bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2137: JAK2 as a novel therapeutic target in anaplastic thyroid cancer
Authors: Pinto Nicole C. , Ruicci Kara , Prokopec Stephenie , Searle Karlee , Lowerison Matthew , Yoo John , Fung Kevin , MacNeil Danielle , Leong Hon S. , Datti Alessandro , Boutros Paul C. , Barrett John W. , Nichols Anthony C. 
Published: July 2017

Abstract
Introduction: Thyroid carcinoma is the most common endocrine malignancy. Anaplastic thyroid cancer (ATC) is rare (1.3%) and represents arguably the most lethal human malignancy with 1-year survival rates of only 10%. There are currently no effective treatments for the majority of patients, highlighting an urgent need for novel therapeutics to manage this disease.
Objective: To validate the functional importance of JAK2 as a therapeutic target in ATC.
Methods: In this study, we have used siRNA knockdown to interrogate the JAK2 signaling pathway as a therapeutic target in ATC. We investigated the mechanism of action and cell death, and assayed for migration and invasion, in vitro. The chick chorioallantoic membrane (CAM) model was also utilized for drug testing, whereby 1x106 Cal62 ATC cells were on-planted to the chick embryo membrane. Two days post on-plant, CAM models were treated with the vehicle (DMSO) or lestaurtinib to measure outcomes including tumor volume and vascularity.
Results: We identified the JAK2 inhibitor lestaurtinib as an inhibitory agent controlling cell line proliferation at submicromolar mean inhibitory concentrations. Immunoblotting revealed the inhibition of phosphorylation of the downstream signaling molecule STAT5 in a dose-dependent manner. Treatment of Cal62 cells resulted in a decrease in cell migration using the scratch-wound assay. The anti-proliferative effective of lestaurtinib did not cause apoptosis, autophagy or cell senescence. CAM models treated with a 4 uM dose of lestaurtinib showed a significant decrease in both tumor volume and vascularity.
Conclusions: Lestaurtinib was found to provide potent control of ATC cell proliferation and migration, and was also found to decrease tumor growth and vascularity in a CAM model. Knockout studies are underway to confirm that the anticancer effect of this drug is indeed mediated through JAK2 signaling. If validated, JAK2 represents a novel therapeutic target for the treatment of aggressive thyroid cancers.
Citation Format: Nicole C. Pinto, Kara Ruicci, Stephenie Prokopec, Karlee Searle, Matthew Lowerison, John Yoo, Kevin Fung, Danielle MacNeil, Hon S. Leong, Alessandro Datti, Paul C. Boutros, John W. Barrett, Anthony C. Nichols. JAK2 as a novel therapeutic target in anaplastic thyroid 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 2137. doi:10.1158/1538-7445.AM2017-2137
Abstract 2140: Understanding molecular mechanisms underlying heme function in non-small cell lung cancer cells
Authors: Sohoni Sagar , Vidal Chantal , Zhang Li 
Published: July 2017

Abstract
Heme is a central molecule for mitochondrial respiration and for all processes involved in oxygen utilization. Heme serves as a prosthetic group or as a cofactor for a number of oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Heme directly regulates the synthesis, translocation and assembly of these enzyme complexes. Most, if not all, human cells can synthesize and uptake heme from the circulation. A number of epidemiological studies have shown that high heme intake is associated with increased risk of cancer, including lung cancer. To assess the status of heme metabolism in lung cancer cells, we performed a series of experiments in non-small-cell lung cancer (NSCLC) cell lines such as HCC4017, H1299, A549, H2009, H1395, H460 and Calu-3. We then compared results with an immortalized normal lung cell line, HBEC30KT and observed significant increase in rates of heme synthesis and heme uptake in NSCLC cells compared to HBEC30KT. Previous studies carried out in our lab showed intensified mitochondrial respiration and increased levels of heme and hemoproteins in NSCLCs. We examined the effect of heme depletion on mitochondrial biogenesis and function. We observed that mitochondrial functions such as ATP production, NAD/NADH ratios and ROS production are also affected by heme depletion. Proteins involved in mitochondrial biogenesis are significantly affected when cells are grown in heme depleted medium. Studies are currently underway to check how heme depletion affects the interactions of various transcription factors involved in mitochondrial biogenesis and function.
Citation Format: Sagar Sohoni, Chantal Vidal, Li Zhang. Understanding molecular mechanisms underlying heme function in non-small cell lung cancer 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 2140. doi:10.1158/1538-7445.AM2017-2140
Abstract 2144: A novel method for high-throughput discovery of neo-antigens and corresponding T-cell receptors
Authors: Peng Songming , Zaretsky Jesse , Bethune Michael T. , Hsu Alice , Baltimore David , Ribas Antoni , Heath James 
Published: July 2017

