bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B201: Targeting HIF-1α in diffuse large B cell lymphoma: Role for HDAC inhibitors.
Authors: Bhalla Savita , Evens Andrew M. , Prachand Sheila , Schumacker Paul T. , Gordon Leo I. 
Published: August 2014

Abstract
Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival. We show here that HIF-1α is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway. PCI-24781, a pan histone deacetylase inhibitor (HDACI), enhanced accumulation of HIF-1α and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1α. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival. We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggest that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B201.
Citation Format: Savita Bhalla, Andrew M. Evens, Sheila Prachand, Paul T. Schumacker, Leo I. Gordon. Targeting HIF-1α in diffuse large B cell lymphoma: Role for HDAC inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B201.
Abstract B22: BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis by targeting TRAIL-R1 and RIPK1.
Authors: Du Jipei , Li Yan , Wang Xinyuan , Cheng Rao , Chen Degao , Zhang Ji , Wang Yufang 
Published: August 2014

Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) appears to be a promising candidate for cancer therapeutics because of its ability to preferentially induce apoptosis in malignant cells. However, heterogeneous sensitivity of cancer cells to TRAIL-induced apoptosis may lead to persistent growth of TRAIL-resistant cells, and preclude successful treatment of cancer by TRAIL. Here we show that that the orally available tyrosine kinase inhibitor BAY61-3606 potently enhances sensitivity of human colon cancer cells to TRAIL-induced apoptosis, and that this is associated with upregulation of TRAIL-R1 and downregulation of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Although treatment with BAY61-3606 only caused moderate colon cancer cell death, it significantly enhanced TRAIL-induced killing. This could be efficiently blocked by the general caspase inhibitor z-VAD-fmk, indicating TRAIL primarily induced apoptosis in the presence of BAY61-3606. Interestingly, exposure of colon cancer cells resulted in upregulation of TRAIL-R1 and downregulation of RIPK1, suggesting that they may play an important role in BAY61-3606-mediated sensitization of colon cancer cells to TRAIL-induced apoptosis. Taken together, our results suggest that combination with BAY61-3606 may be a useful strategy to improve the therapeutic efficacy of TRAIL in the treatment of colon cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B22.
Citation Format: Jipei Du, Yan Li, Xinyuan Wang, Rao Cheng, Degao Chen, Ji Zhang, Yufang Wang. BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis by targeting TRAIL-R1 and RIPK1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B22.
Abstract B222: Dicer substrate siRNAs to MYC, B-catenin, and other target genes effectively induce in vivo target gene knockdown and tumor inhibition.
Authors: Dudek Hank , Wortham Kathleen , Arvan Rokhand , Shah Anee , Ying Bo , Cyr Wendy , Yang Hailin , Zhou Wei , Saxena Utsav , Zhou Yi , Diwanji Rohan , Holmes Ben , Farkiwala Ruchir , Shah Aalok , Brown Bob 
Published: August 2014

