tbuckley/cabot-search huggingface dataset:
Abstract 2863: Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments
Authors: Ali S. Arbab, Meenu Jain, Bhagelu Achyut, Kartik Angara, Mohammad H. Rashid, Asm Iskander, Thaiz F. Borin, Wenbo Zhi, Roxan Ara, Irina Lebedyeva, Hassan Bagher-Ebadian
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 a selective CYP450 inhibitor has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Tumor growth and vascular parameters (tumor blood volume, permeability and, extravascular and extracellular space volume) were determined by in vivo dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The pharmacokinetics of HPßCD-HET0016 were evaluated in plasma and tumor tissues using IV and IP routes of administration. IV treatment with HPßCD-HET0016 decreased tumor growth, tumor blood volume, permeability and, extravascular and extracellular space volume, when compared with the vehicle group (p&amp;lt;0.05). Similar growth inhibition was also observed in syngeneic GL261 GBM (p&amp;lt;0.05). Survival studies using patient derived xenografts of GBM (PDX), showed prolonged survival to 25-27 weeks in animals treated combinedly with focal radiation, IV HET0016 and TMZ (p&amp;lt;0.05). Administration of a single dose resulted in 7-fold higher levels of HET0016 in the IV group in plasma and 3.6-fold higher levels in tumor tissue at 60 min compared to that of IP route. We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA) and migration (MHC-1) in the treated group (p&amp;lt;0.05). Decreased tumor growth was associated with reduced expression of pro-angiogenic markers (IL-8, MCP-1, VEGF, HIF-1α, and VE-Cadherin), inflammation (p-NFκB), intermediates of MAPK pathway (p-AKT, p-ERK and p-STAT1, EGFR), arachidonic acid metabolism (COX-1, CYP4A11) and increased expression of anti-angiogenic markers (Ang2, Angiostatin and Tie-2). Our results indicate that the improved IV formulation of HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, migration, and neovascularization. Furthermore, HET0016 significantly enhanced sensitivity of TMZ and prolonged survival in PDX GBM. Citation Format: Ali S. Arbab, Meenu Jain, Bhagelu Achyut, Kartik Angara, Mohammad H. Rashid, Asm Iskander, Thaiz F. Borin, Wenbo Zhi, Roxan Ara, Irina Lebedyeva, Hassan Bagher-Ebadian. Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments [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 2863. doi:10.1158/1538-7445.AM2017-2863
Abstract 4941: Lysophosphatidic acid receptor signaling and pancreatic adenocarcinoma tumor microenvironment
Authors: Nicholas J. Skill, Mary A. Maluccio
Journal: Cancer Research (2017)

Abstract Introduction: Changes in lipid biosynthesis has attracted significant attention in the study of cancer. Its value in our understanding of pancreatic cancer has not yet been realized. This study examined lysophosphatidic acid (LPA) variant biosynthesis in patients with stage II-III pancreatic ductal adenocarcinoma (PDAC), evaluating serum, bile, and tissue levels of LPA, its receptors, and downstream metabolites. LPA, a product of phospholipase D activity of the enzyme autotaxin (ATX) is a potent mitogenic agent. Data suggests that changes in lipid biosynthesis contribute to the tumor microenvironment in PDAC. Methods: PDAC, matched adjacent non-malignant tissues, gall bladder bile and serum samples were collected from patients with Stage II-III pancreatic cancer at the time of surgery. Control bile and serum were collected from patients undergoing cholecystectomy for benign disease and living renal donors respectively. Results: Serum and biliary LPA levels were increased in patients with PDAC when compared to controls. ATX activity, and LPA receptors, LPAR1, LPAR2, and LPAR5 were greater in PDAC adjacent pancreatic tissue when compared to PDAC tissue. In contrast, TNFα receptors TNFα1 and TNFα2 and LPA receptor LPAR3 receptor expression was greater in PDAC lesions when compared to adjacent tissue. Conclusion: PDAC patients display a modified LPA biosynthesis profile, when compared to non-PDAC patients, potentially providing a paracrine-signaling cascade to promote pancreatic tumorigenesis through increased expression of mitogenic cytokines and growth factors. Citation Format: Nicholas J. Skill, Mary A. Maluccio. Lysophosphatidic acid receptor signaling and pancreatic adenocarcinoma tumor microenvironment [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 4941. doi:10.1158/1538-7445.AM2017-4941
