrophages and prevent metastasis. Citation Format: Ann Hanna, Lalita A. Shevde. The role of hedgehog signaling in breast cancer progression through macrophage polarization [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 2954. doi:10.1158/1538-7445.AM2017-2954
Abstract 15: The Impact of Suboptimal Diet on Cardiovascular Disease Mortality in the United States
Authors: Ashkan Afshin, Patrick Sur
Journal: Circulation (2017)

Introduction: Poor dietary habits are an established risk factor to cardiovascular disease (CVD). Yet, the impact of suboptimal diet on CVD mortality in the US has not been systematically evaluated. Objective: To quantify the effect of suboptimal intake of 11 dietary factors (fruits, vegetables, nuts, whole grains, processed meat, sugar-sweetened beverages, seafood omega-3 fatty acids, polyunsaturated fatty acids, trans fatty acids, fiber, sodium) on CVD mortality by age and sex in the US in 2015. Methods: Using the Global Burden of Disease study analytic framework, we conducted a comparative risk assessment analysis to estimate the number of CVD deaths attributable to 11 dietary factors in the US. We obtained data on intake of each dietary factor from the National Health and Nutrition Examination Survey. Etiologic effect sizes of each dietary factor on CVD endpoints were obtained from the most recent meta-analyses of prospective observational studies. Optimal level of intake was determined based on the level associated with the lowest risk of mortality in cohort studies. Results: In 2015, suboptimal diet accounted for 222,100 (95% UI: 189,500-252,800) CVD deaths among men and 193,400 (95% UI: 161,100-226,100) CVD deaths among women in the US. Low intake of nuts (100,460 [59,690-148,480] CVD deaths; 11.6% of CVD deaths), low intake of vegetables (99,530 [45,370-161,100]; 11.5%), low intake of whole grains (89,670 [(52,300-132,980], 10.4%) and high intake of sodium (77,260 [22,760-169,690], 9%) were the leading dietary risk factors for CVD mortality in the US (Figure). Conclusion: Our results highlights the need for implementation for evidence-based policies to promote the intake of cardioprotective dietary factors in particular nuts, vegetables, and whole grains in the US.
Abstract 189: Development of peptidomimetic inhibitors of the <i>ERG</i> gene fusion product in prostate cancer
Authors: Xiaoju Wang
Journal: Cancer Research (2017)

Abstract Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides and derived peptidomimetics (EIPs) bound with high affinity and specificity leading to proteolytic degradation of ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other cancers. Citation Format: Xiaoju Wang. Development of peptidomimetic inhibitors of the ERG gene fusion product 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 189. doi:10.1158/1538-7445.AM2017-189
Abstract 157: Targeting distinct nodes of the PI3K/AKT/mTOR cascade in prostate cancer cells: impact on cell proliferation, apoptosis and pathway signaling
Authors: Rute B. Marques, Ashraf Aghai, Wendy Stam, Wytske M. van Weerden
Journal: Cancer Research (2017)

