bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3064: Epigenetic manipulation can sensitize AML cells to differentiate with ATRA
Authors: Heimdal Kalsi , Ghimire Bikalpa , Hernandez Edjay Ralph , Super Heidi J. Gill 
Published: August 2019

Abstract
Human acute myeloid leukemia (AML), the most common type of acute leukemia, has approximately eight subtypes, many of which have poor prognosis. Most of these subtypes are associated with specific, recurrent chromosome translocations. These translocations result in fusion genes, which encode oncoproteins that block differentiation and promote proliferation of immature cells. The Myeloid Lymphoid Leukemia gene (MLL) is frequently involved in these translocations, and is considered a driver of the AML. Differentiation promoting drugs, such as all-trans-retinoic acid (ATRA) are an attractive alternative to cytotoxic chemotherapy, but few types of AML, other than acute promyelocytic leukemia (APL), respond to ATRA. We hypothesize that specific genes must be activated or inhibited in AML for drugs like ATRA to induce differentiation, and that gene activation or inhibition may be the result of specific epigenetic modification. We also hypothesize that AML with different genetic alterations may respond differently to specific epigenetic inhibitors. Our initial studies have focused on two MLL-driven AML cell lines, MV4;11 and THP-1, showing translocations t(4;11) and t(9;11), respectively, and one non-MLL related AML cell line, U937. MV4;11, THP-1, and U937 were treated with specific epigenetic modifiers, including tranylcypromine (TCP), an inhibitor of histone demethylase KMD1A/LSD1, N-acetyl-dinaline (CI-994), a general histone deacetylase inhibitor, and 3-deazaneplanocin A (DZNep), a S-adenosylhomocystein hydrolase inhibitor that depletes EZH2 and thus its associated H3K27me3 activity. Evidence for differentiation was noted in a variety of assays, including reduced cell proliferation as measured directly and by MTT assay, upregulation of myeloid-specific cell surface markers such as CD11b as measured by fluorescence-activated cell sorting (FACS), myeloid-related nuclear morphological changes noted with cytospin analysis of cells, and decreased AML-associated gene expression with qPCR. All three drugs seemed to sensitize U937 and THP-1 cells to differentiate when treated with ATRA. MV4;11 cells were sensitized to differentiate by CI-994 and DZNep with or without ATRA, although there was no indication of CD11b upregulation. However, MV4;11 was not sensitized by TCP to differentiate with or without ATRA. These experiments suggest epigenetic inhibitors may increase sensitivity to ATRA differentiation therapy, but since the two MLL cell lines responded differently the response may still be dependent on the specific MLL partner gene driving the AML.
Citation Format: Kalsi Heimdal, Bikalpa Ghimire, Edjay Ralph Hernandez, Heidi J. Gill Super. Epigenetic manipulation can sensitize AML cells to differentiate with ATRA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3064.