Abstract
Although there are now multiple successful examples of targeted therapeutics in cancer, many key protein targets have remained largely ‘undruggable’, including transcription factors such as B-catenin (CTNNB1) and MYC. B-catenin mediates Wnt signaling, which is overactive in many cancers including hepatocarcinoma (HCC). RNAi offers a way to reach such undruggable targets by inhibiting their expression at the mRNA level. Dicer substrate siRNAs (“DsiRNAs”) can be particularly effective for gene silencing. DsiRNAs are longer than conventional siRNAs, and therefore are substrates for processing by Dicer, after which the product RNA duplexes are incorporated into RISC, leading to target mRNA knockdown. We have used DsiRNAs to target B-catenin, MYC, and other key genes in HCC and other cancers. Through large-scale DsiRNA screening, we have identified a series of high potency DsiRNAs with picomolar to sub-picomolar IC50 values for mRNA knockdown. Lead DsiRNAs fully tolerated extensive 2’-OMe modification, retaining high potency, and lacked detectable immunostimulatory activity. To test the effect of target gene knockdown on tumor growth in vivo, we used a lipid nanoparticle (LNP) delivery system. LNP/DsiRNA particles effectively delivered to tumors in mouse tumor models, leading to rapid knockdown of target gene mRNA and protein. Knockdown of B-catenin, MYC, and other target genes strongly inhibited tumor growth. B-catenin knockdown also strongly reduced expression of the B-catenin-regulated genes Axin2 and MYC, a potential mechanism for tumor inhibition. In summary, we have developed high potency DsiRNAs to cancer target genes, and effectively delivered these DsiRNAs to tumors in vivo, resulting in inhibition of target gene expression and inhibition of tumor growth. DsiRNA therapeutics show promise as novel agents for reaching traditionally undruggable target genes.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B222.
Citation Format: Hank Dudek, Kathleen Wortham, Rokhand Arvan, Anee Shah, Bo Ying, Wendy Cyr, Hailin Yang, Wei Zhou, Utsav Saxena, Yi Zhou, Rohan Diwanji, Ben Holmes, Ruchir Farkiwala, Aalok Shah, Bob Brown. Dicer substrate siRNAs to MYC, B-catenin, and other target genes effectively induce in vivo target gene knockdown and tumor inhibition. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B222.
Abstract B226: MiR-148a dependent apoptosis of bladder cancer cells is mediated by the epigenetic modifier DNMT1.
Authors: Lombard Alan P. , Libertini Steve , Costanzo Nicole , Lim Rebecca , Mudryj Maria 
Published: August 2014

Abstract
Introduction: MiRNAs are now recognized as major players in cancer. MiR-148a has been shown to be a tumor suppressor in the context of several cancers including prostate, gastric, and lung but a study investigating its role in bladder cancer has never been performed. Here we sought to characterize the expression and role of miR-148a in bladder cancer.
Methods: Real time PCR was used to assess the levels of miR-148a across several bladder cancer cell lines. MiR-148a mimics were employed in T24 and UM-UC-3 cells to assess proliferation by CCK-8 proliferation assay, colony formation assay, and flow cytometry. Mimics were also used to assess apoptosis by immunoblot and annexin-V staining. SiRNA was used to knock-down DNMT1 to phenocopy miR-148a treatment. CCK-8 proliferation assays and crystal violet staining were used to assess the effects of miR-148a added to either cisplatin or doxorubicin on T24 and UM-UC-3 cells.
Results: All bladder cancer cell lines had significantly reduced expression of miR-148a than that of a control immortalized urothelial cell line. MiR-148a mimic treatment of T24 and UM-UC-3 cells lead to large decreases in viability. Flow cytometry demonstrated an S-phase arrest in miR-148a mimic treated cells versus control oligo treated cells. Immunoblots for cleaved caspase-3 and cleaved PARP along with annexin-V staining showed strong induction of apoptosis in miR-148a mimic treated cells. MiR-148a was shown to target DNMT1 and DNMT1 knock-down was able to phenocopy results from miR-148a mimic treatment suggesting DNMT1 is downstream of miR-148a. Finally, we found that miR-148a can be used with either cisplatin or doxorubicin for an additive effect in inducing apoptosis.
Conclusions: Our work demonstrates for the first time that miR-148a plays a tumor suppressive role in bladder cancer and suggests it could be used as a novel therapeutic agent either alone or in conjunction with chemotherapeutics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B226.
Citation Format: Alan P. Lombard, Steve Libertini, Nicole Costanzo, Rebecca Lim, Maria Mudryj. MiR-148a dependent apoptosis of bladder cancer cells is mediated by the epigenetic modifier DNMT1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B226.
Abstract B229: TBKI kinase inhibition blocks RANTES secretion and exhibits minimal tumor growth inhibition in oncogenic Ras-driven tumor models.
Authors: Van Horn Robert , Yin Tinggui , Zhang Xiaoyi , Yu Chunping , Zhang Youyan , Gong Xue-Qian , Buchanan Sean , Ye Xiang S. , McMillen William , Barda David , Peng Sheng-Bin 
Published: August 2014

