tbuckley/cabot-search huggingface dataset:
Abstract 4104: Intrinsic and acquired resistance to cetuximab in colorectal cancer patients
Authors: Steven M. Bray, Jeeyun Lee, Seung Tae Kim, Philip J. Ebert, John N. Calley, Isabella H. Wulur, Thejaswini Gopalappa, Swee Seong Wong, Hui-Rong Qian, Jason C. Ting, Jiangang Liu, Melinda D. Willard, Amit Aggarwal, Ruslan D. Novosiadly, Hee-Cheol Kim, Christoph Reinhard
Journal: Cancer Research (2017)

Abstract Anti-EGFR antibodies, such as cetuximab, are effective therapies for many late-stage colorectal cancer (CRC) patients; unfortunately, many tumors are initially unresponsive while others show initial efficacy but eventually develop acquired resistance. Genomic studies of patient tumors, cell lines, and xenograft models have identified putative anti-EGFR resistance markers, including mutations in KRAS, NRAS, BRAF, PIK3CA, and the EGFR extracellular domain, as well as amplifications in ERBB2 and MET. In order to further confirm and identify new resistance mechanisms to anti-EGFR treatment in CRC, we performed retrospective genomic profiling of 25 CRC patients treated at Samsung Medical Center from 2006-2015. Patients received cetuximab containing chemo regimens with varying duration of responses, including acquired resistance cases. Our analysis identifies mutations in receptor tyrosine kinases, such as EGFR, NTRK1, and PDGFRA, as well as RAS/MAPK pathway genes that affect cetuximab response. We also uncover genomic alterations in ERBB2 and c-KIT as potential novel mechanisms regulating sensitivity to anti-EGFR antibodies. Additional genomic analyses of acquired resistance tumors and in vitro studies of a patient-derived cell line provide added insights into clonal selection and signaling pathways that bypass the EGFR blockade. Overall, our study elucidates important new facets in the landscape of anti-EGFR resistance mechanisms. Note: This abstract was not presented at the meeting. Citation Format: Steven M. Bray, Jeeyun Lee, Seung Tae Kim, Philip J. Ebert, John N. Calley, Isabella H. Wulur, Thejaswini Gopalappa, Swee Seong Wong, Hui-Rong Qian, Jason C. Ting, Jiangang Liu, Melinda D. Willard, Amit Aggarwal, Ruslan D. Novosiadly, Hee-Cheol Kim, Christoph Reinhard. Intrinsic and acquired resistance to cetuximab in colorectal cancer patients [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 4104. doi:10.1158/1538-7445.AM2017-4104
Abstract 1537: 3p13-14FOXP1-SHQ1deletion spanning multiple potential tumor suppressor genes cooperates withPTENloss in cancer
Authors: Haley Hieronymus, Philip J. Iaquinta, John Wongvipat, Anuradha Gopalan, Rajmohan Murali, Ninghui Mao, Brett S. Carver, Charles L. Sawyers
Journal: Cancer Research (2017)

Abstract The recurrent 3p13-14 deletion spanning from FOXP1 to SHQ1 occurs frequently in prostate cancer and is broadly lost in a range of cancer types, but this deletion has unknown tumor suppressive potential. FOXP1-SHQ1 deletion significantly co-occurs with PTEN loss in prostate cancer and other cancers. We find that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate cancer development in mice, resulting in tumors with increased proliferation and highly anaplastic dedifferentiation. FOXP1-SHQ1 deletion in these PTEN null tumors results in selective mTORC1 pathway hyperactivation beyond that mediated by PTEN loss alone. FOXP1-SHQ1 deletion also partially rescues AR target gene inhibition caused by PTEN loss, circumventing the repression of the androgen axis seen upon PI3K pathway activation. Clinically, combined FOXP1 and PTEN loss is associated with increased prostate cancer recurrence, and this finding extends to other cancer types, most notably breast cancer. Citation Format: Haley Hieronymus, Philip J. Iaquinta, John Wongvipat, Anuradha Gopalan, Rajmohan Murali, Ninghui Mao, Brett S. Carver, Charles L. Sawyers. 3p13-14 FOXP1-SHQ1 deletion spanning multiple potential tumor suppressor genes cooperates with PTEN loss in 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 1537. doi:10.1158/1538-7445.AM2017-1537
Abstract 4481: Translation initiation factor DAP5 plays an essential role in translational control of breast cancer metastasis
Authors: Columba de la Parra, Amandine Alard, Amanda Ernlund, Robert J. Schneider
Journal: Cancer Research (2017)

