tbuckley/cabot-search huggingface dataset:
Abstract 5408: RNA fusion detection in thyroid nodules with a targeted RNA sequencing panel
Authors: Song Tian, Michelle Baird, Frank Reinecke, Jixin Deng, Mohammad Nezami Ranjbar, Raed Samara, Eric Lader
Journal: Cancer Research (2017)

Abstract Thyroid nodules are quite common and detected in as high as 67% of the population. Only a small portion of thyroid nodules are malignant thyroid cancers. Advances in understanding the molecular pathology of thyroid cancer are leading to the development of better biomarkers and novel targeted therapies. The tumorigenic role of RNA fusions has been reported in many forms of cancer. Fusions can result from structural rearrangements like translocations and deletions, transcription read-through of neighboring genes, or the trans- and cis-splicing of pre-mRNAs. Many fusions act as key drivers for cancer development. Detection of fusion RNA is a challenge with traditional technologies like FISH and qPCR, as they are laborious, low throughput, and do not provide detailed information about the fusion. Here we explored the possible use of a tumor fusion-targeted RNA-based panel (QIAseq targeted RNAscan panel, which is targeting 223 fusion gene pairs, 576 unique fusions) as a tool to study fusions in thyroid nodules. The presence of these fusions were surveyed in RNA samples from 10 thyroid cancer (PTC and FVPTC) samples and 19 non-cancer control samples (NH and FA) using this oncology targeted panel and sequenced on the Illumina NextSeq. PAX8-PPARG, a fusion gene with a well-established link to thyroid cancer, was found in the cancer group. In addition, we observed a universal expression of a recurrent read-through transcript, HALC1-COQL, in all thyroid nodules. Our results suggest that a targeted RNA-based panel provided a useful tool for fusion gene study in thyroid cancer. The role of the expected rearrangement and the unexpected read-through fusion in thyroid nodules needs to be further evaluated, as it could provide useful information for thyroid nodule differentiation. Citation Format: Song Tian, Michelle Baird, Frank Reinecke, Jixin Deng, Mohammad Nezami Ranjbar, Raed Samara, Eric Lader. RNA fusion detection in thyroid nodules with a targeted RNA sequencing panel [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 5408. doi:10.1158/1538-7445.AM2017-5408
Abstract LB-172: Chemotherapy impact on the gut microbiota: clinical trial on patients
Authors: Cindy Pensec, Alessandra De Martino, Laure-Anne Serres, Yao Amouzou, Sebastien Leuillet, Mario campone, Thomas Carton, Françoise LE VACON
Journal: Cancer Research (2017)

Abstract The French Consortium IMODI (Innovative MODels Initiative) aims to develop predictive preclinical mouse models for new chemotherapeutic treatment discovery, to progress toward personalized medicine. In this consortium, Biofortis Merieux NutriSciences issue is to better understand the relation between gut microbiota and cancer, particularly during chemotherapeutic treatment. Because chemotherapy can lead to disruption in microbiota composition and several side effects, our purpose is to identify and track the impact of chemotherapy treatment on the gut microbiota. To this aim, we coordinate a clinical study to recruit patients with four types of cancer (breast, ovary, liver and prostate) from 7 clinical centers. Gut microbiota composition is assessed by targeted metagenomic, from patient stool samples, collected before, during and after chemotherapy. The 16S rDNA sequences will be analyzed using an in-house bioinformatic pipeline based on mothur software. Interestingly, preliminary results from preclinical studies showed that some chemotherapeutic treatments could have an effect on gut microbiota composition associated with weight loss. These results support that microbiota is an important additional parameter for evaluating the efficacy and the toxicity of pharmacological treatments. The clinical study is ongoing to better understand the effect of chemotherapy on the gut microbiota. This approach may lead to beneficial intervention for cancer patients, particularly to minimize side effects and infectious complications. Note: This abstract was not presented at the meeting. Citation Format: Cindy Pensec, Alessandra De Martino, Laure-Anne Serres, IMODI consortium, Yao Amouzou, Sebastien Leuillet, Mario campone, Thomas Carton, Françoise LE VACON. Chemotherapy impact on the gut microbiota: clinical trial on 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 LB-172. doi:10.1158/1538-7445.AM2017-LB-172