Abstract
TANK-binding kinase 1 (TBK1) is a non-canonical IKK family member and plays a critical role in innate immunity by modulating cytokine production, interferon, and NF-kB signaling. It is recently reported that TBK1 directly engages Akt survival signaling to support oncogenic Ras-driven transformation. TBK1 is also identified as a synthetic lethal partner in KRas mutant NSCLC through systematic RNA interference. In this study, we have characterized LSN3090729, a 4-aryl-2-aminopyrimidine derivative as a selective TBK1 kinase inhibitor. Biochemical and cellular analyses demonstrate that LSN3090729 is a potent TBK1 kinase inhibitor, and selectively inhibits TBK1 based on in vitro activities in biochemical assays developed with a panel of protein kinases. In Panc-1, a pancreatic tumor cell line with KRas mutation, LSN3090729 inhibits EGF-induced phosphorylation of AKT at both Thr308 and Ser473 sites. Pharmacokinetic analysis shows that LSN3090729 has an over 70% of oral bioavailability with an acceptable half life in rodents. In a mouse pharmacology model, LSN3090729 blocks LPS-induced RANTES secretion in a dose-dependent manner with 67%, 79%, and 90% inhibition at 10, 30, and 100 mg/kg, respectively. LSN3090729 is assessed for its anti-proliferation activities in vitro in a panel of tumor cells with KRas mutation or other genetic background. The sensitivity of these tumor cells to LSN3090729 in two dimensional proliferation or three dimensional soft agar growth assays appears not correlated with status of KRas mutation. In xenograft models of HCT116 and Panc-1, both with a KRas mutation, treatment of LSN3090729 exhibits minimal anti-tumor growth activities, suggesting that a combination approach might be required for TBK1 kinase inhibition to be effective in cancer settings.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B229.
Citation Format: Robert Van Horn, Tinggui Yin, Xiaoyi Zhang, Chunping Yu, Youyan Zhang, Xue-Qian Gong, Sean Buchanan, Xiang S. Ye, William McMillen, David Barda, Sheng-Bin Peng. TBKI kinase inhibition blocks RANTES secretion and exhibits minimal tumor growth inhibition in oncogenic Ras-driven tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B229.
Abstract B254: Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer.
Authors: Kim Woojin , Bird Gregory H. , Neff Tobias , Guo Guoji , Kerenyi Marc A. , Walensky Loren D. , Orkin Stuart H. 
Published: August 2014

Abstract
Enhancer of zeste homolog 2 (EZH2) is the histone lysine N-methyltransferase component of the Polycomb repressive complex 2 (PRC2), which, in conjunction with embryonic ectoderm development (EED) and suppressor of zeste 12 homolog(SUZ12), regulates cell lineage determination and homeostasis. Enzymatic hyperactivity of EZH2 has been linked to aberrant repression of tumor suppressor genes in diverse cancers. Here, we report the development of stabilized a-helix of EZH2 (SAH-EZH2) peptides that selectively inhibit H3 Lys27 trimethylation by dose-responsively disrupting the EZH2-EED complex and reducing EZH2 protein levels, a mechanism distinct from that reported for small-molecule EZH2 inhibitors targeting the enzyme catalytic domain. The essential α-helical domain of EZH2 (residues 40-68) that engages EED established the basis for designing hydrocarbon-stapled derivatives to disrupt the specific protein interaction. Non-natural amino acids with olefinic side chains were substituted at (i, i + 4) positions within the EZH2 α-helical sequence, followed by ruthenium-catalyzed olefin metathesis, to yield SAH-EZH2 peptides. Our lead, cell-permeable analog effectively targeted EED in situ, dissociated the EZH2-EED complex and impaired the function of PRC2, as reflected by reduction of the H3K27me3 and EZH2 protein levels, and increased expression of PRC2-regulated cell differentiation marker genes. In response to SAH-EZH2 treatment, murine MLL-AF9 leukemia cells, which are PRC2-dependent, manifested growth arrest and monocyte-macrophage differentiation, in accordance with the phenotypic consequences of shRNA-mediated reduction of EZH2 (or EED) or genetic ablation of Ezh2 (or Eed). In evaluating SAH-EZH2 activity alongside the small-molecule EZH2 inhibitor GSK126 in a series of B-cell lymphoma lines, we observed sequence-specific antiproliferative responses, transcriptional modulation, cellular specificity and a distinct mechanism of action for SAH-EZH2.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B254.
Citation Format: Woojin Kim, Gregory H. Bird, Tobias Neff, Guoji Guo, Marc A. Kerenyi, Loren D. Walensky, Stuart H. Orkin. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B254.
Abstract B255: Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells.
Authors: Okuhira Keiichiro , Demizu Yosuke , Hattori Takayuki , Ohoka Nobumichi , Shibata Norihito , Nishimaki-Mogami Tomoko , Okuda Haruhiro , Kurihara Masaaki , Naito Mikihiko 
Published: August 2014

