tbuckley/cabot-search huggingface dataset:
Abstract 4681: Histone deacetylase 3 inhibition overcomesBIMdeletion polymorphism-mediated osimertinib resistance inEGFR-mutant lung cancer
Authors: Azusa Tanimoto
Journal: Cancer Research (2017)

Abstract Purpose:The BIM deletion polymorphism is associated with apoptosis resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design:We used EGFR-mutated NSCLC cell lines which were either heterozygous or homozygous for the BIM deletion polymorphism to evaluate the effect of osimertinib in vitro and in vivo. Protein expression was examined by western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations. Conclusions:These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Note: This abstract was not presented at the meeting. Citation Format: Azusa Tanimoto. Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib resistance in EGFR-mutant lung 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 4681. doi:10.1158/1538-7445.AM2017-4681
Abstract 760: Detection of EGFR T790M mutation by ddPCR in untreated NSCLC patients: Correlation with clinical outcome
Authors: Monica Ganzinelli, Eliana Rulli, Elena Tamborini, Adele Busico, Giuseppe Lo Russo, Giulia Corrao, Milena Vitali, Marina Chiara Garassino, Massimo Broggini, Mirko Marabese
Journal: Cancer Research (2017)

Abstract Background: Activating EGFR mutations are associated with response to first generation tyrosine kinase inhibitors (TKI) that significantly increased PFS and OS in NSCLC patients. However, almost invariably, patients relapse while in treatment with TKI, mostly for the presence of EGFR T790M mutation. New second and third generation EGFR inhibitors active against T790M are now under development with very promising results. To date it is not known if the presence of T790M (and its amount) at diagnosis influences clinical outcome of patients with activating EGFR mutation. Methods: We analysed 50 cases with NSCLC. 48 patients harbour TKI sensitizing mutation in either exon 19 (N=24) or 21 (N=19). 2 EGFR wt patients (blinded to the investigator) were analysed in parallel. These patients were screened by ddPCR for the presence of T790M mutation using Biorad QX200 Droplet Digital PCR System. We used rough DNA extract from FFPE sections after deparaffinization and proteinase K digestion, as available in pathology unit for daily diagnosis. Results: 12 samples failed to amplify, maybe due to the poor quality of DNA. 13 samples produced results, but were excluded for the analysis because of too low number of calls retrieved. T790M mutation was detected in a significant proportion of remaining cases. Among the latter, 4 patients were sampled after TKI treatment and here the percentage of T790M were higher compared to those patients not treated [0.65% - 28% vs 0.019% - 1.65%, respectively]. One out four of these patients was not detected by routinely method of sequencing (Sanger or RT-PCR). T790M positive samples harboured mutations affecting exon 19 or 21 in equal manner. Conclusions: ddPCR has proven to be a sensitive method to detect T790M mutation, although the quality of DNA could affect the results. The system has been challenged for specificity an sensitivity and the results proved to be clinically relevant. The correlation between the T790M positivity and clinical outcome will be available and we plan to define a ddPCR threshold value which can help in selecting those patients who are likely to have early recurrence under first generation TKI and that could therefore be directly shifted to second or third generation inhibitors. Citation Format: Monica Ganzinelli, Eliana Rulli, Elena Tamborini, Adele Busico, Giuseppe Lo Russo, Giulia Corrao, Milena Vitali, Marina Chiara Garassino, Massimo Broggini, Mirko Marabese. Detection of EGFR T790M mutation by ddPCR in untreated NSCLC patients: Correlation with clinical outcome [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 760. doi:10.1158/1538-7445.AM2017-760
Abstract 2253: 5 Gene prognostic signature for dedifferentiated liposarcomas
Authors: Deanna Ng, Nicholas Shannon, Johnny Ong, Melissa Teo
Journal: Cancer Research (2017)