Abstract 3144: Prediction of ALK mutations associated with acquired resistance to lorlatinib
Authors: Satoshi Yoda, Leila Dardaei, Manrose Singh, Jeffrey A. Engelman, Alice T. Shaw, Aaron N. Hata
Journal: Cancer Research (2017)

Abstract Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer. They are currently treated with the first-generation ALK inhibitor crizotnib followed by more potent, second-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib. We reported different spectrums of ALK resistance mutations in the biopsies from patients progressing on these drugs. G1202R mutation was found more frequently after treatment with second generation ALK inhibitors. In addition to these drugs, the third-generation ALK inhibitor lorlatinib is currently being evaluated in phase 2 clinical trial. Ba/F3 models indicated that all single ALK mutants are sensitive to lorlatinib and some compound ALK mutations are resistant to lorlatinib. In this study, we performed accelerated mutagenesis screen on Ba/F3 models to predict the resistance mutations which potentially emerge in the patients treated with lorlatinib. Briefly, Ba/F3 cells expressing wild type EML4-ALK or mutant EML4-ALK containing C1156Y, F1174C, L1196M, G1202R, or G1269A were exposed to N-ethyl-N-nitrosourea (ENU). After a 24-hour incubation in normal media, the cells were seeded in 96-well plates and incubated in lorlatinib for 4 weeks. ALK kinase domain was sequenced in clones growing in lorlatinib to identify possible new mutations. As a result, Ba/F3 cells harboring wild type EML4-ALK did not show any mutation on ALK kinase domain. Crizotinib was used as a control to validate the efficiency of mutagenesis. We identified eight different mutations in clones growing in crizotinib, and those were reflecting the spectrum of mutations in the crizotinib-treated patients. Ba/F3 cells with mutant EML4-ALK showed additional compound mutations after incubation with lorlatinib. Those mutations included L1196M + L1198F and G1202R + L1198F which showed high resistance to lorlatinib in Ba/F3 models. Ba/F3 cells with different mutant EML4-ALK showed a distinct spectrum and different frequency of additional mutations. In conclusion, this study predicted that no single mutation would emerge to confer resistance to lorlatinib. Thus, compound mutations and ALK-independent mechanisms become essential mechanisms for lorlatinib resistance. Citation Format: Satoshi Yoda, Leila Dardaei, Manrose Singh, Jeffrey A. Engelman, Alice T. Shaw, Aaron N. Hata. Prediction of ALK mutations associated with acquired resistance to lorlatinib [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 3144. doi:10.1158/1538-7445.AM2017-3144
Abstract 2762: The comparison of allogeneic stem cell transplantation outcomes between haploidentical donor and international donor: A retrospective multi-institutional study in Korea
Authors: Hyunkyung Park, Yoo Jin Lee, Sang-Jin Shin, Jayoun Lee, Inho Kim, Sung-Soo Yoon, Silvia Park, Hyewon Lee, Joonho Moon, Jun Ho Jang, Youngil Koh
Journal: Cancer Research (2017)

Abstract Introduction: The successful rate of hematopoietic stem cell transplantation (HSCT) from HLA-mismatched donor has been increased according to the development in management of complications including graft versus host disease (GVHD) and infections. Especially, haploidentical HSCT provides an opportunity for all patients who do not have HLA-matched sibling donor. Methods: In this study, we compared HSCT outcomes between haploidentical familiar donor and international donor (donors from Japan, China, Germany, Unites States of America and Taiwan) in acute leukemia patients. We reviewed the overall survival (OS), relapse free survival (RFS) and complications. Results: Total 142 acute leukemia patients performed HSCT from 2000 to 2016; 98 patients underwent haploidentical donor transplantation and 44 patients underwent international donor transplantation. Major variables such as age, sex, disease status and the number of CD34 stem cells were not statistically different between two groups. In survival analysis, there was no significant difference according to the donor-type. 1-year OS rate for haploidentical transplantation group was 44.1% and 52.3% for international transplantation group (p=0.345). 