Abstract
Immunotherapies that boost the ability of endogenous T cells to destroy cancer cells have demonstrated therapeutic efficacy in several human malignancies. Cytotoxic T cells actively recognize peptide antigens, which are displayed on major histocompatibility complexes (MHCs) on the surface of the malignant cells, to play a central role in cancer immunotherapy. However, efficient methods for identifying the tumor antigens and the corresponding T cell receptors are still limited. We report here a DNA-barcode nanoparticle and microfluidics-based method to sort and enumerate neoantigen-specific T cells, at an unprecedented level of sensitivity. The method also permits the matching of a single neoantigen to a specific CD8+ T cell with the TCR a/b gene sequence. The resultant information informs an immunotherapy regimen that is specific for that patient, which can be used to custom-design effective ACT therapies.
Citation Format: Songming Peng, Jesse Zaretsky, Michael T. Bethune, Alice Hsu, David Baltimore, Antoni Ribas, James Heath. A novel method for high-throughput discovery of neo-antigens and corresponding T-cell receptors [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 2144. doi:10.1158/1538-7445.AM2017-2144
Abstract 2145: Regulation of YAP1 during hypoxia and its novel role in vascular mimicry and angiogenesis
Authors: Singhal Namrata Bora , Chellappan Srikumar 
Published: July 2017

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. As in other solid tumors, angiogenesis is necessary for the growth and progression of NSCLC. Vascular mimicry is a phenomenon in which non-endothelial tumor cells form angiogenic vascular structures. We have shown in the past that NSCLC cancer stem-like cells (CSCs) have unique ability to undergo vascular mimicry. The present study shows that transcriptional co-activator YAP1, the oncogenic component of the Hippo pathway, enables the NSCLC CSCs to form angiogenic tubule-like structures in matrigel. Inhibition of YAP1 or depletion of YAP1 suppressed vascular mimicry of CSCs as well as angiogenic tubule formation by HUVECs in matrigel as well as in a fibrin gel bead assay (FIBA) assay. The NSCLC CSCs were found to have higher mRNA expression of VEGF receptor II (KDR) and Angiopoietin-2 (AngPT-2) and depletion of YAP1 reduced the expression of VEGF, KDR and AngPT-2 mRNA; these promoters were induced by YAP1 in transient transfection assays, suggesting a possible molecular mechanism by which YAP1 regulates angiogenesis. Hypoxia is a strong inducer of tumor angiogenesis, cancer progression and metastasis. Our experiments showed that NSCLC cells grown in hypoxic conditions or treated with hypoxia mimetic DMOG have higher YAP1 mRNA and protein expression. However, such a change was not observed in the expression of YAP1 orthologue, TAZ, nor in the canonical Hippo pathway proteins like LATS1&2, Mst1&2, Sav or Mob. We identified a novel regulation of YAP1 by prolyl hydroxylase PHD2, which is mainly known to regulate HIF1α. PHD2 was found to hydroxylate proline residue(s) in YAP1 in a region between aa 284 to aa 289 as seen by mutational analysis. YAP1 was found to directly bind to PHD2 and depletion of PHD2 or treatment with DMOG which is an inhibitor of prolyl hydroxylases, elevated YAP1 protein levels in the nucleus. Further, YAP1 was found to associate with HIF1α as detected by co-immunoprecipitation experiments and could enhance HIF1α-mediated induction of the VEGF promoter. Proximity ligation assays performed on TMA showed enhanced YAP1 and HIF1α interaction in lung tumor tissues compared to normal cells. Our data suggest a novel regulation of YAP1 in hypoxic environment that supports angiogenesis and tumor growth.
Citation Format: Namrata Bora Singhal, Srikumar Chellappan. Regulation of YAP1 during hypoxia and its novel role in vascular mimicry and angiogenesis [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 2145. doi:10.1158/1538-7445.AM2017-2145
Abstract 2157: P73 isoforms regulate cellular survival and response to treatment in diffuse large B-cell lymphoma
Authors: Hassan Hesham M. , Varney Michelle L. , Althof Pamela A. , Caponetti Gabriel C. , Fu Kai , Weisenburger Dennis D. , Singh Rakesh K. , Dave Bhavana J. 
Published: July 2017