Abstract Introduction: Liposarcomas, despite being rare consist of a number of entities spanning low to high grade sarcomas. De-differentiated liposarcoma (DDLS) is associated with increased frequency of recurrence and lower overall survival. We aimed to identify gene expression changes associated with OS in DDLS. Secondary aims was to postulate a mechanism for DDLS. Methods: We analysed data from gene expression omnibus (GEO, ID = GSE30929) to identify genes associated with DDLS (n=39). A signature representing genes overexpressed in DDLS was then applied to an independent dataset, utilising data from The Cancer Genome Atlas (TCGA, n=58 DDLS) to segregate samples based on gene expression and groupings compared for survival. Results: A 5 gene signature was generated consisting of genes with increased expression in DDLS and its relation to OS. The signature was significantly enriched for genes involved in lipid metabolism (AQP7, PRKAR2B, FABP4 p&amp;lt;0.01) and genes involved in the cell cycle and cell proliferation (FBN2, CEBPA p&amp;lt;0.01). Segregation of DDLS in the TCGA cohort on the basis of median gene signature score gave a significant difference in overall survival. High score (stronger DDLS signature) was associated with a lower median survival(33.5 vs 76.4 months, p = 0.027), and poorer 2 year (63.4% vs 89.2%) and 5 year survival (20.6% vs 71.1%). The survival difference remained significant when applied to retroperitoneal DDLS only (n=51, median survival 34.5 vs 54.2 months, p = 0.034) and poorer 2 year survival (. A postulated mechanism is that DDLS have gained deficiency in AQP7, PRKAR2B and FABP4 leading to fatty acid and glycerol accumulation in cells, increasing cancer cell replication. CEBPA inhibits CDK4 and a deficiency of CEBPA in DDLS leads to up regulation of CDK4, increasing cell proliferation. An upregulation of FBN2 in DDLS up regulates TGF-β1, increasing cell proliferation. Conclusion: Gene expression changes associated with dedifferentiated liposarcomas include changes in cell cycle checkpoint regulation. The signature is associated with poorer overall survival in DDLS and can be used to prognosticate patients. Citation Format: Deanna Ng, Nicholas Shannon, Johnny Ong, Melissa Teo. 5 Gene prognostic signature for dedifferentiated liposarcomas [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 2253. doi:10.1158/1538-7445.AM2017-2253
Oncogenic KRAS and p53 Loss Drive Gastric Tumorigenesis in Mice That Can Be Attenuated by E-Cadherin Expression
Authors: Jacob E. Till, Changhwan Yoon, Bang-Jin Kim, Kerry Roby, Prince Addai, Evan Jonokuchi, Laura H. Tang, Sam S. Yoon, Sandra Ryeom
Journal: Cancer Research (2017)

Gastric adenocarcinoma is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases that are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of gastric adenocarcinoma tumorigenesis based on
Abstract 5010: Activation of the notch signaling pathway confers a tumor-suppressive phenotype on melanoma-associated fibroblasts
Authors: Hongwei Shao, Mecker G. Moller, Long Cai, Leiming Zhang, Zhao-Jun Liu
Journal: Cancer Research (2017)

Abstract Objectives. The tumor microenvironment (TME) is an emerging therapeutic target for cancer treatment. Cancer-associated fibroblasts (CAF) play a crucial role in cancer progression. We aim to target TME by altering intracellular signaling which determines the biological function of CAF. We have recently showed that the Notch signaling pathway likely functions as a molecular switch in controlling the tumor regulatory role of CAF in animal models and experimentally created “CAF”. Here, we investigated the status of Notch signaling in human melanoma-associated fibroblasts (MAF) versus their normal counterparts and tested whether manipulation of the Notch pathway activity in MAF alter their tumor-regulating function. Methods. We examined levels of Hes1, a canonical Notch target, in MAF of human malignant melanoma at different stages (I-IV) and fibroblasts in either adjacent or non-adjacent normal skin tissues using tissue microarray. MAF were isolated from human metastatic melanoma tissues. Notch pathway RT2-PCRArray and immunoblot were used to assess Notch pathway activity in MAF versus normal human dermal fibroblasts. Activation of Notch signaling pathway in MAF was achieved by lentiviral vector encoding active form of Notch1 (NIC). The effect of Notch1-engineered MAF on melanoma growth was tested by in vitro co-cultures and in a mouse co-xenograft model (n=6/group). Tumor angiogenesis was analyzed by immunochemistry. Results. MAF expressed decreased levels of Hes1 compared with adjacent skin fibroblasts. Isolated MAF also exhibited lower Notch activity than normal human dermal fibroblasts. Notch1-engineered MAF significantly inhibited melanoma cell growth in vitro (p&amp;lt;0.01) and suppressed melanoma growth and tumor angiogenesis in mice (p&amp;lt;0.05). Conclusions. Notch pathway activity is down-regulated in MAF. Increase of Notch pathway activity confers MAF with inhibition to melanoma growth and tumor angiogenesis. Our study demonstrates that Notch signaling is a critical molecular switch in determining the tumor regulatory role of MAF and provides potential targets for cancer therapeutic interventions on the TME. Citation Format: Hongwei Shao, Mecker G. Moller, Long Cai, Leiming Zhang, Zhao-Jun Liu. Activation of the notch signaling pathway confers a tumor-suppressive phenotype on melanoma-associated fibroblasts [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 5010. doi:10.1158/1538-7445.AM2017-5010
Abstract 5669: Targeting post-surgical breast cancer metastasis through combining natural killer T cell immunotherapy and low dose chemotherapy
Authors: Simon Gebremeskel, Kaitlyn Tanner, Lynnea Lobert, Brent Johnston
Journal: Cancer Research (2017)