Abstract Metastasis is the cause of 90% of cancer-related deaths. Selective mRNA translation has been found to be crucial for breast cancer development, progression and metastasis; however, there is a poor biological and mechanistic understanding of the role of translation in these processes. Our work and others have pioneered an understanding of translational regulation in breast cancer. We have previously shown that overexpression of initiation factor eIF4GI in advanced breast cancer cells selectively increases the translation of mRNAs encoding survival, cell cycle inhibition, and DNA damage and repair proteins, among other DNA damage-protective mRNAs. eIF4G consists of three family members: eIF4GI, eIF4GII, and the poorly studied eIF4G homolog, DAP5, the subject of this study. DAP5 lacks the N-terminal domain for eIF4E and PABP binding. DAP5 is therefore suspected to promote eIF4E-independent or IRES-driven translation of mRNAs involved in cell stress and oncogenesis, but its role in metastasis hasn’t been investigated. We analyzed the NCI human tissue genome cancer atlas (TCGA) and found that higher DAP5 mRNA expression is strongly associated with estrogen receptor negative breast cancer metastasis with lower overall survival. We then engineered a highly metastatic breast cancer cell line MDA-MB-231TR to express dox-inducible shRNA to DAP5 or a non-silencing (NS) control. Tumors were developed in clinically relevant orthotopic mouse models, with and without DAP5 silencing by addition of dox to the drinking water. Remarkably, reduction of DAP5 expression by ~70% had no impact on primary tumor growth but fully eliminated metastasis to the lung. Genome-wide transcriptome and translatome analysis of DAP5 and in vivo ultraviolet-crosslinking and high-throughput sequencing (HITS-CLIP) identified specific mRNAs that interact directly with DAP5. A significant fraction of DAP5 mRNA targets are involved in cell death and survival, cell proliferation, cell mobility, DNA repair and translation initiation and do not have IRESs, suggesting a novel role for DAP5 in a non-classical translation initiation process upon cellular stress and metastasis. Our results suggest that the translation initiation factor DAP5 likely plays a critical role in breast cancer metastasis by a unique mechanism for metastasis-specific translation initiation and provides new concepts for therapeutic strategies involving translational regulation. Citation Format: Columba de la Parra, Amandine Alard, Amanda Ernlund, Robert J. Schneider. Translation initiation factor DAP5 plays an essential role in translational control of breast cancer 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 4481. doi:10.1158/1538-7445.AM2017-4481
New Kid on the Block
Authors: Thomas Reinheckel
Journal: Theranostics (2017)

Cysteine cathepsins are a group of proteases involved in many physiological and pathological processes.Yet, the selective detection and inhibition of individual cathepsins is still challenging.This editorial is discussing the context of a recent work introducing a designed ankyrin repeat protein (DARPin) as novel approach for selective targeting of the protease cathepsin B.
Abstract 4652: Profiling of immunity biomarkers in whole blood
Authors: Alex Chenchik, Andrei Komarov, Michael Makhanov, Costa Frangou
Journal: Cancer Research (2017)

Abstract Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, significant number of patients do not respond to immunotherapy and responders often experience significant toxicities. Therefore, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of dynamic immunity mechanisms involved in cancer development. The genome-wide expression profiling of whole blood is an attractive method for the discovery of biomarkers due to its non-invasiveness, possibility for retrospective simple clinical site processing, and rich biological content. To this end, we have developed GeneNet, a genome-wide targeted RNA expression assay that profiles 19,000 genes based on multiplex RT-PCR followed by NGS in whole blood samples stabilized in PAXgene. The GeneNet 19K assay provides comprehensive and unbiased profiling of immune cell activation and canonical immune pathway genes for both innate adaptive and humoral immune responses. In this study, we present the performance of the assay for immunophenotyping of immune cells in blood samples from TNBC patients and assess the immune responses to complex immunomodulatory stimuli in ex vivo model system. Preliminary studies demonstrate the assay’s unparalleled specificity and sensitivity resulting in better detection of low abundance mRNA transcripts as well as an improved cost-effectiveness for high-throughput clinical applications. Citation Format: Alex Chenchik, Andrei Komarov, Michael Makhanov, Costa Frangou. Profiling of immunity biomarkers in whole blood [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 4652. doi:10.1158/1538-7445.AM2017-4652
All-Cause and Specific-Cause Mortality Risk After Roux-en-Y Gastric Bypass in Patients With and Without Diabetes
Authors: Michelle R. Lent, Peter N. Benotti, Tooraj Mirshahi, Glenn S. Gerhard, William E. Strodel, Anthony T. Petrick, Jon D. Gabrielsen, David D. Rolston, Christopher D. Still, Annemarie G. Hirsch, Fahad Zubair, Adam Cook, David J. Carey, G. Craig Wood
Journal: Diabetes Care (2017)