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (NHL) and is curable in more than 60% of the cases. Despite long-term remission achieved with current therapies, relapse occurs in almost one-third of the cases. Rearrangements of chromosome locus 1p36 with ensuing deletion or disruption of TP73, one of the most distally located putative tumor suppressor genes, is frequent in many NHL subtypes, including DLBCL, and confers inferior prognosis. Recent reports in normal B-cells and lymphoma animal models suggest an important role of p73 in B-cell lymphomas; however, the biological significance of p73 isoforms in DLBCL is not clear. TP73 is a member of the TP53 family that shares structural homology and hence is capable of transactivating p53 target genes. We investigated the relationship between rearrangements of chromosome locus 1p36 and p73 expression and examined whether differential expression of p73 isoforms (TAp73 and ΔNp73) correlate with proliferation and apoptosis in DLBCL. We utilized molecular techniques in conjunction with fluorescence in situ hybridization (FISH) in untreated histologically confirmed DLBCL patient specimens. In our data set, the 1p36 chromosomal locus was disrupted (mainly heterozygous deletion) in 35% of the cases and was significantly associated with ΔNp73 expression. Subsequent immunohistochemical analysis showed a significant positive correlation between TAp73 and cleaved caspase-3 expression and between ΔNp73 and Ki-67 expression. Additionally, we observed a negative correlation between TAp73 and the anti-apoptotic molecules Bcl-2 and Bcl-6. We then performed in vitro studies in DLBCL cells and modulated the expression of TAp73 and ΔNp73 using expression vectors and siRNA. TAp73-transfected cells were more susceptible to serum deprivation and doxorubicin treatment, conversely the ΔNp73-transfected cells were more resistant to serum deprivation and doxorubicin treatment compared to control cells. Thus, rearrangements of 1p36 consequently deregulates p73 isoform expression in DLBCL. Our data emphasizes the importance of delineating the functional aspect of genetic alterations and underscores the significant role of p73 isoforms in DLBCL pathogenesis and treatment.
Citation Format: Hesham M. Hassan, Michelle L. Varney, Pamela A. Althof, Gabriel C. Caponetti, Kai Fu, Dennis D. Weisenburger, Rakesh K. Singh, Bhavana J. Dave. P73 isoforms regulate cellular survival and response to treatment in diffuse large B-cell lymphoma [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 2157. doi:10.1158/1538-7445.AM2017-2157
Abstract 2158: Targeted intracellular disruption of oncogenic p53/HDM2 and p53/HDMX complexes underlies the therapeutic activity of a stapled peptide drug
Authors: Walensky Loren D. , Wachter Franziska , Morgan Ann , Godes Marina , Bird Gregory 
Published: July 2017

Abstract
The first anti-cancer stapled peptide drug has now been advanced to clinical testing in relapsed human cancers that retain the expression of wild-type p53. A common mechanism for cancer cell suppression of wild-type p53 is overexpression of the negative regulators HDM2 and HDMX, which neutralize p53 through protein interaction. Selective HDM2 inhibitor molecules can effectively reactivate p53 in certain cancers, but the co-expression of HDMX can cause resistance, highlighting the need for dual HDM2/HDMX targeting. We previously developed stapled peptides modeled after the p53 transactivation domain to harness the natural propensity of this alpha-helical motif to engage both targets with high affinity and selectivity. Here, we demonstrate that ALRN-7041, a next-generation, clinical-grade stapled peptide, achieves time-dependent cellular uptake and nuclear localization without membrane perturbation, dose-dependently dissociates p53/HDM2 and p53/HDMX complexes as assessed by real-time protein interaction monitoring in live cells, and impairs the viability of cancer cells bearing wild-type p53 by inducing a surge in p53 protein level. Applying an unbiased statistical approach to determine which biophysical parameters dictate the cellular uptake of stapled peptides, we elucidated the design features of ALRN-7041 that confer intracellular access, providing a roadmap for generating cell-permeable stapled peptides with on mechanism cellular activity for clinical translation. We find that cancer cells exhibiting a signature of HDM2, HDMX, and wild-type p53 co-expression are strikingly susceptible to ALRN-7041, highlighting the therapeutic potential of dual HDM2/HDMX inhibition by a cell-penetrant stapled peptide in human cancer.
Citation Format: Loren D. Walensky, Franziska Wachter, Ann Morgan, Marina Godes, Gregory Bird. Targeted intracellular disruption of oncogenic p53/HDM2 and p53/HDMX complexes underlies the therapeutic activity of a stapled peptide drug [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 2158. doi:10.1158/1538-7445.AM2017-2158
Abstract 2162: MEK signaling marks resistance to synthetic lethality induced by PI3K/Akt and BCL-XL inhibition in PTEN-mutant cancers
Authors: Joshi Raghav , Ren Wenying , Mathew Paul 
Published: July 2017

