bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A212: Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model
Authors: Dong Mingjie , Liu Xianqiong , Evert Katja , Utpatel Kirsten , Zhang Shanshan , Che Li , Gordan John , Calvisi Diego , evert Matthias , Liu Yan , Chen Xin 
Published: August 2018

Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a form of deadly malignancy with limited treatment options. Gain-of-function mutations in KRAS are one of the most frequent mutations, found in ~25% of human CCA patients. MEK inhibitors have been developed and show some activity against solid tumors with Ras mutants. However, whether MEK inhibitors are effective against KRas mutant CCAs remains unknown. In the current study, we established a new mouse iCCA model (NICD/KRas) by expressing activated forms of Notch (NICD) and KRas (KRasV12D). We investigated the therapeutic potential of MEK inhibitors in vitro using human CCA cell lines and in vivo using KRasV12/NICD iCCA preclinical model. We found that in general, CCA cell lines with KRas mutations are more sensitive to MEK inhibitor U0126. Treatment of U0126 in KRas mutant CCA cells leads to increased apoptosis and decreased expression of pro-apoptosis gene Survivin. Furthermore, we found that treating KRasV12/NICD tumor-bearing mice with MEK inhibitor PD0325901 (PD901) resulted in stable disease. At molecular levels, PD901 efficiently inhibited p-ERK expression KRasV12/NICD tumor cells, leading to increased apoptosis. In summary, our studies demonstrate that KRasV12/NICD mice represent a novel and useful preclinical model to study KRas-driven CCA development. Our data further support the usefulness of MEK inhibitors for treatment of KRas mutant CCA in patients.
Citation Format: Mingjie Dong, Xianqiong Liu, Katja Evert, Kirsten Utpatel, Shanshan Zhang, Li Che, John Gordan, Diego Calvisi, Matthias evert, Yan Liu, Xin Chen. Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A212.
Abstract B010: Antitumor cellular immune response elicited by Toca 511 and Toca FC therapy in preclinical and clinical studies
Authors: Montellano Tiffany T. , Ostertag Derek , Hogan Daniel J. , Diago Oscar R. , Gammon Dawn , Haghighi Ali , Accomando William , Mitchell Leah , Das Asha , Gruber Harry , Jolly Douglas J. 
Published: August 2018

Abstract
Toca 511 (vocimagene amiretrorepvec), in combination with Toca FC (5-FC; flucytosine extended-release tablets), is an investigational combination product currently under development for the treatment of high-grade glioma (HGG) and other solid tumors. Toca 511 is a gamma-retroviral replicating vector (RRV) delivering a cytosine deaminase transgene to infected cells to convert antifungal drug 5-fluorocytosine (5-FC) into antineoplastic drug 5-fluorouracil (5-FU). Toca 511 can be administered by multiple routes; selectively infects, spreads, and persists in cancer cells; and through multiple mechanisms of action can elicit an antitumor immune response. Treatment directly kills infected cancer cells. Diffusible 5-FU also kills neighboring susceptible cells that contribute to the immune-suppressed tumor microenvironment, especially myeloid immune suppressor cells. After multiple cycles of 5-FC, treated animals that clear tumor are resistant to tumor rechallenge. Adoptive transfer recipients of splenocytes from animals that previously cleared their tumor through treatment with Toca 511 and 5-FC experience a significant survival benefit compared to animals receiving spleen cells from naïve donors. Toca 511 and Toca FC have been administered to 126 recurrent high-grade glioma (rHGG) patients in three phase I studies (NCT01156584, NCT01470794, NCT01985256), and a phase 2/3 trial (Toca 5) is ongoing (NCT02414165). Toca 511 plus Toca FC has been well tolerated in these patients. In the clinical study presented, Toca 511 is injected into resection cavity walls at time of tumor resection, and followed with multiple courses of Toca FC. In a subset of phase I patients that mimic the phase 2/3 rHGG enrollment criteria, there were 3 complete responses and 2 partial responses out of 24 patients observed. The median duration of response is 26.7 months. These responders have an overall survival range from 24.0+ to 42.6+ months and ongoing. Data are consistent with induction of antitumor immune responses after Toca FC administration. Changes in peripheral immune populations as well as interrogation of immunogenic biomarkers in responding compared to nonresponding patients will be presented.
Citation Format: Tiffany T. Montellano, Derek Ostertag, Daniel J. Hogan, Oscar R. Diago, Dawn Gammon, Ali Haghighi, William Accomando, Leah Mitchell, Asha Das, Harry Gruber, Douglas J. Jolly. Antitumor cellular immune response elicited by Toca 511 and Toca FC therapy in preclinical and clinical studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B010.
Abstract B028: Beta 2-microglobulin promotes human pancreatic cancer cell migration
Authors: Sliker Bailee , Liu Cassie , Poelaert Brittany , Goetz Benjamin , Solheim Joyce C. 
Published: August 2018