OBJECTIVE This study assessed all-cause and specific-cause mortality after Roux-en-Y gastric bypass (RYGB) and in matched control subjects, stratified by diabetes status. RESEARCH DESIGN AND METHODS RYGB patients were matched by age, BMI, sex, and diabetes status at time of surgery to nonsurgical control subjects using data from the electronic health record. Kaplan-Meier curves and Cox regression were used to assess differences in all-cause and specific-cause mortality between RYGB patients and control subjects with and without diabetes. RESULTS Of the 3,242 eligible RYGB patients enrolled from January 2004 to December 2015, control subjects were identified for 2,428 (n = 625 with diabetes and n = 1,803 without diabetes). Median postoperative follow-up was 5.8 years for patients with diabetes and 6.7 years for patients without diabetes. All-cause mortality was reduced in RYGB patients compared with control subjects only for those with diabetes at the time of surgery (adjusted hazard ratio 0.44; P &amp;lt; 0.0001). Mortality was not significantly improved in RYGB patients without diabetes compared with control subjects without diabetes (adjusted hazard ratio 0.84; P = 0.37). Deaths from cardiovascular diseases (P = 0.011), respiratory conditions (P = 0.017), and diabetes P = 0.011) were more frequent in control subjects with diabetes than in RYGB patients with diabetes. RYGB patients without diabetes were less likely to die of cancer (P = 0.0038) and respiratory diseases (P = 0.046) than control subjects without diabetes but were at higher risk of death from external causes (P = 0.012), including intentional self-harm (P = 0.025), than control subjects without diabetes. CONCLUSIONS All-cause mortality benefits of RYGB are driven predominantly by patients with diabetes at the time of surgery. RYGB patients with diabetes were less likely to die of cardiovascular diseases, diabetes, and respiratory conditions than their counterparts without RYGB.
Abstract 2599: COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis
Authors: Zbyslaw Sondka, Sally Bamford, Charlotte G. Cole, Elisabeth Dawson, Laura Ponting, Raymund Stefancsik, Sari A. Ward, John Tate, Peter J. Campbell, Simon A. Forbes
Journal: Cancer Research (2017)

Abstract The Cancer Gene Census is an ongoing effort to catalogue genes for which somatic mutations have been causally implicated in cancer. The Census comprises manually curated summaries of the most relevant information for cancer-driving genes and their somatic mutations and brings together the expertise of a dedicated curation team, cancer scientists and the comprehensive resources of the COSMIC database. Current research focuses on characterising the participation of 609 census genes in hallmarks of cancer and identification of additional genes involved in these biological traits primarily via altered expression, CNA or epigenetic changes. New overviews of cancer gene function focused on hallmarks of cancer pull together manually curated information on the function of proteins coded by cancer genes and summarises the data in simple graphical form. It presents a condensed overview of most relevant facts with quick access to the literature source, aiming to provide summary characteristics of a cancer gene, rather than a full monography, to avoid information overload. This functional characterisation enables the creation of lists of genes of interest focused on the particular role they play in the development of cancer, as well as aiming to identify the cellular functions affected by mutations in particular tumours, and help to choose right targets for targeted therapy or synthetic lethality experiments. The Census is available from the COSMIC website for online use or download at: http://cancer.sanger.ac.uk/census. Citation Format: Zbyslaw Sondka, Sally Bamford, Charlotte G. Cole, Elisabeth Dawson, Laura Ponting, Raymund Stefancsik, Sari A. Ward, John Tate, Peter J. Campbell, Simon A. Forbes. COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis [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 2599. doi:10.1158/1538-7445.AM2017-2599
A phase II study of atezolizumab as neoadjuvant and adjuvant therapy in patients (pts) with resectable non-small cell lung cancer (NSCLC).
Authors: Dwight Hall Owen, Paul A. Bunn, Bruce E. Johnson, David J. Kwiatkowski, Mark G. Kris, Ignacio Ivan Wistuba, Mayank Gandhi, See Phan, David S. Shames, Katja Schulze, Wei Yu, Dara Aisner, Jamie E. Chaft, Edward B. Garon, Jay M Lee, John D. Minna, Valerie W. Rusch, Karen L. Reckamp, Antoinette J. Wozniak, David P. Carbone
Journal: Journal of Clinical Oncology (2017)