Abstract Inactivation of the PTEN gene is a common event in PCa, leading to activation of the PI3K/AKT/mTOR pathway and promoting PCa progression. Inhibitors targeting this pathway are currently being developed as anticancer agents. While recent clinical trials with mTORC1 inhibitors have shown limited single-agent efficacy in castration-resistant prostate cancer (CRPC), it is still not known whether targeting alternative nodes of the PI3K/AKT/mTOR cascade may improve response. The current study aimed to characterize the response of PCa cell lines to multiple inhibitors targeting the PI3K, AKT and mTOR nodes of the cascade and identify possible mechanisms of resistance. The impact of the different PI3K/AKT/mTOR inhibitors on cell proliferation and apoptosis was measured by WST-1 and ApoTox-Glo assays, respectively, in a broad panel of established PCa cell lines and primary cell cultures generated from patient-derived xenografts. PTEN-negative PCa cell lines showed strong response to PI3Kβ/δ, AKT and mTOR inhibition, whereas PTEN-positive cells were resistant to PI3Kβ/δ and showed variable sensitivity to mTOR inhibitors. MTORC1 inhibitor showed low IC50 but reached plateau at about 70-80% growth inhibition. In contrast, mTORC1/2 inhibitor could reach complete growth inhibition at ~1μM concentration, in sensitive cell lines. Furthermore, treatment with PI3K or AKT inhibitor in combination with androgen depletion induced apoptosis in various PTEN-negative models, which is consistent with previously reported synergistic effect of PI3K/AKT and androgen receptor co-targeting. The effect of the inhibitors on phosphorylation of PI3K downstream targets (AKT, PRAS40, GSK3, S6K1 and 4EBP1) was analyzed by phospho-specific western blotting. Perturbation of different nodes of the PI3K/AKT/mTOR cascade resulted in differential phosphorylation of downstream targets, but there was no evident correlation with in vitro growth inhibition. In conclusion, the current study validates PI3Kβ and AKT as alternative targets in PTEN-negative PCa, whereas PTEN-positive models showed preferential yet variable responses towards mTOR inhibitors. Citation Format: Rute B. Marques, Ashraf Aghai, Wendy Stam, Wytske M. van Weerden. Targeting distinct nodes of the PI3K/AKT/mTOR cascade in prostate cancer cells: impact on cell proliferation, apoptosis and pathway signaling [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 157. doi:10.1158/1538-7445.AM2017-157
Abstract 5152: Cancer stem cell targeted exosomes for the treatment of metastatic breast cancer
Authors: Golam Kibria, Katelyn E. Lee, Erika K. Ramos, Simo Huang, Clifford V. Harding, Jan Lötvall, Huiping Liu
Journal: Cancer Research (2017)

Abstract Introduction: Therapy resistance and metastasis remain the two biggest challenges of breast cancer that result in a majority of cancer deaths. Cancer stem cells (CSCs) are a subpopulation of cancer cells that can initiate new tumors, remain refractory to conventional therapies, and spread throughout the body. In order to effectively block metastasis, the present study aims to develop novel therapeutics that specifically target breast CSCs and spare normal cells. While nanomedicine represents one of the promising future directions, it is necessary to overcome the shortcomings of synthetic nanoparticles, including bio-instability and off-target toxicity. Here, we aim to bio-engineer the naturally produced cell-secreted small vesicles, exosomes (~100 nm diameter), for a novel therapeutic delivery system. Methods: Exosomes from the human mesenchymal stem cells (MSCs) were isolated by differential ultracentrifugation, and characterized by multiple approaches including transmission EM, Immunoblotting and immunofluorescence assays to confirm the size, shape and presence of exosomal markers CD63, CD81 and LAMP2B. Exosomes were engineered to express a peptide ligand on its surface to specifically recognize and target CSCs, and the presence of the ligand was confirmed by western blot, flow cytometry (FCM) and a super resolution confocal laser scanning microscopy (CLSM, Leica SP8). The CSC targeting efficiency of the exosomes was evaluated in vitro by FCM and CLSM. Further, the exosomes were loaded with microRNAs (miR-200, miR-30c), as one of the key factors that regulate breast CSC functions, by following a novel transfection technology. Results: The bio-engineered exosomes specifically target and internalize into the CSCs compared to normal cells with absent expression of the ligand-binding protein. The developed exosomes can effectively deliver candidate miRNAs into the recipient cells and knock down the genes important for functional CSCs. The in vivo targeting of CSCs and therapeutic applications of the exosomes using patient-derived human-in-mouse breast tumor xenograft models are underway. Conclusion: It is expected that exosome-based miRNA therapeutics will have high biocompatibility, low toxicity, high specificity, and promising efficiency in preclinical and clinical applications to reduce breast cancer metastasis and improve patient survival. Citation Format: Golam Kibria, Katelyn E. Lee, Erika K. Ramos, Simo Huang, Clifford V. Harding, Jan Lötvall, Huiping Liu. Cancer stem cell targeted exosomes for the treatment of metastatic 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 5152. doi:10.1158/1538-7445.AM2017-5152
Abstract 3719: Bicyclic peptides for PET imaging of MT1-MMP expressing tumors
Authors: Daniel Teufel, Helen Harrison, Spencer Campbell, Catherine Stace, Edward Walker, Robert J. Lutz, Peter Park, Matthias Eder, Ulrike Bauder-Wüst, Ursula Schierbaum, Karin Leotta, Klaus Kopka, Uwe Haberkorn
Journal: Cancer Research (2017)