Abstract 5103: Development of MJ-66 as a novel anticancer agent for the treatment of malignant gliomas
Authors: Mann-Jen Hour, Tai-Lin Chen, Po-Wu Gean, Hong-Zin Lee
Journal: Cancer Research (2017)

Abstract Malignant glioma is the most common aggressive adult primary tumor of the central nervous system. Treatments of malignant gliomas include surgery, radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. However, inherent- and acquired resistance to TMZ present major obstacles to successful treatment, and the prognosis of patients with malignant gliomas remains very poor. MJ-66, a synthetic qunazoline compound, was identified in our study as a potent anti-proliferative agent especially on human glioma with IC50 of approximately 60 nM. In intracranial glioma xenograft model, MJ-66 (0.14 mg/kg in saline, i.p., q.d., 10 days) significantly inhibited tumor growth and increased the survival of the experimental mice, however, did not decrease the body weight of mice. Currently, there is a profound unmet medical need for a new drug in the treatment of malignant brain tumor. The MJ-66 demonstrated superior efficacy to TMZ that are the only first-line-drug in clinical use. MJ-66 is suggested to be a promising anticancer candidate. Note: This abstract was not presented at the meeting. Citation Format: Mann-Jen Hour, Tai-Lin Chen, Po-Wu Gean, Hong-Zin Lee. Development of MJ-66 as a novel anticancer agent for the treatment of malignant gliomas [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 5103. doi:10.1158/1538-7445.AM2017-5103
Abstract 1673: Mass spectrometric characterization of peptides associated with molecules of the major histocompatibility complex
Authors: Michael Ford, Richard Jones, David Allen, Ravi Amunugama, Paul Del Rizzo, Michael Pisano, James Mobley, Paul Domanski, Bill Ho, Daniel Bochar
Journal: Cancer Research (2017)

Abstract The major histocompatibility complex (MHC) is a region of highly polymorphic genes encoding for glycoproteins (MHC molecules) that form part of the cell-mediated branch of the acquired immune system. In the cytosol, cellular self and foreign (non-self) proteins are constantly being degraded; it is the peptides generated that are presented, non-covalently bound to MHC molecules, on the surface of cells for inspection by cytotoxic T-lymphocytes (CTLs). Non recognition of the presented peptide ultimately leads to cell destruction. Characterizing the factors associated with Non recognition is an attractive proposition for anyone interested in generating tools for targeted cell destruction. In the field of oncology the obvious application then is the targeted destruction of cancerous cells. To enable the molecular level characterization of peptides associated with molecules of the major histocompatibility complex requires a targeted protein complex enrichment, an unbiased peptide elution and finally a peptide analysis method. Most frequently an immunoprecipitation is used to isolate the target complex. The peptide elution is performed under conditions minimizing protein contamination and finally peptide analysis is accomplished by mass spectrometry. Here we present a case study of our recent work optimizing and performing a workflow for the analysis of peptides associated with Class I MHC molecules. The goal of the assay optimization was to minimize the amount of antibody required for the assay, to minimize the amount of biological material needed from which the complex is isolated and to achieve the optimum sensitivity towards the hitherto unknown target peptides. Citation Format: Michael Ford, Richard Jones, David Allen, Ravi Amunugama, Paul Del Rizzo, Michael Pisano, James Mobley, Paul Domanski, Bill Ho, Daniel Bochar. Mass spectrometric characterization of peptides associated with molecules of the major histocompatibility complex [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 1673. doi:10.1158/1538-7445.AM2017-1673