Abstract
Background: Loss of PTEN represents one of the most common disruptions of tumor suppressor activity in the progression of human neoplasia. There are no established precision medicine approaches defined in PTEN-deficient neoplasms which include prostate, breast, glioblastoma (GBM) and uterine cancers. In PTEN-mutant prostate cancer cells, the PI3K/Akt pathway collaborates with BCL-XL specifically, to regulate the apoptotic threshold (Ren, MCR 2016). Whereas single agent PI3K/Akt inhibitors are ineffective in inducing cell death, combined inhibition of PI3K/Akt and BCL-XL in PTEN-mutant prostate cancer cells results in synergistic apoptosis suggesting a novel therapeutic strategy with translational potential in this important subset of disease.
Hypothesis: We hypothesized that synthetic lethality following combinatorial PI3K/BCL-XL inhibition is conserved across the range of PTEN-mutant cancers.
Methods: PTEN-mutant cell lines (ATCC), validated for PTEN-loss and p-Akt expression, were assessed in apoptosis (cleaved Parp) and cell-viability assays following combined PI3K (Buparlisib, SelleckChem) and BCL-XL (A-1331852, AbbVie) inhibition (1µM each, 24h). Since MEK signaling has been associated with resistance to PI3K pathway inhibition, p-Erk was profiled as a candidate marker of resistance. The contribution of MEK signaling to the apoptotic threshold in p-Erk expressing PTEN-mutant cells was tested with pharmacological MEK inhibition (Trametinib, SelleckChem; 1,3,5 µM 48h) in combination.
Results:
MEK signaling and PI3K/BCL-XL inhibition in PTEN-mutant cancersSourceCell linePTENp-Aktp-ErkSynergistic Apoptosis with PI3K / BCL-XL inhibitionLoss of cell viabilityp-Erk suppression with MEK inhibitionApoptosis with concomitant MEK inhibitionProstatePC3AbsentPresentAbsentYesYesN/AN/AProstateLNCaPAbsentPresentAbsentYesYesN/AN/AProstateC4-2BAbsentPresentAbsentYesYesN/AN/ABreastZR-75-1AbsentPresentWeakYesYesN/AN/AUterineSK-UT-1AbsentPresentPresentNoNoYesYesGBMA-172AbsentPresentPresentNoNoYesNoCervixC33-AAbsentPresentPresentNoNo--
Conclusions: Synthetic lethality in PTEN-mutant tumor cells with PI3K/BCL-XL inhibition was confined to tumor cells without active MEK signaling. MEK inhibition inconsistently overcomes resistance to therapy suggesting heterogeneity of survival pathways in p-erk expressing PTEN-deficient tumors. These data have implications for precision medicine approaches in PTEN-deficient tumors as absence of p-Erk expression may predict for a responsive phenotype.
Citation Format: Raghav Joshi, Wenying Ren, Paul Mathew. MEK signaling marks resistance to synthetic lethality induced by PI3K/Akt and BCL-XL inhibition in PTEN-mutant cancers [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 2162. doi:10.1158/1538-7445.AM2017-2162
Abstract 2163: Combined targeting of MEK and MCL-1 induces apoptosis and tumor regression of KRAS mutant NSCLC
Authors: Hata Aaron N. , Siddiqui Faria M. , Gomez-Caraballo Maria , Bilton Samantha J. , Timonina Daria , Nangia Varuna , Coxon Angela , Caenepeel Sean , Hughes Paul 
Published: July 2017