1-year RFS rate was 36.6% versus 40.9%, respectively (p=0.362). In addition, the incidence of complication events was similar between two groups. The acute GVHD in haploidentical group and international group were 42.9% and 43.2% (P=0.97), and the infection event within 30days after transplantation were 49.5% in haploidentical group and 34.1% in international group (p=0.09). The cumulative incidence of chronic GVHD was no significantly different (P=0.34), respectively. Conclusion: These data suggest that HSCT from haploidentital donor shows similar outcomes including survival outcomes and complications with international donor transplantation. Therefore, haploidentitial donor transplantation can be good choice for acute leukemia patients who have no HLA_matched sibling donor. Citation Format: Hyunkyung Park, Yoo Jin Lee, Sang-Jin Shin, Jayoun Lee, Inho Kim, Sung-Soo Yoon, Silvia Park, Hyewon Lee, Joonho Moon, Jun Ho Jang, Youngil Koh. The comparison of allogeneic stem cell transplantation outcomes between haploidentical donor and international donor: A retrospective multi-institutional study in Korea [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 2762. doi:10.1158/1538-7445.AM2017-2762
Abstract 2399: Metabolic and epigenetic targets in multiple myeloma therapy
Authors: Laure Maneix, Fu-Yuan Shih, Polina Iakova, Joanne I. Hsu, Andre Catic
Journal: Cancer Research (2017)

Abstract The dynamic interaction of transcription factors (TFs) with promoters and enhancers allows cells to continuously adjust gene expression. Whereas the composition and binding of TFs at genomic sites is the focus of a widespread research effort, relatively little is known about how these complexes are being removed. We previously devised a method to detect genomic locations that are associated with nuclear protein turnover mediated by the ubiquitin-proteasome system (UPS). Multiple myeloma, the second most common hematopoietic malignancy, has become a model disease for drugs that interfere with the UPS through either blocking or facilitating protein elimination. The proteasome inhibitor Velcade, for instance, has become first-line treatment in myeloma. Yet, our knowledge of how myeloma cells are killed by this drug is incomplete. Our research is focused on defining how proteolysis regulates transcriptional dynamics in this disease and how this impacts Velcade sensitivity. Following proteasome inhibition, we are utilizing next generation sequencing to identify sites of nuclear protein turnover and evaluate epigenetic changes. Our aim is to identify TFs and epigenetic marks that may qualify as more specific targets for treatment compared to blunt proteasome inhibition. Our findings reveal that certain TFs, including metabolic and cell growth regulators, are particularly sensitive to Velcade. Among these transcriptional regulators, the co-repressor NCoR1 plays a key role in controlling cell metabolism by adjusting mitochondrial gene expression. We are currently validating the mechanism of NCoR1 degradation, with a particular emphasis on the new role of its E3-ubiquitin ligase Seven in absentia 2 (Siah2) in mitochondrial regulation, to better understand how this degradation pathway impacts myeloma proliferation and metabolism. This research project will contribute to our understanding of epigenetic and transcriptional dynamics in multiple myeloma. With the focus on gene programs that are continuously adapting or changing, we seek to unlock new attractive targets for molecular therapy. Citation Format: Laure Maneix, Fu-Yuan Shih, Polina Iakova, Joanne I. Hsu, Andre Catic. Metabolic and epigenetic targets in multiple myeloma therapy [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 2399. doi:10.1158/1538-7445.AM2017-2399
Abstract LB-167: A novel metabolite of citrus tangeretin epigenetically inhibits the growth of human prostate cancer cells
Authors: Yen-Hsiang Chao, Zheng-Yuan Su
Journal: Cancer Research (2017)