Abstract
Beta 2-microglublin (β2m) is a 12-kilodalton protein that serves as the non-covalently bound light chain in complex with the major histocompability complex (MHC) class I heavy chain. The human MHC class I heavy chain is known as human leukocyte antigen (HLA), which exists in three isotypes (HLA-A, -B, and -C). Much of the known function of β2m is in regards to its role in stabilizing the HLA class I heavy chain and thereby helping to present endogenous antigenic peptides to cytotoxic T cells. Notably, β2m has recently been found to be elevated in expression in a variety of cancers, including renal cell carcinoma, oral squamous cell carcinoma, prostate cancer, lung cancer, breast cancer, and multiple lymphocytic malignancies. In most of these cancers, β2m is correlated with more advanced disease and poorer prognosis. It has also been shown that in some cancer models, such as a renal cell carcinoma and an oral squamous cell carcinoma model, β2m can affect the proliferation and migration of these tumor cells. The levels and effects of β2m in pancreatic cancer, however, have not been reported thus far. Recent results from our laboratory have revealed high expression of β2m in nearly all members of a panel of pancreatic cancer cell lines. To examine the functional role that β2m plays in pancreatic cancer, we used siRNA specific for β2m to decrease its expression in the mentioned panel of pancreatic cancer cell lines and evaluated migration by transwell assay. Our results showed that the migration of the tested pancreatic cancer cell lines significantly decreases when β2m expression is reduced. Furthermore, we found that when β2m levels are downregulated, there are corresponding decreases in the levels of the HLA-A and -B heavy chains and in the expression of amyloid precursor-like protein 2 (APLP2). Previous research from our laboratory has shown that β2m affects APLP2/MHC association and that reducing expression of APLP2 slows pancreatic cancer cell migration. Additionally, our current research demonstrated that downregulation of β2m expression reduces the steady-state level and the half-life of APLP2. In conclusion, our results indicate that β2m promotes the migration of pancreatic cancer cells and suggest that this effect may be mediated through stabilization of the HLA class I heavy chain and, secondarily, APLP2. These studies thus provide evidence of β2m as a potential target for novel therapies directed against pancreatic cancer.
Citation Format: Bailee Sliker, Cassie Liu, Brittany Poelaert, Benjamin Goetz, Joyce C. Solheim. Beta 2-microglobulin promotes human pancreatic cancer cell migration [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B028.
Abstract B045: Structure-activity relationship study of a novel PKC activator, vibsanin A, for induction of differentiation in leukemia cells
Authors: Simizu Siro , Matsuki Wataru 
Published: August 2018