Abstract Breast cancer is the most common cancer in Canadian women and the second leading cause of cancer deaths. Given that most mammary tumors are surgically resectable and over 90% of breast cancer-associated deaths are due to metastasis, new therapeutic strategies targeting metastasis are required. Natural killer T (NKT) cells are a rare population of immune cells that have been shown to limit primary tumor growth and target distant metastatic disease in various animal models. We have shown that NKT cell activation improves survival in a model of post-surgical metastatic breast cancer. We are now expanding this work to determine whether NKT cell activation can be combined with chemotherapies to improve outcomes. In our model, 4T1 mammary carcinoma cells were injected into the mammary fatpad of syngeneic BALB/c mice. Tumors were resected at day 12, and mice were treated with cyclophosphamide or gemcitabine. On day 17, NKT cells were activated by transfer of dendritic cells loaded with the glycolipid antigen α-GalCer. We also examined whether gemcitabine or mafosphamide (active component of cyclophosphamide) would induce immunogenic cell death of 4T1 cells in culture. Chemotherapeutics did not affect NKT cell activation as measured by serum IFNγ levels. Treatment with cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cells alone reduced metastasis and prolonged survival. Combined treatments significantly enhanced survival. NKT cell activation decreased the frequency and immunosuppressive function of myeloid derived suppressor cells (MDSCs). Treatments resulted in enhanced tumor specific immunity as surviving mice exhibited slower tumor growth following secondary tumor challenge. Gemcitabine and mafosphamide also increase the immunogenicity of cancer cells in vitro by increasing the exposure/release of MHCI, MHCII, CD1d, Calreticulin, HMGB1 and ATP. NKT cell activation therapy can successfully be combined with low doses of gemcitabine or cyclophosphamide to enhance protection against tumor metastasis and recurrence. This work provides a clear rationale for combining chemotherapy with NKT cell immunotherapy to target metastatic disease in the clinical setting. Citation Format: Simon Gebremeskel, Kaitlyn Tanner, Lynnea Lobert, Brent Johnston. Targeting post-surgical breast cancer metastasis through combining natural killer T cell immunotherapy and low dose chemotherapy [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 5669. doi:10.1158/1538-7445.AM2017-5669
Abstract 1678: A flow-based immunoprofiling strategy for interrogating system-wide leukocyte composition in response to glioblastoma
Authors: Gregory J. Baker, P.S. Thiagarajan, Sucheendra K. Palaniappan, Stephanie H. Davis, Jodene K. Moore, Peter K. Sorger
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is a deadly brain cancer that suppresses cellular immunity through the production of anti-inflammatory cytokines/catabolites, expression of immune checkpoint molecules, and induction of tolerogenic immune cell subsets. While preclinical models have shown each of these mechanisms to negatively impact survival outcome, it remains unclear how these distinct processes manifest themselves within the context of a coordinated immune system and whether additional immunosuppressive mechanisms exist. To address these questions, we have developed an extensible in vivo screening platform to holistically determine how GBM affects cellular immune organization. The method allows for temporal assessment of leukocyte population dynamics in response to tumor progression. Leukocytes derived from lymphoid tissues of tumor-bearing mice are isolated and immunolabeled with a 12-color optimized immunofluorescence panel (OMIP) targeting several major leukocyte lineages. Single-cell data is acquired by flow cytometry and is clustered in an unsupervised manner based on cell-surface protein expression. A vector-based classification system is then used to map phenotypically distinct clusters onto known immune cell lineages. The platform allows for the extraction of immune signatures whose divergence from tumor-naïve standards may be quantified and statistically analyzed; such signatures may also be correlated with response/resistance to therapy. The approach has been validated on orthotopic GL261 glioma in syngeneic C57BL6/J mice, yet it is readily amenable to the study of diverse model systems, including de novo tumors driven by clinically-relevant oncogenes. Alternative flow cytometry antibody panels may easily be substituted to probe more specific immune cell subsets of interest. Systems biology approaches applied to the field of tumor-induced immunosuppression hold promise in identifying novel network-level immune signatures, facilitating a better understanding of immunotherapeutic drug action, and driving next generation high-dimensional biomarker discovery. Citation Format: Gregory J. Baker, P.S. Thiagarajan, Sucheendra K. Palaniappan, Stephanie H. Davis, Jodene K. Moore, Peter K. Sorger. A flow-based immunoprofiling strategy for interrogating system-wide leukocyte composition in response to glioblastoma [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 1678. doi:10.1158/1538-7445.AM2017-1678
Abstract 3392: Genomic analysis of prostate cancer in Korean men
Authors: Se Song Jang, Min Jung Kim, Dong Wan Hong, Jae Young Joung, Sung Han Kim, Kang Hyun Lee, Weon Seo Park, Jong-Il Kim
Journal: Cancer Research (2017)