Abstract Prostate cancer is the second leading cause of cancer death in men in the United States. Polymethoxyflavonoids (PMFs) such as tangeretin which exclusively exist in citrus fruit peels have been studied to have many bioactivities. In this study, we investigated the inhibitory effect of the metabolites of tangeretin in human prostate cancer LNCaP and PC3 cells. The results showed that PMF1 is a synthetic tangereitin metabolite can significantly inhibits the growth of LNCaP and PC-3 cells (IC50 14.0 and 13.5 µM, respectively) while PMF1 at 15 µM cannot affect the growth of human normal prostate epithelial RWPE-1 cells. The results of the anchorage-independent growth analysis indicated that PMF1 can suppress the colony formation in LNCaP and PC-3 cells as well as LNCaP and PC-3 stem-like cells which were isolated when the parent cells were cultured in the serum-free medium on the ultra-low attached dishes. Furthermore, PMF1 can induce apoptosis in LNCaP cells in which PMF1 increases protein expressions of Bax and Bad and decreases protein expressions of procaspases-3 and Bcl-2. We also found that PMF1 also decreases the protein levels of DNA Methyltransferase 1 and histone deacetylases 1, 2, and 4/5/9. These results suggested that PMF1 might effectively inhibit the growth of human prostate cancer cells as well as prostate cancer stem cells, which provides new insights in the prevention and treatment of prostate cancer. Citation Format: Yen-Hsiang Chao, Zheng-Yuan Su. A novel metabolite of citrus tangeretin epigenetically inhibits the growth of human prostate 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 LB-167. doi:10.1158/1538-7445.AM2017-LB-167
Abstract 2938: Tumour-associated macrophage polarisation and re-education with oncolytic viruses
Authors: Munitta Muthana, Emer Murphy, Amy Kwan, Natalie Winder, Joe Conner
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages (TAMs) promote key processes in tumour progression through their plasticity and capacity to become polarised by tumours to have an immunosuppressive phenotype. However, the plasticity of these cells provides an opportunity for therapeutic ‘reprogramming’ towards a classically activated inflammatory phenotype thus preventing tumour-associated immunosuppression and inducing anti-tumour immunity. Oncolytic viruses (OV) represent a new class of anti-cancer therapeutics that promote anti-tumour responses through selective tumour cell killing and the induction of systemic anti-tumour immunity. We propose that TAMs can be targeted using an OV, leading to altered macrophage polarization and a reduction in tumour growth and metastasis. Experimental Design: In-vitro, cytotoxicity, viral replication and cytokine expression was assessed in a panel of primary human and murine macrophages following exposure to Sephrevir, an ICP34.5-deleted oncolytic herpes-simplex virus currently in Phase 1/2a trials. In-vivo, murine TS1-PyMT cells were implanted into the mammary fat pads of female FVB mice to establish a syngeneic immunocompetent mouse model of breast cancer. Tumour growth and overall survival were assessed following administration of Sephrevir given either by intratumoural (I.T) or intravenous injection (I.V). Immune cell enumeration and protective immunity were assessed post-mortem by immunofluorescence and flow cytometry. Results: Both primary human and mouse macrophages served as a host for oncolytic viral replication. Sephrevir was also found to attenuate TAM phenotypes as evidenced by increased “M1” receptor signatures (e.g. CD40, CD80, CD86, MHC II), increased pro-inflammatory gene expression (e.g. IL-1, IL-6, IL-8, CXCL10, TNF-a) and increased nitric oxide production. I.T and I.V administration of Sephrevir led to marked tumour shrinkage as well as the recruitment of cytotoxic T cells. Moreover, TAM polarisation was evident based on a change in signature with TAMs becoming skewed to IL-12hi/IL-10lo and a change in the iNOS/arginase1 ratio. Conclusions: Our results demonstrate that Sephrevir is associated with in vivo anti-tumour effects and importantly can be used for manipulating the phenotype of the abundant macrophage population located within the tumour microenvironment. Citation Format: Munitta Muthana, Emer Murphy, Amy Kwan, Natalie Winder, Joe Conner. Tumour-associated macrophage polarisation and re-education with oncolytic viruses [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 2938. doi:10.1158/1538-7445.AM2017-2938
Abstract 5947: The <i>NCI Best Practices for Biospecimen Resources</i>: 2016 revised recommendations
Authors: Abhi Rao, Jim Vaught, Ping Guan, Carol Weil, Helen M. Moore
Journal: Cancer Research (2017)