Abstract 3070: Discovery of novel potent allele-selective KRAS-G12C covalent inhibitors stemming from DNA-encoded library
Authors: McCort Gary , Arrebola Rosalia , Calvet Loreley , Ronan Baptiste , Vergne Fabrice , Duffieux Francis , Rak Alexey , Meaux Isabelle , Papin David , Fassy Florence , Delorme Cecile , Matthieu Magali , Nicolas Jean-Paul , Marcireau Christophe , Steier Valerie , Abecassis Pierre-Yves , Czepczor Valerie , Thomson Heather A. , Hupp Christopher D. , Guilinger J.P. , Zhang Ying , Keefe Anthony D. , Cuozzo John W. , Liu Julie , Debussche Laurent 
Published: August 2019

Abstract
From a screening of 27 106 covalent DNA-encoded compound library, a novel KRAS G12C chemical series has been identified. Original hit series compound displayed low µM covalent binding activity to KRAS G12C under GDP form associated with a k(inact)/Ki of 1,03 M-1.s-1, a stable electrophilic covalent warhead (T1/2 in 5mM GSH &gt; 24h), +12°C stabilization Delta Tm in DSF assay and 3 µM IC50 value in GEF assay, while no detectable covalent binding to KRAS G12C under GTP form and to KRAS WT or KRAS G12D under GDP form. From 3 µM, it also induced significant pERK inhibition in H358 KRAS-G12C but not in A549 KRAS G12S NSCLC cell lines. Unique binding mode to SII pocket was demonstrated by Xray crystallography. Multi-parametric and structural biology guided chemical optimization yielded potent KRAS G12C lead compounds which combine k(inact)/Ki &gt; 500 M-1.s-1, Delta Tm=20°C, 10 nM range pERK IC50 values with correlated direct KRAS G12C selective covalent modification. They also exhibited 100 nM range KRAS G12C allele-specific anti-proliferative activity and triggered significant apoptosis induction. In vivo treatment of mice bearing H358 tumour xenografts through oral route with optimized candidates showed a marked and prolonged inhibition of both pERK and DUSP6 mRNA as well as consistent direct KRAS-G12C covalent modification as evidenced by LC-MS in tumor samples. Altogether, these data demonstrate the power of DNA-encoded library approach to deliver potential drug candidates with selective cysteine-targeted irreversible mechanism of action on challenging oncology targets such as KRAS.
Citation Format: Gary McCort, Rosalia Arrebola, Loreley Calvet, Baptiste Ronan, Fabrice Vergne, Francis Duffieux, Alexey Rak, Isabelle Meaux, David Papin, Florence Fassy, Cecile Delorme, Magali Matthieu, Jean-Paul Nicolas, Christophe Marcireau, Valerie Steier, Pierre-Yves Abecassis, Valerie Czepczor, Heather A. Thomson, Christopher D. Hupp, J.P. Guilinger, Ying Zhang, Anthony D. Keefe, John W. Cuozzo, Julie Liu, Laurent Debussche. Discovery of novel potent allele-selective KRAS-G12C covalent inhibitors stemming from DNA-encoded library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3070.
Abstract 3075: Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2
Authors: Friese-Hamim Manja , Bogatyrova Olga , Ortiz Maria J. , Wienke Dirk , Heinrich Timo , Rohdich Felix , Duecker Klaus , Schultes Christoph , Huck Bayard , Zenke Frank T. , Blaukat Andree 
Published: August 2019

Abstract
N-terminal cleavage of methionine by methionine aminopeptidases is a crucial step in the maturation of proteins during protein biosynthesis. MetAP2, one of the two methionine aminopeptidases expressed in mammalian cells, has been identified as the target of the highly potent and irreversible inhibitor fumagillin to which antiangiogenic and antitumoral properties have been ascribed. This and other findings support the rationale to develop MetAP2 inhibitors for cancer therapy. The fumagillin derivative TNP-470 has been evaluated in several clinical trials, but development was discontinued following demonstration of unfavorable pharmacokinetics and side effects likely attributed to the reactivity of the compound. We have developed M8891, an orally bioavailable, potent, and reversible inhibitor of MetAP2. M8891 inhibited growth of primary endothelial cells as well as patient-derived tumor cells and demonstrated antiangiogenic and antitumoral activity in mouse models. Accumulation of an unprocessed MetAP2 substrate, methionylated elongation factor 1 α, Met-EF1a, was observed upon treatment with M8891 in vitro as well as in vivo confirming that MetAP2 can be effectively inhibited with this compound. In combination with sunitinib, M8891 demonstrated strong and durable antitumor activity in a cohort of patient-derived renal cancer xenografts at well-tolerated exposure levels. Predictive biomarker hypotheses generated from CRISPR sensitivity/resistance screens as well as analyses of molecular profiling data from PDX tumors are currently being evaluated in further nonclinical studies. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing.
Citation Format: Manja Friese-Hamim, Olga Bogatyrova, Maria J. Ortiz, Dirk Wienke, Timo Heinrich, Felix Rohdich, Klaus Duecker, Christoph Schultes, Bayard Huck, Frank T. Zenke, Andree Blaukat. Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3075.