Abstract
Background and Objective: Chemotherapeutic agents are widely used for acute myeloid leukemia (AML) treatment; however, their severe side effects in patients limit the clinical use of chemotherapy for AML. Differentiation-inducer such as PKC activators was expected to show therapeutic potentials, but many natural derived PKC activators, including phorbol 12-myrystate 13-acetate (PMA), act as tumor-promoting activity. Therefore, the development of differentiation inducing-agents may contribute to constructing the next-generation AML treatment. Vibsanin A (VibA) was recently reported to induce differentiation of myeloid leukemia cells by activating PKC and to prolong survival of mouse xenograft model; however, the detailed chemical feature of VibA remains unclear. In this study, to determine the key partial structure of VibA for its activity, we compared the activity of VibA analogs in the activation of PKC and differentiation of AML cells. Results: To know whether the analogs functioned as PKC activator similarly to VibA, we detected phosphorylation of ERK, which acts downstream of PKC, by Western blotting. As a result, only one analog (VibA-1) induced ERK phosphorylation in a dose-dependent manner like PMA and VibA; however, other analogs had no effect on ERK phosphorylation. We examined whether VibA-1-induced ERK phosphorylation was mediated by PKC activation as well as VibA. We treated with PMA of the cells for long term to downregulate PKC. VibA-1-induced ERK phosphorylation was suppressed by pretreatment with PMA for the long term, indicating that VibA-1 activated PKC, thereby ERK phosphorylation. These data suggested that only VibA-1 retained the ability to activate PKC, which was originally observed in VibA. We observed that VibA-1-treated THP-1 cells became adherent to the culture plate and showed considerable morphologic change. Moreover, several lines of evidences including increased cell size, lowered nuclear to cytoplasmic ratio, and highly vacuolated cytoplasm, characterized by Giemsa staining suggested, that VibA-1 triggered monocytic differentiation similarly to VibA. Thus, our results suggested that VibA and/or its analog VibA-1 may be a novel chemotherapeutic agent for treatment of AML.
Citation Format: Siro Simizu, Wataru Matsuki. Structure-activity relationship study of a novel PKC activator, vibsanin A, for induction of differentiation in leukemia cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B045.
Abstract B047: A novel and efficient therapeutic strategy to target β1 integrin in metastatic cells from different cancer types
Authors: Casal Ignacio , Bartolomé Ruben A. , Jaén Marta , Aizpurua Carmen , Calviño Eva , Imbaud Juan I. 
Published: August 2018

Abstract
Purpose: We aim to develop new therapeutic strategies to control advanced metastatic disease in cancer. We hypothesized that targeting α2β1 integrin activation with cadherin RGD blocking monoclonal antibodies is an efficient procedure to reduce metastatic spread in multiple tumors. Experimental Procedures: Monoclonal antibodies (mAbs) were generated against a 9-mer peptide containing the RGD motif and flanking sequences of CDH17 (aka LI-cadherin). Antibodies were tested for inhibition of β1 integrin activation, cell adhesion, proliferation and invasion assays using cell lines from different cancer types (KM12SM (colorectal), PANC1 (pancreatic), BLM (melanoma,) and MDA-MB-468 (breast)) expressing CDH17 and VE-cadherin. The impact of the CDH RGD-specific mAbs on cell signaling was assessed by Western blot. Swiss nude mice were used to generate liver and lung metastasis with colorectal and melanoma cancer cell lines. Results: CDH RGD-specific mAbs were prepared and characterized. They recognized CDH17 and VE-cadherin positive cells by immunoprecipitation, flow cytometry, and confocal microscopy. CDH RGD mAbs blocked β1 integrin activation in metastatic cancer cell lines from different cancer types, causing a significant reduction in cell adhesion and proliferation. Signaling events related with FAK, JNK, ERK, Src, and AKT phosphorylation were blocked by the mAbs at different extent, according to the cancer type. Finally, CDH RGD mAbs caused a significant and persistent survival in nude mice developing lung and liver metastasis after intravenous or intrasplenic cell inoculation. Conclusions: CDH RGD mAbs constitute a promising therapy to control metastatic spread in colorectal cancer, melanoma, and probably other tumors expressing CDH17, VE-cadherin, or related RGD cadherins.
Citation Format: Ignacio Casal, Ruben A. Bartolomé, Marta Jaén, Carmen Aizpurua, Eva Calviño, Juan I. Imbaud. A novel and efficient therapeutic strategy to target β1 integrin in metastatic cells from different cancer types [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B047.
Abstract B059: SETD2-PI3Kβ synthetic lethality
Authors: Terzo Esteban , Jansen Valerie M. , Chiang Yun-Chen , Rathmell Kimryn W. 
Published: August 2018