Abstract The Bicycle® technology is based on repertoires of short peptides displayed on the surface of bacteriophages which can be modified with homo-trifunctional organochemical scaffolds, thus creating large diverse libraries of constrained, bicyclic peptides. These large combinatorial libraries have been extensively used for iterative selections to identify high affinity binding peptides to a wide array of targets, including receptors, interleukins and proteases. Bicyclic peptides are chemically synthesized macrocyclic entities with drug-like properties that exhibit sub-nanomolar affinities and exquisite selectivity towards targets. Unlike biologics, their synthetic nature allows facile modulation of metabolic and pharmacokinetic properties, as well as site-specific conjugation to effector molecules such as fluorophores, radionuclides, and cytotoxic drugs. In the present work, novel phage display derived bicyclic peptides were identified targeting the matrix metalloproteinase 14 (also known as MT1-MMP), a tumor associated surface protein overexpressed in a variety of cancers (i.e. lung, breast). A prototype bicyclic peptide with high affinity to MT1-MMP (Kd at ~1 nM) was identified, and confocal microscopy using fluoresceinated bicyclic peptide derivatives shows target-dependent internalisation in MT1-MMP+ cells. In the in vivo mouse, selective tumor binding in an MT1-MMP+ xenograft model is demonstrated for a DOTA conjugate loaded with Ga-68 or Lu-177. Upon proteolytic optimization of the prototype bicycle peptide, a striking enhancement in tumor signal is observed in biodistribution studies. Compared to radiolabeled antibodies directed against the same target, the lead compound showed fast background clearance (&amp;lt; 1 %ID/g for all organs apart from kidneys) resulting in high imaging contrast in µPET studies as early as 30 minutes post injection. Importantly, most of the non-tumor associated bicyclic peptide rapidly clears into the bladder. Together, tumor targeting bicyclic peptides can, through their small size and high selectivity, facilitate efficient penetration and visualization of tumors in vivo, demonstrating their potential as diagnostic imaging agents in profiling and therapeutic management of patients. Citation Format: Daniel Teufel, Helen Harrison, Spencer Campbell, Catherine Stace, Edward Walker, Robert J. Lutz, Peter Park, Matthias Eder, Ulrike Bauder-Wüst, Ursula Schierbaum, Karin Leotta, Klaus Kopka, Uwe Haberkorn. Bicyclic peptides for PET imaging of MT1-MMP expressing tumors [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 3719. doi:10.1158/1538-7445.AM2017-3719
Investigating palpitations: the role of Holter monitoring and loop recorders
Authors: Charbel Abi Khalil, Fadi Haddad, Jassim Al Suwaidi
Journal: BMJ (2017)

#### What you need to know A 62 year old man complains of palpitations four times in the last week. He felt his heart beating very fast and was short of breath. Symptoms were variable in their timing and duration, however two episodes followed alcohol intake. On direct questioning, he did not have chest pain or syncope. He is on amlodipine for hypertension. On examination, his blood pressure is 160/90 mm Hg; his heart rate is regular at 82 beats/ min. Heart sounds and respiratory examination are normal. Palpitations are a common presentation in primary care and can be distressing. In a patient presenting with palpitations, note the type and severity of symptoms, the timing of palpitations, and comorbid medical conditions. Suggestions for history and examination are in box 1. #### Box 1: What to consider in history and examination for palpitations
Abstract 4284: Gate keeping role for endometrial cancer about Lynch syndrome by surgeon
Authors: Min Kyu Kim, Min Jung Kwon, Min Jeong Yun
Journal: Cancer Research (2017)