Abstract 3085: A novel salicylanilide derivative inhibits castration-resistant prostate cancer via endoplasmic reticulum stress-triggered PERK autophagic signaling pathway
Authors: HSIEH Chia-Ling , Hung Hsu-Shan , Chen Kuan-Chou , Saka Teigi , Chiang Chih-Ying , Sung Shian-Ying 
Published: August 2019

Abstract
Background and Purpose: Metastatic castration-resistant prostate cancer (CRPC) is currently incurable. This study is to extend pharmacological value of our synthesized salicylanilide derivative, that has previously testified for its osteoclastogenesis activity, by exploring its additional cytotoxic properties and underlying mechanism in CRPC cells.
Experimental Approach: LCC03, a 5-(2′,4′-Difluorophenyl)-salicylanilide derivatives, was chemically synthesized and examined for cell growth inhibition in a serial of CRPC cell lines. Possible mechanisms involved in the anticancer activity was elucidated based on the changes in pathway-related protein expression and cellular events, together with antagonists for functional validation. The therapeutic efficacy and safety of LCC03 for the treatment of bone metastatic CRPC was evaluated in an experimental animal model.
Key Results: LCC03 dose-dependently suppressed proliferation and retarded cell cycle progression in CRPC cells. The classical autophagy features including autophagsomes formation and LC3-II conversation were dramatically shown in LCC03-treated CRPC cells, and it was associated with the suppressed AKT/mTOR signaling pathways, a major negative regulator of autophagy, Moreover, an expanded morphology of the ER, increased expression of the ER stress markers GRP78 and PERK, and eIF2α phosphorylation were observed. Blockage of autophagy and PERK pathways using small molecule inhibitors or shRNA knockdown reversed LCC03-induced autophagy and cell death, thus indicating that the PERK-eIF2α pathway contributed to the autophagy induced by LCC03. Furthermore, treatment of tumor-bearing mice with intraperitoneal administered LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity.
Conclusion and Implications: LCC03 induces cellular responses toward ER stress-induced autophagy via the PERK-eIF2α pathway that impairs proliferation and cell cycle progression and exhibits cytotoxicity against CRPC cells. The dual action of 5-(2′,4′-difluorophenyl)-salicylanilide on both the osteoclasts and the tumor cells strongly indicates that LCC03 is a promising anticancer candidate for preventing and treating metastatic CRPC.
Citation Format: Chia-Ling HSIEH, Hsu-Shan Hung, Kuan-Chou Chen, Teigi Saka, Chih-Ying Chiang, Shian-Ying Sung. A novel salicylanilide derivative inhibits castration-resistant prostate cancer via endoplasmic reticulum stress-triggered PERK autophagic signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3085.
Abstract 3092: Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine
Authors: Ohtani Hitoshi , Ørskov Andreas D. , Helbo Alexandra S. , Gillberg Linn , Liu Minmin , Zhou Wanding , Ungerstedt Johanna , Hellstrom-Lindberg Eva , Sun Weili , Liang Gangning , Jones Peter A. , Grønbæk Kirsten 
Published: August 2019

Abstract
The DNA methyltransferase inhibitors 5-azacitidine (AZA) and 5-aza-2-deoxycytidine (DAC) have been approved for the treatment of higher-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). A more comprehensive understanding of the molecular changes in patients treated with AZA is needed to help explain why only about 50% of these patients have clinical responses. We examined gene expression profiles in a total of 150 RNA samples taken before, during and after treatment with AZA, in three cohorts of patients with hematological cancers (40 patients total; 15 non-responders, 25 responders). We show that activation of the innate immune system is linked to clinical response to AZA treatment. We also measured the induced expression of transposable elements (TEs) to determine whether this was a potential trigger for the immune response. Both responders and non-responders showed robust upregulation of TEs however responders showed the statistically significant upregulation of specific classes of evolutionarily young transposable elements (TEs). These include short and long nuclear elements (SINEs and LINEs) and endogenous retroviruses (ERVs). Moreover, the upregulation of type I interferon signaling pathway genes in responders was significantly higher than non-responders, but not cancer testis antigens (CTAs) or tumor suppressor genes with the exception of CDKN2A and CDKN2B. Therefore, we suggest that induction of specific subsets of silenced evolutionarily young TEs may be a key to the success of epigenetic therapy in hematological cancer patients.