Abstract
Introduction: Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer for which several new targeted therapies exist. However, responses of primary clear cell RCC (ccRCC) tumors and metastases to these targeted agents are variable, and complete responses are relatively uncommon, underscoring the need to identify reliable biomarkers to predict tumor behavior. Mutations in the tumor suppressor gene SETD2, encoding a lysine methyltransferase, occur in 3-16% of ccRCC tumors while the SETD2 protein deficiency rate has been reported to be as high as 34%. The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematologic malignancies, including ccRCC. In this study, we determine the extent to which small-molecule inhibitors against the p110α, p110β, and p110δ isoforms of PI3K inhibit growth of RCC with SETD2 loss. Methods: RNAi oligonucleotides and small-molecule inhibitors targeting the p110α (BYL719), p110β (TGX221, AZD8186), and p110δ (idelalisib) isoforms of PI3K were tested against ccRCC cell lines with SETD2 loss. The effect of drugs on cell growth and survival was determined by (1) proliferation in monolayer, (2) 3D growth in Matrigel, and (3) cell migration in wound healing assay. Downstream signaling pathways were evaluated by immunoblot analysis. Results: Genetic and pharmacologic inhibition of p110β resulted in inhibition of ccRCC cell lines with SETD2 loss. ccRCC-derived SETD2 deficient (-/-) 786-O and A498 cells exhibited increased sensitivity to TGX221 (IC50 = 2.3 - 4.5 µM, respectively) and AZD8186 (IC50 = 1.79 - 0.24 µM, respectively) as compared to SETD2 proficient (+/+) 786-O cells (IC50 = &gt;10 µM). Inhibition of the p110δ isoform alone had a modest effect on ccRCC cell growth and migration. Importantly, genetic (with siRNA) and pharmacologic (with BYL719) inhibition of p110α had no effect on the ccRCC cell lines. Inhibition of AKT with the small-molecule inhibitor MK2206 recapitulated the effects seen with AZD8186 in ccRCC cell lines with SETD2 loss, suggesting PI3Kβ mediates the synthetic lethality via AKT signaling in the context of SETD2 loss in ccRCC. Conclusions: Our work strongly suggests a synthetic lethal-type of interaction between PI3Kβ inhibition and SETD2 loss and offers a rationale for further translational and clinical investigation of small-molecule inhibitors of PI3Kβ in RCC. Xenograft studies are ongoing to investigate the in vivo efficacy of AZD8186.
Citation Format: Esteban Terzo, Valerie M. Jansen, Yun-Chen Chiang, Kimryn W. Rathmell. SETD2-PI3Kβ synthetic lethality [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B059.
Abstract B066: Unique roles of group I PAK isoforms in regulating MPNST cell viability
Authors: Semenova Galina , Stepanova Dina , Karchugina Sofiia , Dubyk Cara , Deyev Sergey , Lazar Alexander , Chernoff Jonathan 
Published: August 2018

Abstract
Group I p21-activated kinases (PAKs) include three members (PAK1, PAK2, and PAK3) that represent key components of several cell signaling networks. By transmitting growth factor-induced signals from Rho family GTPases, PAK1/2/3 regulate cytoskeletal dynamics, cell shape, and motility. Group I PAKs modulate several oncogenic and survival pathways and are thought to play a critical role in initiation and progression of certain tumor types. Although group I PAK members share significant sequence similarity, mechanism of regulation, and substrates, PAK isoforms show different gene expression patterns in tissues and play unique functions in development and immune responses. While the described PAK1/2/3 functions in tumorigenesis are generally assigned to PAK1, there are increasing hints of isoform-specific roles for group I PAKs in cancer. We have recently demonstrated that PAK1/2/3 signaling is upregulated in malignant peripheral nerve sheath tumors (MPNSTs) and that small-molecule PAK inhibitors suppress MPNST growth and dissemination. The selective group I PAK inhibitors (Frax1036 and GST-PID) tested in this study target all three isoforms and exhibit moderate effects on MPNST cell viability as single agents. We have now used an RNAi approach to knock down individual group I PAK isoforms and their combinations to show that PAK1 and PAK3 knockdown inhibits MPNST cell proliferation, while PAK2 knockdown does not impede the growth of most MPNST cell lines, and in some cases, augments it. Interestingly, combined depletion of PAK1/2/3 has less profound cytotoxic effects compared to single knockdowns of PAK1 or PAK3, suggesting the potential need for isoform-selective PAK inhibitors as therapeutic agents for MPNSTs.
Citation Format: Galina Semenova, Dina Stepanova, Sofiia Karchugina, Cara Dubyk, Sergey Deyev, Alexander Lazar, Jonathan Chernoff. Unique roles of group I PAK isoforms in regulating MPNST cell viability [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B066.
Abstract B088: Identification of a novel regulator in GIST tumorigenesis
Authors: Yun Seongju , Kim Won Kyu , Kim Hoguen 
Published: August 2018