Abstract 2415: Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation therapy
Authors: Anna C. Ferrari, Hatem Sabaawy, Mark Stein, David Foran, Ying Chen, Srinivasan Yegnasubramanian
Journal: Cancer Research (2017)

Abstract Background: Although androgen deprivation therapy initially decreases PC tumor burden, resistance to further androgen receptor (AR)-directed treatments or chemotherapy is inevitable once CRPC is established. We postulated that the stress of ADT triggers widespread alterations in expression that renders a metastable physiologic state conditioned by epigenetic changes that might be initially reversible by targeting non-androgen pathways. We conducted a pilot study to explore genome-wide expression alterations in PC foci surviving 3 months ADT (eADT). Methods: mRNA from 7 frozen microdissected PC foci and normal counterparts (NC) were processed for RNA-seq. RNA-seq changes in eADT specimens were compared first with NC and the untreated PC in the TCGA PRAD (TCGA) database to castrate resistant (mCRPC) specimens in the dbGAP study phs000915.v1.p1database. The raw data (fastq files) was quantified using kallisto, normalized by TMM using R package edgeR, batch effects corrected using R package SVA. Analysis of differential gene expression by R package sleuth. Pathway and gene set by GSEA, GAGE/pathview packages for Gene Ontology (GO) and KEGG. Results: TMPRSS2-ERG+, 5/7. Highest DEG in eADT vs. TCGA vs mCRPC were non-coding RNA’s. Among 17431 differentially regulated paths; GSEA of eADT vs TCGA or mCRPC: 341 (1.95%) and 1366 (7.84%) up- vs 46 (0.26%) and 59 (0.34%) down-regulated. KEGG paths, eADT vs. TCGA or mCRPC, 11 and 53 up vs. 2 and 3 down- respectively. Highly down- path in eADT vs TCGA (log q&amp;lt;10-17) was ribosomal vs. cell cycle and DNA replication in mCRPC. Six paths significantly up- in eADT vs TCGA or mCRPC: Wnt, adherence junction, steroid biosynthesis, unsaturated fatty acids, citrate cycle, ErbB. Calcium, MAPK, insulin, GnRH and Hedgehog were also up- in eADT vs mCRPC. AR full-length was marginally higher in eADT than TCGA and lower than mCRPC, no differences in gene targets. Conclusions: This pilot data shows that ADT triggers a wide range of gene expression alterations that support PC cell survival and may be vulnerable to therapeutic targeting in addition to the androgen pathway. Validation of these findings is planned in a larger set of samples from the same bank. Citation Format: Anna C. Ferrari, Hatem Sabaawy, Mark Stein, David Foran, Ying Chen, Srinivasan Yegnasubramanian. Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation 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 2415. doi:10.1158/1538-7445.AM2017-2415
Abstract 2374: Mixed-Lineage Kinase 3 signals through the FRA1-MMP1 axis to drive triple-negative breast cancer invasion and transendothelial migration
Authors: Chotirat Rattanasinchai, Brandon Llewellyn, Susan E. Conrad, Kathleen A. Gallo
Journal: Cancer Research (2017)

Abstract Mixed-lineage kinase 3 (MLK3), a mitogen-activated kinase kinase kinase (MAP3K), contributes to metastasis of triple-negative breast cancer (TNBC), in part through its regulation of paxillin phosphorylation and focal adhesion turnover. However the signaling mechanisms through which MLK3 promotes invasion and metastasis are not fully understood. We found that in non-metastatic, estrogen receptor positive (ER+) breast cancer cells, induced MLK3 expression robustly upregulates the oncogenic transcription factor, FOS-related antigen-1 (FRA-1), as well as matrix metalloproteinases (MMPs), MMP-1 and MMP-9. MLK3-induced MMP-1 induction is abrogated by FRA-1 silencing, demonstrating that MLK3 signals through FRA-1 to control MMP-1. In complementary experiments performed in metastatic TNBC models, high levels of FRA-1 are significantly reduced upon gene silencing of MLK3 or by MLK3 disruption using the CRISPR/Cas9n approach. Furthermore, both MMP-1 and MMP-9 are decreased upon ablation of MLK3 or MLK inhibitor treatment. Reduced endothelial permeability and transendothelial migration is observed in experiments with MLK3-depleted TNBC cells compared with parental counterparts. In addition, MLK inhibitor treatment or MLK3 depletion renders TNBC