Abstract
There are currently no effective targeted therapeutic strategies for KRAS mutant non-small cell lung cancer (NSCLC). Single agent MEK inhibitors have demonstrated showed disappointing clinical activity, partly due to inability to induce a robust apoptotic response. Combining MEK inhibitors with BCL-XL/BCL-2 inhibitors may be effective for a subset of KRAS mutant cancers that are dependent on BCL-XL for survival, however this combination is unlikely to be an effective strategy for cancers dependent on MCL-1. We investigated the effect of combining the MEK inhibitor trametinib with a novel MCL-1 inhibitor (compound A), which possesses potent and selective anti-MCL-1 activity in vitro and in vivo, on KRAS mutant cancers. In contrast to colorectal cancer models, which are largely sensitive to combined MEK + BCL-XL inhibition, a subset of cell line and patient-derived mouse xenograft (PDX) KRAS mutant NSCLC models were significantly more sensitive to MEK + MCL-1 inhibition compared to MEK + BCL-XL. To model potential clinical strategies, we tested intermittent dosing regimens and unexpectedly discovered a method strategy for dramatically sensitizing KRAS mutant NSCLC cells to the MEK + MCL-1 combination. These studies provide rationale for the clinical evaluation of combined MEK + MCL-1 inhibitors for KRAS mutant NSCLC.
Citation Format: Aaron N. Hata, Faria M. Siddiqui, Maria Gomez-Caraballo, Samantha J. Bilton, Daria Timonina, Varuna Nangia, Angela Coxon, Sean Caenepeel, Paul Hughes. Combined targeting of MEK and MCL-1 induces apoptosis and tumor regression of KRAS mutant NSCLC [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 2163. doi:10.1158/1538-7445.AM2017-2163
Abstract 2166: Arsenic trioxide targets BCL6 oncoprotein for degradation in BCL6-dependent diffuse large B-cell lymphoma
Authors: Yue Lok Man , Chau David Hau Wing , Piao Wenying , Tse (Eric) Wai Choi , Kwong Yok Lam 
Published: July 2017

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma throughout the world. B-cell lymphoma 6 (BCL6) overexpression is frequently observed in DLBCL. Several recent studies have supported that BCL6 is a critical pathogenic oncoprotein in DLBCL. BCL6 represses various downstream genes, including ATR, TP53 and CDKN1A, thereby impairing DNA repair leading to derangement of cellular proliferation. Most importantly, a specific small molecule inhibitor targeting BCL6 successfully suppressed growth of BCL6-dependent DLBCL cell lines and primary human DLBCL cells, further suggesting that BCL6 plays an important pathogenetic role. Arsenic trioxide (As2O3) has been reported to target various oncogenic proteins, including PML-RARA in acute promyelocytic leukemia, cyclin D1 in mantle cell lymphoma, NPMc+ in acute myeloid leukemia and NPM-ALK in anaplastic large cell lymphoma, for degradation through ubiquitin-proteasome pathway. In this study, we investigated the effects of As2O3 on BCL6 in DLBCL.
As2O3 was found to inhibit cell proliferation and induce cell death via apoptosis in DLBCL cells. More interestingly, BCL6-dependent DLBCL cells were found to show higher sensitivity towards As2O3-induced cytotoxicity. BCL6 was found to be degraded by As2O3 at posttranslational level through the ubiquitin-proteasome pathway. Such degradation led to an upregulation of several downstream targets of BCL6, including PRDM1, CD44 and CD69. Moreover, As2O3 synergized with cisplatin to inhibit cell proliferation and enhance apoptosis in BCL6-dependent DLBCL cell lines. Concomitant treatment with As2O3 and cisplatin further enhanced the phosphorylation of Chk1 and γH2AX in these cells.
In conclusion, our data suggest that As2O3 is a potential therapeutic agent for the treatment of BCL6-dependent DLBCL. On top of that, new combination therapies can be developed to expand the therapeutic spectrum of As2O3 to other neoplasms.
Citation Format: Lok Man Yue, David Hau Wing Chau, Wenying Piao, (Eric) Wai Choi Tse, Yok Lam Kwong. Arsenic trioxide targets BCL6 oncoprotein for degradation in BCL6-dependent diffuse large B-cell lymphoma [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 2166. doi:10.1158/1538-7445.AM2017-2166