Citation Format: Hitoshi Ohtani, Andreas D. Ørskov, Alexandra S. Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellstrom-Lindberg, Weili Sun, Gangning Liang, Peter A. Jones, Kirsten Grønbæk. Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3092.
Abstract 3094: Reclassification of pancreatic adenocarcinoma with distinct fibroblast and immune characteristics and therapeutic targets
Authors: Poudel Pawan , Neuzillet Cindy , Kocher Hemant , Sadanandam Anguraj 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDA) with overall poor prognosis is characterized by an abundant desmoplastic stroma comprised of extracellular matrix proteins producing cancer-associated fibroblasts (CAFs). PDA treatment is still primarily based on the use of cytotoxic chemotherapies in unselected patients with modest benefit. To define biomarkers of potential treatment prediction, we (Collisson and Sadanandam; PDAssigner) defined three cancer and four intrinsic CAF (pCAFassigner; first classification to our knowledge) subtypes using PDA patient tumors and primary CAF cultures, respectively. While other groups defined up to four cancer subtypes, there exists additional unrevealed heterogeneity at the level of cancer, stromal and immune cell interactions that defy systematic classification of PDA due to small sample sizes.
To circumvent this issue and to better characterize heterogeneity along with cellular phenotypes, we successfully applied signatures from our pCAFassigner and heterocellular subtypes (representing different cell types/phenotypes of colorectal cancer) along with CIBERSORT to clinical PDA (~757) samples. Interestingly, this analysis identified a subset of our published quasi-mesenchymal (QM)-PDA subtype samples with either increased stem/stroma or inflammatory (not immunogenic subtype) heterocellular characteristics. The stem-like subtype showed variable enrichment of intrinsic CAF (pCAFassigner) subtype characteristics with distinct tumor promoting capabilities (as assessed using CAF:cancer co-culture system) and immune cell interactions. Hence, QM-PDA subtype samples with stem-like characteristics were further split into four stroma-enriched sub-subtypes with significant (p&lt;0.05; log-rank test) differences in patient prognosis. In contrast, the other stem-like QM-PDA subtype patients were enriched for adaptive immunity and may benefit from B cell therapy. On the other hand, inflammatory-enriched QM-PDA subtype samples contained increased macrophages and highly invasive CAFs leading to poorest patient prognosis. These inflammatory subtype patients may respond well to immune therapies targeting macrophages. While all PDA samples are considered to have uniformly high stroma, our study demonstrates that the stromal content is highly variable depending on the sub-subtypes leading to potential personalized therapy responses targeting immune and/or stromal compartments in this devastating cancer type.
Note: This abstract was not presented at the meeting.
Citation Format: Pawan Poudel, Cindy Neuzillet, Hemant Kocher, Anguraj Sadanandam. Reclassification of pancreatic adenocarcinoma with distinct fibroblast and immune characteristics and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3094.