Abstract
Purpose: Gain-of-function mutations of KIT are pathognomonic in the majority of sporadic gastrointestinal stromal tumors (GISTs). Several micro-RNAs have been shown to be dysregulated in GISTs and impact KIT expression levels. Little is known, though, about KIT-independent targets of KIT-regulating mRNAs. We sought to investigate how miR-494 inhibits GIST proliferation and to identify novel target gene. Experimental Design: We used gene expression analyses to identify pathways and target genes affected by miR-494. The expressional relationship between Survivin and miR-494 was determined in 35 GIST tissues. Cell proliferation assay, FACS analysis, colony formation assay, and promoter assays were performed to clarify the roles of Survivin in GIST progression. Results: Gene expression microarray analysis revealed that miR-494 inhibited GISTs by affecting multiple genes in the cell cycle pathway. Survivin was a key target gene of miR-494. Analysis of the 35 GISTs revealed that there was an inverse correlation between Survivin and miR-494 expression (Pearson’s correlation coefficient, r = -0.418, P = 0.012). Downregulation of Survivin inhibited proliferation and colony formation, and resulted in cell cycle alteration. Induced Survivin overexpression relieved miR-494 mediated inhibition of GIST progression. Targeting PI3K effectively suppressed proliferation of GISTs with downregulation of Survivin. Survivin regulated KIT expression at the transcription level. Immunohistochemical analysis using 113 GIST tissues revealed that Survivin expression was significantly correlated with overall survival of GIST patients (P = 0.004). Conclusion: Our findings indicated that miR-494 synergistically suppressed GISTs by concomitantly targeting Survivin and KIT, with accompanying vertical blockade of the PI3K pathways.
Citation Format: Seongju Yun, Won Kyu Kim, Hoguen Kim. Identification of a novel regulator in GIST tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B088.
Abstract B110: Brusatol-induced degradation of HIF-1α by inhibiting c-Myc causes colorectal cancer cell death under hypoxia
Authors: Oh Eun-Taex , Kim Chan Woo , Kim Ha Gyeong , Park Heon Joo 
Published: August 2018

Abstract
Hypoxia-inducible factor-1 (HIF-1) regulates the expression of ~100 genes involved in metastasis, tumor growth, angiogenesis, chemoresistance, and radioresistance. Therefore, there is growing interest in targeting HIF-1 for cancer treatment. Here, we investigated the molecular mechanisms underlying brusatol-induced degradation of HIF-1α and colorectal cancer cell death under hypoxia. Brusatol pretreatment enhanced degradation of HIF-1α and increased colorectal cancer cell death under hypoxia. Brusatol activated the prolyl hydroxylases (PHDs), and siRNA-mediated knockdown of PHDs prevented brusatol-induced degradation of HIF-1α and colorectal cancer cell death. Additionally, 2,2’-bypyridyl, a ferrous iron chelator, effectively inhibited brusatol-induced degradation of HIF-1α and colorectal cancer cell death in hypoxia by inhibiting PHD activation. We also found that brusatol inhibited c-Myc expression, and showed that overexpression of c-Myc prevented brusatol-induced degradation of HIF-1α and colorectal cancer cell death by inhibiting mitochondrial ROS generation and subsequent ROS-mediated transition of ferrous iron to ferric iron. Consistent with these results, treatment of tumor-bearing mice with brusatol significantly suppressed tumor growth by promoting PHD-mediated HIF-1α degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1α degradation by promoting PHD activity and induces colorectal cancer cell death under hypoxia.
Citation Format: Eun-Taex Oh, Chan Woo Kim, Ha Gyeong Kim, Heon Joo Park. Brusatol-induced degradation of HIF-1α by inhibiting c-Myc causes colorectal cancer cell death under hypoxia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B110.