Abstract
Breast cancer is the leading cause of cancer death in women. Most of the primary breast cancers express estrogen receptor α (ERα) and they show estrogen-dependent proliferation. Since tamoxifen antagonizes estrogen in breast cancers, it is widely used to treat the primary breast cancers. However, tamoxifen also shows a partial agonistic activity in different tissues and cellular context, which sometimes causes a detrimental effect.
An alternative strategy to kill the estrogen signaling is to downregulate ERα protein. We have developed a protein knockdown system to induce degradation of target proteins via the ubiquitin-proteasome system (UPS) in cells. The molecules for protein knockdown, which we named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser), are composed of two different ligands connected by a linker; one is a ligand for cellular inhibitor of apoptosis protein 1 (cIAP1) and the other is a ligand for a target protein. Accordingly, SNIPER is expected to crosslink a ubiquitin ligase cIAP1 and the target protein in the cells, thereby inducing the cIAP1-mediated ubiquitylation and proteasomal degradation of the target protein.
By using tamoxifen as a ligand for ERα, we developed novel SNIPER to knockdown ERα protein. SNIPER(ER) induced degradation of ERα and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer MCF-7 cells. Intriguingly, after the ERα degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, and reactive oxygen species (ROS) mediate the necrotic cell death in the SNIPER(ER)-treated MCF-7 cells. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα-positive breast cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B255.
Citation Format: Keiichiro Okuhira, Yosuke Demizu, Takayuki Hattori, Nobumichi Ohoka, Norihito Shibata, Tomoko Nishimaki-Mogami, Haruhiro Okuda, Masaaki Kurihara, Mikihiko Naito. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B255.
Abstract B272: Rationale for combinatorial therapeutics to inhibit BRAF fusion activation.
Authors: Sievert Angela Jae , Lang Shih-Shan , Silva Amanda , Brewington Danielle , Mueller Sabine , Haas-Kogan Daphne A. , Storm Phillip B. , Resnick Adam C. 
Published: August 2014

