tbuckley/cabot-search huggingface dataset:
Abstract 59: Engineering glypican-3 targeting immunotoxins for the treatment of liver cancer
Authors: Bryan D. Fleming, Brittany Nixon, Ira Pastan, Mitchell Ho
Journal: Cancer Research (2017)

Abstract The expression of glypican-3 (GPC3) in hepatocellular carcinoma offers a target with high tissue specificity and cell signaling implications. A human single domain antibody discovered by phage display technology, HN3, was fused to domain II and domain III of Pseudomonas exotoxin A. This protein (HN3-PE38) showed a high level of cytotoxic activity with a IC50 of 0.4 nM on Hep3B cells, but a relatively low maximum tolerated dose of 0.8 mg/kg in mice. In order to produce an immunotoxin with reduced toxicity, a new version was constructed that removed domain II and seven B cell epitopes from the Pseudomonas toxin. This deimmunized immunotoxin (HN3-mPE24) was shown to have a similar IC50 of 0.2 nM on Hep3B cells. To determine if further deimmunization was possible, three new versions have been generated with T cell epitopes or a series of both B and T cell epitopes removed. These include the HN3-T20 immunotoxin which had six T cell epitopes removed, HN3-T19 with 4 B cell, 4 T cell and 2 shared epitopes, and HN3-M11 with 5 B cell, 4 T cell and 2 shared epitopes. A comparative analysis of these immunotoxins was made using in vitro cell proliferation assays using Hep3B. Both the HN3-T20 (IC50 = 0.6 nM) and HN3-T19 (IC50 = 0.8 nM) immunotoxins had similar activity to HN3-mPE24 (IC50 = 0.7 nM) in a side by side comparison. The HN3-M11 variant had poor cytotoxicity and was excluded from in vivo examination. A Hep3B subcutaneous xenograft model was generated in athymic nude mice and was followed by nine rounds of intravenous immunotoxin treatments. The mPE24, T20 and T19 immunotoxins all showed an increase in average survival rate 70 days (mPE24), 76 days (T20) and 72 days (T19) when compared to the 55 days for PE38 and the 41 days for PBS alone. Additionally, the T20 and the T19 showed a maximum tolerated dose that was similar to that of the mPE24 with dosages as high as 10 mg/kg being well tolerated. This data would suggest that the HN3-T19 immunotoxins has potential clinical applications because it represents the most deimmunized immunotoxin to date. Citation Format: Bryan D. Fleming, Brittany Nixon, Ira Pastan, Mitchell Ho. Engineering glypican-3 targeting immunotoxins for the treatment of liver 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 59. doi:10.1158/1538-7445.AM2017-59
Abstract 176: Early development of GMC1, a novel molecule targeting FKBP52 for the treatment of hormone-refractory prostate cancer
Authors: Huan Xie, Oscar Ekpenyong
Journal: Cancer Research (2017)