cells defective in Matrigel invasion. Furthermore, circulating tumor cells (CTCs) derived from a TNBC-bearing mouse which show an intermediate epithelial-mesenchymal phenotype display increased levels of MLK3, FRA-1, and MMP-1 compared with parental cells, supporting a role for the MLK3-FRA-1-MMP-1 signaling axis in tumor cell invasion and vascular intravasation. Consistent with the role of MMP-1 in multiple steps of metastasis, high levels of MMP-1 in breast cancer patient tumor samples are associated with increased distant metastases and poorer overall survival, particularly in TNBC. Our results demonstrating the requirement for MLK3 in controlling the FRA-1/MMP-1 axis suggest that MLK3 is a potentially effective therapeutic target for TNBC. Citation Format: Chotirat Rattanasinchai, Brandon Llewellyn, Susan E. Conrad, Kathleen A. Gallo. Mixed-Lineage Kinase 3 signals through the FRA1-MMP1 axis to drive triple-negative breast cancer invasion and transendothelial migration [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 2374. doi:10.1158/1538-7445.AM2017-2374
Abstract 3298: Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1)
Authors: Hossam Draz, Alexander Goldberg, Thomas Sanderson, Stephen Safe
Journal: Cancer Research (2017)

Abstract 3,3’-diindolylmethane (DIM) and its halogenated derivatives (ring-DIMs) are recently shown to induce protective autophagy in human prostate cancer cells. The mechanism of induction of autophagy by DIM has not been elucidated. As DIM is a mitochondrial ATP synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of AMP/ATP ratio and activation of AMPK signaling in prostate cancer cells. Autophagic activity was monitored by LC3B-I to LC3B-II conversion in LNCaP and C42B prostate cancer cells. Autophagic vacuoles were examined using Cyto-ID autophagy detection kit and transmission electron microscope (TEM). Protein levels for AMPK, pAMPK, acetyl-CoA carboxylase (ACC), pACC, AEG-1, pULK-1 and β-actin were measured by western blot. AMPK and AEG-1 gene expression was downregulated using siRNA. DIM and ring-DIMs induced autophagy by increasing autophagic vacuoles and LC3B-I to LC3B-II conversion in LNCaP and C42B cells. These compounds also induced AMPK, ULK-1 and ACC phosphorylation in a time dependent manner. Interestingly, DIM, 4,4’ dibromoDIM and 7,7’ dichloroDIM induced the oncogenic protein AEG-1 time dependently in LNCaP and C42B cells. Downregulation of AEG-1 or AMPK inhibited DIM- and ring-DIM-induced autophagy. Pretreatment with ULK1 inhibitor MRT 67307 or siRNAs targeting AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with toxic concentrations of DIM or ring-DIMs, and inhibited the onset of apoptosis in response to DIM or ring-DIMs. In summary, we identified a novel mechanism for DIM- and ring-DIM-induced protective autophagy, via induction of AEG-1 and activation of AMPK. Our findings could help towards the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants. Citation Format: Hossam Draz, Alexander Goldberg, Thomas Sanderson, Stephen Safe. Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1) [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 3298. doi:10.1158/1538-7445.AM2017-3298
Abstract 3034: A programmed ribosomal frameshifting defect potentiates the transforming activity of the JAK2-V617F mutation
Authors: Yousuf A. Khan, Sergey O. Sulima, Joe Kendra, Vivek M. Advani, John E. Jones, Joseph Briggs, Kim de Keersmaecker, Jonathan D. Dinman
Journal: Cancer Research (2017)

Abstract The JAK-STAT pathway is one of the major mechanisms through which cellular proliferation, differentiation, migration, survival and apoptosis are regulated in response to external stimuli. Promiscuous activation of this pathway is a major driver in the pathogenesis of myeloproliferative neoplasms, often characterized by clonal expansion of mature myeloid cells. The JAK2-V617F allele is the most common and well characterized mutation linked to this class of leukemias. A change of G to T at nucleotide 1849 of the coding sequence (CDS) results in substitution of valine to phenylalanine at codon 617. JAK2-V617F mutant cells have strongly increased activation of JAK-STAT signaling, which can partially be