Abstract Improved biospecimen handling practices are increasingly important for cancer research as advanced molecular analysis becomes routine in clinical trials and more frequently available in standard of care medicine. Biospecimens and associated clinical data collected in a consistent, established fashion can greatly facilitate cancer biomarker validation and development and validation of clinical diagnostic assays. In order to establish a set of guidelines to improve the quality of biospecimen-related research, the NCI’s Biorepositories and Biospecimen Research Branch developed the NCI Best Practices for Biospecimen Resources which includes technical recommendations on biospecimen handling as well as ethical and regulatory best practices. The 3rd, 2016 revised version of these Best Practices focused on updating technical and operational best practices with recommendations based on more recent research, guidance and standards for collecting, processing and storing biospecimens; revised informatics best practices; and updated ethical, legal and policy sections describing new developments on return of research results, informed consent for genomics research, data sharing, and community engagement. These Best Practices aim to help patients by improving the reproducibility of cancer research data. The NCI Best Practices are also foundational to the NIH Precision Medicine Initiative, part of which aims to establish the world’s largest research biobank that will support studies that utilize biospecimens from a cohort of one million individuals in the United States. Citation Format: Abhi Rao, Jim Vaught, Ping Guan, Carol Weil, Helen M. Moore. The NCI Best Practices for Biospecimen Resources: 2016 revised recommendations [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 5947. doi:10.1158/1538-7445.AM2017-5947
Abstract 5629: Modeling cyclophosphamide induced ovarian toxicity in a novel translational canine model
Authors: Puja Basu, Rebecca Egbert, Evan Pasternak, Brian Petroff, Nucharin Songsasen
Journal: Cancer Research (2017)

Abstract Reproductive failure following chemotherapy and/or ionizing radiation is a major adverse event, for which there are no established preventive measures. In previous studies, our laboratory has documented that the selective estrogen receptor modulator, tamoxifen (TAM) is effective in both prevention and reversal of ovarian toxicity from cyclophosphamide (CTX) in rodent models. To validate the effectiveness of this approach in a more relevant model system, we have developed a canine ovarian explant tissue model system. Dogs present with many cancers spontaneously and their pathology and treatment approaches mirror those of the human cancers. Thus, canine cancers and their treatments are excellent translational models for human diseases. Furthermore, dogs share the same environment as humans and have longer life spans than rodents. Our laboratory has recently established a dog ovarian explant tissue model system using fresh ovaries collected at the time of ovariohysterectomy. In the current study, we hypothesized that ovarian toxicity induced by CTX will be reduced by co-administration of TAM. Using this system, freshly prepared ovarian cortical tissue sections are cultured in the presence of TAM and CTX. Ovarian tissue viability is assessed by primordial and primary follicle morphometry, where the number of primordial, primary and apoptotic follicles were counted in 9 sections of 1 mm3 of ovarian cortical tissue from each dog, using CTX (at 0, 1 and 10µM) concentrations combined with TAM (0 and10µM). The number and percentage of each follicle was assessed. In addition, granulosa cells proliferation is assessed using bromodeoxyuridine (BrdU) incorporation. Further, we show that, as in women, anti-mullerian hormone (AMH) can be used as an indicator of follicle reserves in the dog, thereby establishing their use as an in-vivo monitoring system to test ovarian viability in future clinical studies. This study is intended to underpin a subsequent canine clinical trial testing TAM as a countermeasure against infertility from cancer treatment in dogs. Note: This abstract was not presented at the meeting. Citation Format: Puja Basu, Rebecca Egbert, Evan Pasternak, Brian Petroff, Nucharin Songsasen. Modeling cyclophosphamide induced ovarian toxicity in a novel translational canine model [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 5629. doi:10.1158/1538-7445.AM2017-5629