Abstract Purpose: GMC1 directly inhibits FKBP52, effectively blocking androgen receptor dependent gene expression and androgen-stimulated proliferation. This make it an attractive option for the treatment of hormone-dependent and hormone-independent prostate cancer. This study investigated an analytical method for GMC1 quantification, pre-formulation characteristics of GMC1, and developed intravenous formulations for the evaluation of GMC1 in animal models. Method: An LC/MS/MS method for the quantification of GMC1 in solution, plasma and urine was developed, validated and applied to the determination of the stability, log P, plasma protein binding and solubility of GMC1 in various solvents. Liposomal formulations and co-solvent systems with various ratios of high capacity vehicles were formulated and the optimal formulation applied, at 2 mg/kg single IV bolus dose, to the pharmacokinetic study of GMC1 in a rat model. Result: The intra- and inter-day accuracy (%RE) and precision (%CV) of the LC/MS/MS method ranged from 1.6 – 11.7 % and 1.4 – 8.8 %, respectively. GMC1 is stable in solid and solution state, moderately lipophilic (log P = 1.38 ± 0.05), poorly water soluble (0.4 ± 0.01 mg/mL), and highly plasma protein bound (&amp;gt;71%). The optimal formulation consisting of PEG 300 and Labrasol ® (1:1, v/v) allowed us to achieve a GMC1 concentration of 10 mg/mL, and tolerated an aqueous environment. GMC1 has a tri-exponential disposition with a Cmax of 7.6 ± 1.97 mg/L, clearance of 0.53 L/kg/hr, α-distribution, β-phase and terminal elimination half-lives of 0.1 ± 0.04 hr, 1.2 ± 0.34 hr, and 19.7 ± 5.09 hr respectively. Conclusion: The LC/MS/MS method, formulations and pharmacokinetic study can be applied to the pre-clinical and clinical development of GMC1. Grant Support: This work was performed under funding from NIH/NIGMS grant (5SC3GM102018) and NIH/NIMHD/RCMI grant (5G12MD007605). Citation Format: Huan Xie, Oscar Ekpenyong. Early development of GMC1, a novel molecule targeting FKBP52 for the treatment of hormone-refractory prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 176. doi:10.1158/1538-7445.AM2017-176
Abstract 2481: RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types
Authors: Kevin D. Mills, Marly I. Roche, Amber Cyr, Tyler Maclay, Muneer G. Hasham, Kristin Lamont, Jane Branca, Francesca Cavallo, Francesca Cavallo, Maria Jasin, Alvin Stern, Youngho Kwon, Weixing Zhao, Patrick Sung
Journal: Cancer Research (2017)

Abstract Antigen stimulated B-cells transiently express Activation Induced Cytidine Deaminase (AID) which initiates point mutations and DNA double strand breaks (DSB) in immunoglobulin genes to promote B-cell maturation. However, AID is capable of broadly damaging the B-cell genome. We have shown that AID-induced DSBs require the homologous recombination factor RAD51 for their repair. Using genetic approaches, we discovered that reduced HR function is cytotoxic to AID-expressing B-cells. We subsequently demonstrated the feasibility of small molecule inhibition of RAD51 to sensitize AID-overexpressing tumor cells. Here we build on those observations, finding that AID-RAD51 synthetic lethality occurs via mitotic catastrophe, involving the mTOR pathway. We have now developed potent and selective RAD51 modulatory small molecules that preferentially kill AID-expressing tumor cells. Using mouse models of lymphoma and leukemia we provide in vivo efficacy data demonstrating the potential therapeutic feasibility of RAD51 modulation. These studies provide evidence for a novel “synthetic lethal” approach for treating AID-expressing malignancies, via the induction of mitotic catastrophe. Citation Format: Kevin D. Mills, Marly I. Roche, Amber Cyr, Tyler Maclay, Muneer G. Hasham, Kristin Lamont, Jane Branca, Francesca Cavallo, Francesca Cavallo, Maria Jasin, Alvin Stern, Youngho Kwon, Weixing Zhao, Patrick Sung. RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types [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 2481. doi:10.1158/1538-7445.AM2017-2481
Abstract 1982: β-arrestin 2 mediates tumor growth and metastasis in renal cell carcinoma cells
Authors: Jude Masannat, Yushan Zhang, Hamsa Purayil, Iqbal Mahmud, Yehia Daaka
Journal: Cancer Research (2017)