Abstract 31: Organoid derived from human operative sample of NET shows NET characteristics
Authors: Ichikawa Yasushi , Hiroshima Yukihiko , Kobayashi Noritoshi , Masuda Yusaku , Goto Ayumu , Tokuhisa Motohiko , Takeda Yuma , Ishikawa Takashi , Endo Itaru 
Published: August 2019

Abstract
Background: Neuroendocrine tumor is a rare neoplasm, then, it was difficult to examine using in vitro or animal models. Recently, patient-derived tumor organoid (PDTO) is considered as a promising method to analyze natural characteristics of human tumor, because PDTO is cultured in near-natural circumstances compared with cell lines. We established PDTO of neuroendocrine tumor (NET) utilizing operative samples from a pancreatic NET patient. Aim: Aim of this study is to establish organoid derived from an operative sample of pancreatic NET patient and to compare its characteristics with original tumor using immuno-histochemistry. Material and Method: A pancreatic NET tissue derived from operative sample was cut into small pieces and was treated by collagenase. Prepared tissues were 3-dimensionally cultured on the Matrigel in a serum-free medium (Advanced MEM/F12) with 4 growth factors (Respondin, EGF, Rock inhibitor, Noggin), then PDTO was established. To evaluate growth rate of PDTO, Major axis of the organoid was measured on the day 1, 2, 3, and 6. One week after primary culture of the organoid, subculture was performed. Then major axis of the 2nd, 6th and 7th filial organoid was also measured and compared with each filial. To evaluate characteristics of PDTO as neuroendocrine tumor, immunohistochemistry was performed for the 1st, 2nd and 3rd filial PDTO using anti-chromogranin-A antibody (Dako, mouse IgG), anti-synaptophysin antibody (Abcam, rabbit IgG), anti-NCAM antibody (Abcam mouse IgG) and Neuro-specific enolase (Dako, rabbit IgG). Results: Growth rate of the 2nd and 3rd filial on the day 6 did not show significant difference compared with that of the 1st filial. On the other hand, Growth rate of the 2nd and 3rd filial was significantly lower than that of the 1st filial. Expression of the 4 factors in the 1st, 2nd and 3rd filial PDTO was kept as much as the primary tumor. Conclusion: PDTO derived from neuroendocrine tumor showed the same characteristics as the primary tumor. The 6th and 7th filial PDTO might show cellular aging.
Citation Format: Yasushi Ichikawa, Yukihiko Hiroshima, Noritoshi Kobayashi, Yusaku Masuda, Ayumu Goto, Motohiko Tokuhisa, Yuma Takeda, Takashi Ishikawa, Itaru Endo. Organoid derived from human operative sample of NET shows NET characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 31.
Abstract 3103: Intraparenchymal delivery of chemokines and immunomodulators to eliminate pediatric brain tumor cells
Authors: Nealy Eric S. , DeForest Cole A. , Olson James 
Published: August 2019

Abstract
Pediatric brain tumors are among the leading causes of cancer-related death in children. These malignancies tend to occur in locations of the brain where surgery and radiation can permanently impair a patient’s quality of life. Migratory cells from high grade brain tumors can invade nearby, inaccessible areas of the brain where they may grow unchecked and ultimately lead to patient death. This project seeks to tailor the microenvironment around the tumor cavity to promote the recruitment and elimination of remnant brain tumor cells by microglia and macrophages found in the brain. Our data suggests gradients of classical immune cell chemokines, like CCL2, are also potent chemotactic signals for a variety of patient-derived brain tumor types. Monoclonal antibody blockade of CD47, a cell-surface “don’t eat me” ligand often over-expressed on tumor cells, is effective at promoting the elimination of tumor cells in close-proximity to murine macrophages in vitro. We engineered user-programable hydrogel depots capable of month-long molecule release and implanted them into tumor-bearing mouse brains. Hydrogels incorporated with CCL2 and CD47mAb demonstrated statistically significant co-recruitment of tumor and immune cells and evidence of macrophage-mediated tumor cell death compared to PBS-incorporated gels. These results suggest proper stimulation of immune cells within the brain could be an effective means to eliminate pediatric brain tumor cells without causing structural damage to vital nervous tissues. Our data may be the first steps towards clinical trials for children with incompletely resected brain tumors.
Citation Format: Eric S. Nealy, Cole A. DeForest, James Olson. Intraparenchymal delivery of chemokines and immunomodulators to eliminate pediatric brain tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3103.