explained by its ability abolish inhibition of kinase activity and increase the Km of the enzyme. It is however unclear if these effects are sufficient to explain the strong activation of the JAK-STAT pathway induced by the V617F mutation. Here, we demonstrate that this mutation destabilizes a programmed -1 ribosomal frameshift (-1 PRF) signal in the JAK2 mRNA, leading to decreased rates of -1 PRF promoted by this element. There is an inverse relationship between -1 PRF and mRNA stability. Thus, decreased -1 PRF results in increased abundance of the JAK2 mRNA and increased JAK2 protein expression. Prior studies established that elevated expression levels of JAK proteins are sufficient to transform cells in vitro, suggesting that -1 PRF may normally help to limit JAK2 expression. Silent protein coding changes in the -1 PRF signal slippery sequence ablating JAK2 frameshifting also increased JAK2 expression and phenocopied the transforming activity of JAK2-V617F in cell culture. Further, the combination of the V617F and slippery site mutations conferred an additive effect on cellular transformation. The presence at least three additional -1 PRF signals in the JAK2 mRNA suggests that -1 PRF plays a significant role in controlling JAK2 expression. Citation Format: Yousuf A. Khan, Sergey O. Sulima, Joe Kendra, Vivek M. Advani, John E. Jones, Joseph Briggs, Kim de Keersmaecker, Jonathan D. Dinman. A programmed ribosomal frameshifting defect potentiates the transforming activity of the JAK2-V617F 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 3034. doi:10.1158/1538-7445.AM2017-3034
Abstract 5654: Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy
Authors: Masashi Arita, Satoshi Watanabe, Takahashi Miho, Miyuki Sato, Aya Ohtsubo, Kosuke Ichikawa, Rie Kondo, Tetsuya Abe, Junta Tanaka, Toshiyuki Koya, Toshiaki Kikuchi
Journal: Cancer Research (2017)

Abstract Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) blockade therapy has demonstrated to enhance antitumor immunity. Recent evidence has shown that anti-PD-1/PD-L1 therapy restores the function of exhausted effector T cells and augments antitumor immune responses. The expression of PD-L1 has been best studied as a biomarker for the anti-PD-1/PD-L1 therapy. Because PD-L1 expression on tumor cells is induced by IFN-γ which is mainly produced by effector T cells, induction of antitumor effector T cells in cancer patients could be an important for the anti-PD-1/PD-L1 therapy. Indeed, previous studies have suggested that the increase of tumor-infiltrating lymphocytes is the predictive biomarker for PD-1/PD-L1 blockade therapy. We and others have demonstrated that lymphodepletive therapies, such as chemotherapy and radiotherapy, induce tumor-specific effector T cells from naïve T cells. Naïve T cells rapidly proliferate and elicit memory-like functions after lymphodepletion (homeostatic proliferation). These findings indicate that lymphodepletive regimens could augment the antitumor efficacies of the anti-PD-1/PD-L1 therapy. In the current study, we transferred naïve T cells into mice after whole-body irradiation or chemotherapy. These mice were inoculated s.c. with PD-L1+ B16F10 melanoma cells or PD-L1- MCA205 fibrosarcoma and then were treated with anti-PD-1 mAbs. Lymphodepletion by whole body irradiation, but not cytotoxic agents following the transfer of naïve T cells significantly enhanced antitumor immunity of anti-PD-1 mAbs. This augmentation required both of CD4+ and CD8+ T cells, but not NK cells. Further experiments revealed that immune cells infiltrating MCA205 expressed PD-L1. Transfer of naïve T cells from IFN-γ knockout mice abrogated the enhancement of antitumor effects of anti-PD-1 mAb therapy by lymphodepletion. These results suggest that lymphodepletion induces homeostatic proliferation of T cells and augments antitumor effects of PD-1/PD-L1 blockade therapy. Citation Format: Masashi Arita, Satoshi Watanabe, Takahashi Miho, Miyuki Sato, Aya Ohtsubo, Kosuke Ichikawa, Rie Kondo, Tetsuya Abe, Junta Tanaka, Toshiyuki Koya, Toshiaki Kikuchi. Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade 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 5654. doi:10.1158/1538-7445.AM2017-5654