TPS8580 Background: Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with early stage disease. Atezolizumab is a humanized IgG1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. In the OAK trial, a randomized phase III trial of patients with metastatic NSCLC who progressed on platinum based chemotherapy, atezolizumab improved overall survival in patients regardless of PD-L1 expression compared with docetaxel (13.8 months vs. 9.6 months, HR 0.73 [95% CI 0.62 – 0.87]) with a manageable safety profile. Methods: NCT02927301 is a phase II, open-label, single-arm study designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant and adjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. The study has two parts: the primary part will evaluate the ability of neoadjuvant atezolizumab to produce pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit in Part 1. The primary endpoint is major pathologic response rate (defined as ≤ 10% of viable tumor tissue) based on surgical resection. Secondary end points include overall response rate by status of mutation load, neoantigen score and gene expression signatures. OS and DFS are exploratory end points. This trial presents a unique opportunity to evaluate exploratory biomarkers given the availability of pre- and post-treatment biopsy specimens for assessment of evolution of immune related markers associated with response. The study opened to accrual in January 2017. Clinical trial information: NCT02927301.
Preliminary Safety and Clinical Activity in a Phase 1 Study of Blu-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis (SM)
Authors: Mark W. Drummond, Daniel J. DeAngelo, Michael W. Deininger, Deepti Radia, Albert Thomas Quiery, Elizabeth O Hexner, Hongliang Shi, Terri Alvarez-Diez, Erica K. Evans, Mary Ellen Healy, Beni B. Wolf, Srdan Verstovsek
Journal: Blood (2016)
Abstract 5528: The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene
Authors: Léon C.L. Van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas Papadakis, James Willmott, Richard Scolyer, Per-Henrik Edqvist, Fredrik Ponten, Dirk Schadendorf, Anke van Rjk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia Greenwood, G. Elias Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz
Journal: Cancer Research (2017)

Abstract Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesize that gene expression from gonosomes may play an important role. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit of two X-chromosomes. The gonosomal PPP2R3B gene is located on the pseudo-autosomal region (PAR) of the X-chromosome in females and on the Y-chromosome in males. We observed that despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression is lower in males than in females, and is independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate recognizing subunit of PP2A, that decreases melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction that delays the firing of origins of DNA replication. As such, PR70 behaves functionally as an X-linked tumor suppressor gene. Citation Format: Léon C.L. Van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas Papadakis, James Willmott, Richard Scolyer, Per-Henrik Edqvist, Fredrik Ponten, Dirk Schadendorf, Anke van Rjk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia Greenwood, G. Elias Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene [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 5528. doi:10.1158/1538-7445.AM2017-5528
Abstract 1123: Sphingolipids transfer proteins (GLTP and CPTP) regulate the neoplastic progression of colon and breast cancer cells
Authors: Shrawan K. Mishra, Rhoderick E. Brown
Journal: Cancer Research (2017)

Abstract Sphingolipids have previously been shown to affect cancer progression by regulating cell death (apoptosis) and survival (autophagy). While apoptosis is promoted by elevations in sphingosine and ceramide, increases in sphingosine-1-phosphate and ceramide-1-phosphate can tip the balance toward survival. Changes in the expression of sphingolipid transfer proteins such as GLTP (glycolipid transfer protein) and CPTP (ceramide-1-phosphate transfer protein) have been shown to modulate cell shape change and regulate pro-inflammatory cytokine release, respectively, in human cancer epithelial cell lines. To gain a better understanding of the situation, we investigated further. We discovered that GLTP overexpression inhibits the growth of human colon carcinoma cell lines (HT-29; HCT-116), but spares normal colonic epithelial cells (HCEC) largely due to growth arrest at the G0/G1 cell cycle checkpoint. Mechanistically, we found that GLTP overexpression modulated cell cycle progression by upregulating Kip1/p27 and Cip1/p21 protein and mRNA levels, while decreasing CDK2, CDK4, cyclin E and cyclin D1 protein levels. The cell cycle arrest and growth inhibition induced by GLTP overexpression led to apoptotic cell death of HT-29 cells. Neither GLTP nor CPTP overexpression induced apoptosis in breast cancer cell lines (T47D and HTB-126). However, depletion of CPTP, but not GLTP, induced autophagy as indicated by increased LC3 transcript and autophagosome levels (GFP-LC3-II puncta). In the breast cancer cell lines, increased transcript levels of cPLA2 and CERK were detected consistent with the earlier pro-inflammatory effect reported for CPTP depletion in A549 lung epithelial carcinoma cells. Our findings shed light on the mechanistic ways by which GLTP and CPTP affect apoptosis and autophagy to impact cancer progression. Future in vivo studies are planned to ascertain the role(s) of these new players in cancer development and therapy. [Support: NIH GM45928, HL-125353, Paint-the-Town-Pink (PTTP) Cancer Funds, Hormel Fdn] Citation Format: Shrawan K. Mishra, Rhoderick E. Brown. Sphingolipids transfer proteins (GLTP and CPTP) regulate the neoplastic progression of colon and breast cancer 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 1123. doi:10.1158/1538-7445.AM2017-1123