Abstract Renal Cell Carcinoma (RCC) is one of the most lethal urological cancers worldwide, with incidence and mortality rates increasing in the past two decades. The disease does not present early clinical symptoms and is commonly diagnosed at the metastatic stage, leaving the 5-year survival rate at ≈ 10-20%. For a wide array of neoplasms, many key molecular determinants involved in mediating the process of tumor cell growth, invasion, and colonization at a secondary site (i.e. metastasis) have been reported. However, few molecular predictors have been identified for RCC, rendering the mechanism(s) underlying RCC metastases poorly understood. This results in the lack of effective treatment for patients with advanced RCC. G protein-coupled receptors (GPCRs) and their effectors, such as the arrestin proteins, have been implicated in tumor growth, metastasis, and angiogenesis. Arrestin proteins are well known for their function in the desensitization and trafficking of GPCRs, but have also been implicated in unique signaling pathways to regulate fundamental cellular functions, including cell cycle progression, cell migration, and survival. Furthermore, arrestin involvement has been identified in a number of breast, colorectal, lung, and hematological malignancies. However, the role of arrestin proteins in RCC is yet to be determined. Our preliminary data show that β-arrestin 2 (βarr2) protein levels correlate with growth and metastatic potential in several RCC cell lines, including ACHN and SN12C. We hypothesize that βarr2 regulates RCC tumor progression, specifically through involvement in proliferation, invasion, and metastatic processes. To test our hypothesis, we used genetic-based loss of function approaches such as interfering RNA and CRISPR/Cas9. βarr2 knockdown results indicated a role in RCC malignancy as it significantly reduces the migration and invasion of RCC cell lines in vitro. βarr2 knockout (KO) impaired 3D spheroid formation of these cells and induced morphological changes compared to control cells as observed under confocal microscopy imaging. Moreover, epithelial marker E-cadherin expression levels were elevated while mesenchymal markers twist1, twist2 and vimentin levels were decreased in the βarr2 KO cells compared to control, indicating a mesenchymal to epithelial transition. In vivo data support our hypothesis that βarr2 plays a critical role in tumor growth and metastasis. Our data suggests a role for βarr2 in RCC malignancy and present a possible target in development of therapies for patients with advanced RCC. Citation Format: Jude Masannat, Yushan Zhang, Hamsa Purayil, Iqbal Mahmud, Yehia Daaka. β-arrestin 2 mediates tumor growth and metastasis in renal cell carcinoma 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 1982. doi:10.1158/1538-7445.AM2017-1982
Abstract 3873: Novel non-genetic mechanisms drive rhabdomyosarcoma tumorigenesis
Authors: Justina McEvoy, Michael Dyer, Xiang Chen
Journal: Cancer Research (2017)

Abstract Most pediatric solid tumors originate from perturbations during development, however the mechanisms that drive these disruptions and promote tumor progression are still poorly understood. We believe that epigenetic deregulation of cancer genes and developmental pathways is a common driver in pediatric cancers, especially those with a low mutation rate. To test this novel idea, we are focusing on rhabdomyosarcoma (RMS), a developing muscle tumor with striking genetic differences between two of the major subtypes. We hypothesize that differential epigenetic deregulation of differentiation programs and cancer genes between the major subtypes are essential for tumorigenesis. Indeed, our preliminary integrative analysis reveal distinct epigenetic landscapes between the two subtypes particularly at the loci of HOX cluster genes A-C, including an oncogenic HOXC long non-coding RNA (lncRNA) called HOTAIR. Knockdown of HOTAIR led to derepression of HOXD10, a candidate tumor suppressor, and a decrease in RMS proliferation, migration, and invasion. Thus, we believe HOX gene deregulation is required for tumorigenesis, and their implication in several adult cancers suggests this currently unappreciated mechanism is likely to be more broadly relevant. In addition, we identified a group of RMS specific novel lncRNAs, of which one demonstrates an essential role in cell survival. Our innovative approach to integrate epigenetic data sets from tumor types with varying genetic differences shed light on the mechanisms that drive tumorigenesis, which may lead to identifying previously unknown potential therapeutic targets. Since current therapeutic options have not changed over the last twenty-five years, these data will especially provide a strong translational impact for children with RMS, whose survival outcomes are less than 20% in the case of metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Justina McEvoy, Michael Dyer, Xiang Chen. Novel non-genetic mechanisms drive rhabdomyosarcoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2017-3873
Abstract 252: Resveratrol and pterostibene selectively chemosensitize Burkitt’s lymphoma cells to 5-Fluorouracil
Authors: Connor J. Peck, Michelle H. Townsend, Kim L. O'Neill
Journal: Cancer Research (2017)