Abstract Prostate cancer currently has the fifth highest incidence rate in Korean males, and is the most common cancer in western males. Prostate cancer is the second most common malignancy in men worldwide, and is responsible for approximately 250,000 cancer-related deaths annually. The search for accurate biomarkers and characterization of prostate cancer is critical for evolution of accurate management of prostate cancer. Previous studies have identified that several genomic alterations in prostate cancer including TMPRSS2-ERG fusion, PTEN deletion and SPOP single nucleotide variants (SNVs), the majority of which are from western population. In order to investigate the somatic mutations of Korean prostate cancers, we performed whole exome sequencing on 51 prostate cancer patient’s tumor tissues, and matched normal tissue. For the accurate detections of structural variations, we additionally performed whole genome sequencing on 9 matched pairs (tumor, normal). A total of 738 somatic non-silent variants affecting 692 distinct genes were identified. In addition to already known genes such as SPOP, FOXA1, TP53 and PTEN, we also found previously uncharacterized genes such as GRIN2A, LRP1, FNDC1 and LRP1B. Of the 40 mutated genes across multiple cases, missense SNVs of SPOP (10/60 cases, 16.7%) were the most frequent, followed by missense and splice-site SNVs of GRIN2A (5/60 cases, 8.3%). Mutations in low-density lipoprotein-related protein encoded by LRP1 and LRP1B affected considerable portion of all cases (7/60, 11.7%), describe the probable relation between lipid metabolism and prostate cancer. We found TMPRSS2-ERG fusion in 4 of 9 whole genome samples. Moreover, 5 samples had 8p whole arm deletion, which is found frequent in western prostate cancers. As a result, we describe the genomic patterns of genetic variations and structural variations involved in prostate cancer of Korean population. Citation Format: Se Song Jang, Min Jung Kim, Dong Wan Hong, Jae Young Joung, Sung Han Kim, Kang Hyun Lee, Weon Seo Park, Jong-Il Kim. Genomic analysis of prostate cancer in Korean men [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 3392. doi:10.1158/1538-7445.AM2017-3392
Survival of Patients With Cancer of the Large Intestine and Rectum, Connecticut, 1935–54&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Fred Ederer, Sidney J. Cutler, Henry Eisenberg, M.D., John R. Keogh
Journal: JNCI Journal of the National Cancer Institute (1961)

We are presenting a detailed 15-year survival analysis by stage, age, calendar period of diagnosis, and type of treatment for 7,128 patients with cancer of the large intestine and 5,082 patients with cancer of the rectum diagnosed in the State of Connecticut between 1935 and 1954. The data are unique in that they describe the experience of virtually all patients with these diseases in a community rather than that of patients admitted to an individual treatment center. Observed survival is measured relative to expected survival in the general population. For cancer of the large intestine and rectum, 5-year survivors experienced considerably higher mortality than persons of similar age in the general population. Ten-year survivors experienced approximately normal survival between the 10th and 15th years after diagnosis. Five-year relative survival rates improved dramatically from 1935–44 to the post-World War II period 1945–54: large intestine: males, 19 to 32 percent; females, 23 to 39; rectum: males, 15 to 30; females, 23 to 32. Improvement was noted for patients with localized disease and with regional spread. The relative number of untreated patients decreased from 1 in 4 to 1 in 6 for cancer of the large intestine, and from 1 in 5 to 1 in 7 for cancer of the rectum. More frequent use of surgery and increase in length of survival of the surgically treated patients contributed to the over-all improvement. Most of the increase in the 5-year relative survival rate for the surgically treated patients resulted from increase in the 1-year survival rate, which suggests that reduction of operative mortality was an important factor. Women tended to have a more favorable outlook than men, but for cancer of the rectum this sex difference disappeared during the second period of diagnosis, 1945–54.