Abstract Background: It is well known that Lynch syndrome increases risk of endometrial and colorectal cancer. There is not much study about detecting Lynch syndrome patient fast among Korean population by gynecologic oncology surgeon. We undertook this study to investigate this. Methods: A review of endometrial cancer patients who was counseled about Lynch syndrome in Department of Obstetrics and gynecology, Samsung Changwon Hospital by single surgeon was done. Clinical information was extracted from the medical record including age, family and personal history of cancer, immunohistochemistry(IHC), microsatellite instability test(MSI), and gene sequencing results. Risk management and posttest education after result were offered about risk reducing options and cascade testing for affected individual Results: App patient was 16.There were two germline mutations (both MSH2) (c.23C&amp;gt;T (p.Thr8Met), c.187delG (p.Val63*).Both were negative for MSH2 IHC, But no patient matched criteria of Amsterdam. Four variation of unknown significance (VUS) was found (Three MSH2 and One MLH1).Among those all were abnormal in IHC and there was only one Amsterdam criteria matched patient. There were two unstable MSI patients, one was MSH2 germline mutation and the other was MSH2 VUS. Median age was 57(41~76).Most cases were endometrioid type (11/16, 69 %).Seventy five percent were stage I(12/16). Conclusion: Two MSH2 germline mutation patients among this population was found. Gynecologic oncology surgeon can be adapted to develop the ability to assess and evaluate genetic risk among endometrial cancer. Citation Format: Min Kyu Kim, Min Jung Kwon, Min Jeong Yun. Gate keeping role for endometrial cancer about Lynch syndrome by surgeon [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 4284. doi:10.1158/1538-7445.AM2017-4284
Abstract 3149: Identification of genes associated with the cisplatin resistance in cervical cancer cells expressing E545K mutation
Authors: Wani Arjumand, Nicholas Jette, Jb McIntyre, Prafull Ghatage, Corinne M. Doll, Susan P. Lees-Miller
Journal: Cancer Research (2017)

Abstract The phosphatidylinositol-3 kinase (PI3K)/AKT/ mTOR signaling pathway is activated in several human cancers and activation is frequently mediated by “hotspot” mutations including E542K, E545K and H1047R in the PIK3CA gene. Approximately 30% of cervical cancer patients have the PIK3CA-E545K mutation. Cisplatin with radiotherapy (RT) is the standard treatment of cervical cancer world-wide, used in both the radical and post-operative adjuvant settings. However, details of the molecular mechanisms responsible for cisplatin resistance remain unclear. We previously reported PIK3CA mutation in patients with earlier stage (IB/II) cervical cancer was associated with poor survival (McIntyre et al. Gynecol Oncol. 2013, PMID:23266353), and in our recent study we observed that PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin or cisplatin plus RT and results in a more migratory phenotype than isogenic cell lines with wild type-PIK3CA. Moreover, these phenotypes are reversed by the PI3K inhibitor GDC-0941/Pictilisib (Wani et al. Oncotarget. 2016, PMID:27489350). The aim of the present study is to identify the expression of genes related to cisplatin resistance in cervical cancer cells engineered to express PIK3CA-E545K. Microarray analysis identified 161 genes that were up-regulated and 189 that were down-regulated in the cervical cancer cells stably expressing PIK3CA-E545K, some of which are involved in well-characterized mechanisms that could be relevant to cisplatin resistance. We are currently validating some of those genes by Real-time PCR that will help us to determine the mechanism of PIK3CA-E545K induced cisplatin resistance and enhanced migration in cervical cancer cells expressing PIK3CA-E545K and extending our in vitro findings to animal models. Together, our data will provide a useful basis for screening candidate targets for risk stratification and provide valuable information for potential targeted intervention in patients whose tumors harbor cisplatin-resistant molecular characteristics. Citation Format: Wani Arjumand, Nicholas Jette, Jb McIntyre, Prafull Ghatage, Corinne M. Doll, Susan P. Lees-Miller. Identification of genes associated with the cisplatin resistance in cervical cancer cells expressing E545K mutation [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 3149. doi:10.1158/1538-7445.AM2017-3149