Abstract In the current study, we assess the chemosensitization activity of the naturally occurring polyphenols resveratrol (RES) and pterostilbene (PTER) to 5-Fluorouracil (5-FU) in Burkitt’s B-cell lymphoma. RES is a stilbenoid compound found in a variety of fruits, plants, and nuts. In addition to antioxidant and anti-aging properties, RES has been shown to exhibit significant anti-tumor activity against a variety of malignancies. Since the compound is typically protective of normal cells, its anti-cancer activity makes it a promising candidate as both a chemopreventative nutritional supplement and a chemotherapeutic agent. PTER, an analog of RES, has likewise shown anti-cancer activity. Its therapeutic potential, however, is much less understood. Recent studies have investigated the use of these and other natural compounds in adjuvant chemotherapy strategies, many of which continue to produce underwhelming rates of response. Here, we investigate the chemosensitization capacity of both RES and PTER to 5-FU, a commonly used drug in chemotherapy, in healthy lymphocytes and in Burkitt’s B-cell lymphoma (Raji) cells. MTS assays are used to measure the viability of malignant and normal lymphocytes after 5-FU treatment with or without co-incubation of RES, PTER, or RES/PTER combinations. We find that Raji co-incubation with physiologically relevant concentrations (&amp;lt;10uM) of either RES or PTER significantly increases 5-FU toxicity in Raji cells, with data suggesting PTER to be slightly more effective than RES. Interestingly, RES/PTER combinatorial treatments further increase chemosensitization, an important finding considering the typically low bioavailability of each individual compound in vivo. Together, these data support the potential use of RES as a chemosensitizing adjuvant and provide new evidence that its analog, PTER, also possesses significant chemosensitization capacity. Furthermore, our studies suggest that low physiological concentrations of PTER and RES may be still be sufficient to induce significant anti-cancer effects. Citation Format: Connor J. Peck, Michelle H. Townsend, Kim L. O'Neill. Resveratrol and pterostibene selectively chemosensitize Burkitt’s lymphoma cells to 5-Fluorouracil [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 252. doi:10.1158/1538-7445.AM2017-252
Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis
Authors: Ming Liang, Michael Yu, Ruohan Xia, Ke Song, Jun Wang, Jinlong Luo, Guang Chen, Jizhong Cheng
Journal: Journal of the American Society of Nephrology (2017)

In damaged kidneys, increased extracellular matrix (ECM) and tissue stiffness stimulate kidney fibrosis through incompletely characterized molecular mechanisms. The transcriptional coactivators yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) function as mechanosensors in cancer cells and have been implicated in the regulation of myofibroblasts in the kidney. We hypothesized that the development of kidney fibrosis depends on Yap-induced activation and proliferation of kidney fibroblasts. In mice, Yap expression increased in renal fibroblasts after unilateral ureteral obstruction (UUO), in association with worsening of interstitial fibrosis. In cultured fibroblasts, inhibition of Yap/Taz signaling blocked TGF- β 1–induced fibroblast-to-myofibroblast transformation and ECM production, whereas constitutive activation of Yap promoted fibroblast transformation and ECM production even in the absence of TGF- β 1. Moreover, in the absence of TGF- β 1, fibroblasts seeded on a stiffened ECM transformed into myofibroblasts in a process dependent on the activation of Yap. In mice with UUO, the Yap inhibitor verteporfin reduced interstitial fibrosis. Furthermore, Gli1 + cell-specific knockout of Yap/Taz in mice suppressed UUO-induced ECM deposition, myofibroblast accumulation, and interstitial fibrosis. In a UUO-release model, induction of Gli1 + cell-specific Yap/Taz knockout partially reversed the development of interstitial fibrosis. Thus, in the kidney, Yap is a tissue mechanosensor that can be activated by ECM and transforms fibroblasts into myofibroblasts; the interaction of Yap/Taz and ECM forms a feed-forward loop resulting in kidney fibrosis. Identifying mechanisms that interrupt this profibrotic cycle could lead to the development of anti-fibrosis therapy.
Abstract 108: <i>In vitro</i> and <i>in vivo</i> characterization of novel scorpion venom-based peptides for the treatment of colon cancer
Authors: Bin Li, Hang Fai KWOK
Journal: Cancer Research (2017)