Abstract
We have previously shown that pediatric gliomas harbor BRAF mutations, including the canonical BRAF V600E mutation as well as BRAF fusion genes. KIAA1549 was the first fusion partner identified in gliomas, and more recently several other partners have been found albeit at a much lower frequency. Regardless of the partnered gene, all of the BRAF fusions (BRAF-f) retain the BRAF kinase domain but lose the N-terminal regulatory domain. Our recently published work has demonstrated the KIAA1549-BRAF fusion is resistant to and instead undergoes paradoxical activation in response to PLX4720, a research analog of the BRAF inhibitor vemurafenib. In contrast, the second generation "paradox-breaking" inhibitor PLX8394 successfully targeted KIAA1549-BRAF in vitro. We now demonstrate PLX8394's efficacy in vivo in models of BRAF-f. However, as has been demonstrated for vemurafenib, single agent targeting with PLX8394 can give rise to emergent resistance through activation of the PI3K/mTOR pathway, suggesting additional and/or combinatorial targeting of pathways may be necessary to prevent resistance in BRAF-f expressing cells. Using BRAF-f expressing cells we have characterized mechanisms of emergent resistance and combinatorial targeting approaches targeting MEK and PI3K/mTOR pathways. As there are ongoing clinical trials with everolimus and MEK inhibitors in pediatric gliomas, a strong rationale exists for combinatorial mTOR and MEK inhibitors in treating tumors that harbor BRAF-f.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B272.
Citation Format: Angela Jae Sievert, Shih-Shan Lang, Amanda Silva, Danielle Brewington, Sabine Mueller, Daphne A. Haas-Kogan, Phillip B. Storm, Adam C. Resnick. Rationale for combinatorial therapeutics to inhibit BRAF fusion activation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B272.
Abstract B3: Anti-angiogenic properties of FAK-VEGFR3 scaffold inhibitors, C9 and C10.
Authors: Agharkar Priyanka A. , Ethirajan Manivannan , Liao Jianqun , Yemma Michael , Buckley Brian , Chernov Mikhail , Cance William , Pandey Ravindra , Kurenova Elena 
Published: August 2014

Abstract
Introduction: Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor 3 (VEGFR3) are tyrosine kinases, which function as key modulators of survival and metastasis signals in cancer cells. We have previously shown that VEGFR3 binds to the FAT domain of FAK and this interaction promotes the survival of tumor cells. We developed novel small molecule compounds C9 and C10 which specifically bind and inhibit the FAK-VEGFR3 interaction. Both these compounds inhibit cancer cell proliferation, induce apoptosis, disrupt the FAK-VEGFR3 signaling axis, and significantly inhibit tumor growth in xenograft mouse models of breast and pancreatic cancer. Since FAK and VEGFR3 have been implicated in tumor angiogenesis, we investigated the potential anti-angiogenic effects of C9 and C10.
Methods: Binding of C9 and C10 to the FAT domain of FAK was tested using fluorescence polarization. Effects of C9 and C10 were tested in vitro by MTS assay (viability) and tube formation assay using HUVEC cells. Directed in vivo angiogenesis assay (DIVAA) kit was used to determine anti-angiogenic effects of both compounds. Single agent efficacy of C9 and C10 was tested in a pancreatic xenograft mouse model for 30 days. Mouse tumor tissues were analyzed for markers of proliferation (Ki67), endothelial vessels (CD31), and lymphangiogenic vessels (LYVE1) using immunohistochemistry.
Results: Fluorescence polarization confirmed that C9 and C10 effectively bind to the FAT domain of FAK. C9 and C10 reduced cell viability of HUVEC cells and dramatically decreased tube formation by reducing total branching points, total loops and total tube length in a dose and time dependent manner. DIVAA assay confirmed that C9 and C10 significantly reduced the formation of endothelial blood vessels as compared to untreated groups. In vivo, 30 days treatment with low doses of C9 and C10 as single agents led to 40% to 45% reduction in tumor volume (P&lt;0.05). Further analyses of these mouse tumors confirmed the anti-angiogenic effects of C9 and C10.
Conclusions: We have shown that targeting the FAK-VEGFR3 protein protein interaction site allows for dual inhibition of tumor proliferation as well as tumor angiogenesis. This study highlights the importance of oral-based small molecule inhibitors that might impact the therapeutic management of solid tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B3.
Citation Format: Priyanka A. Agharkar, Manivannan Ethirajan, Jianqun Liao, Michael Yemma, Brian Buckley, Mikhail Chernov, William Cance, Ravindra Pandey, Elena Kurenova. Anti-angiogenic properties of FAK-VEGFR3 scaffold inhibitors, C9 and C10. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B3.