Abstract In the last decade, many of the venom-based bioactive peptides demonstrated with a broad and diverse spectrum of pharmacological activities, which help to enlarging the current drug-screening library for searching of new specific biomarkers and novel prototype drugs for diagnosis of diseases such as cancer. Moreover, it paved a new insight to overcome the current drug discovery problems, which including drug resistance problem, side effect and so on. Here we report the discovery of a panel of novel venom-based peptides, which can significantly inhibit the growth of human colon cancer cells. Through our in-house developed high throughput screening techniques and bioinformatics analysis, we successfully isolated eight novel peptides from scorpion venoms with anticancer activities. We performed a series of anti-proliferative assays to demonstrate that these peptides could inhibit the growth of a broad spectrum of tumor cells, especially in human colon cancer cell line; while almost have no effect on normal human epithelial cells. Haemolysis assay was also performed to show our peptides do not cause any harm on normal human red blood cells, which point to the direction of bringing those peptides into the preclinic trial studies. Before the in vivo studies, we are currently investigating the anticancer mechanisms and involved signal pathways of these peptides. LDH assay and real-time live cell analysis were performed, and from those data it indicates that the peptides might actually work by inhibiting the cancer cell growth instead of disrupt their cell membrane directly. Flow cytometry and western bolt results also showed that the peptides have a significant G1 phase cell cycle arrest effect through inhibiting cyclin dependent kinases CDK4 and up-regulating the expression of cell cycle protein regulator Cyclin D3, p27, p21. Moreover, from our current data, it demonstrated that our peptides wouldn’t induce any apoptosis during the cell cycle process. With the solid anticancer mechanism/pathway data, the potential anticancer peptides to target in vivo malignant tumor will be evaluated in cancer xenograft animal model to demonstrate the growth inhibitor activity of our lead peptides. In summary, our study demonstrate that our peptides can inhibit tumor cell growth via cell-cycle arrest, and almost have no cytotoxicity on human epithelial cells, which could lead our lead peptides to further clinical investigation for the new strategy of peptide mono-/combination therapy. Citation Format: Bin Li, Hang Fai KWOK. In vitro and in vivo characterization of novel scorpion venom-based peptides for the treatment of colon 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 108. doi:10.1158/1538-7445.AM2017-108
Abstract 373: Wnt signaling induces anti-apoptotic effect in colorectal cancer cells through the suppression of IFITs
Authors: Tomoyuki Ohsugi, Kiyoshi Yamaguchi, Chi Zhu, Tsuneo Ikenoue, Yoichi Furukawa
Journal: Cancer Research (2017)

Abstract Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through the activation of β-catenin/TCF complex. Although genes up-regulated by Wnt/β-catenin signaling has been well studied, the down-regulated genes are poorly understood. To clarify the comprehensive changes regulated by the signaling in colorectal cancer cells, we explored a global gene expression of CRC cells transfected with β-catenin siRNAs or dominant negative form of TCF7L2 (dnTCF7L2). Consequently, a set of genes that were negatively regulated by β-catenin/TCF were identified. Among the genes, three members of interferon-induced proteins with tetratricopeptide repeats (IFIT) family (IFIT1, IFIT2, and IFIT3) expression were significantly increased by the inhibition of β-catenin/TCF. Comparison of gene expression data from normal colonic mucosa and the tumor tissues showed that the expression of IFIT1 and IFIT2 in the tumors was significantly lower than that in normal tissues. To elucidate the mechanism of IFITs expression regulated by β-catenin/TCF, we performed a reporter assay using plasmid containing 1.2-kb of 5’-flanking region of the IFIT2 gene. As a result, the reporter activity was significantly enhanced by either transduction of β-catenin or dnTCF7L2, suggesting that blockage of β-catenin/TCF stimulated IFITs through the promoter. In addition, we found that overexpression of IFIT2 increased apoptosis and decreased cell proliferation in SW480 and HCT116 cells. These results imply that Wnt signaling may promote anti-apoptotic effect in cancer cells through the suppression of IFIT2. Our findings suggest that analysis of down-regulated genes in response to activated Wnt/β-catenin signaling provides a better understanding of human colorectal carcinogenesis. Citation Format: Tomoyuki Ohsugi, Kiyoshi Yamaguchi, Chi Zhu, Tsuneo Ikenoue, Yoichi Furukawa. Wnt signaling induces anti-apoptotic effect in colorectal cancer cells through the suppression of IFITs [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 373. doi:10.1158/1538-7445.AM2017-373