bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 169: Discovery of clinically distinct CLL subgroups by integrative mapping of large-scale genetic, epigenetic, expression and clinical data
Authors: Knisbacher Binyamin A. , Lin Ziao , Stewart Chip , Hahn Cynthia K. , Stevenson Kristen E. , Neuberg Donna S. , Martín-Subero José I. , Puente Xose S. , Campo Elias , Wu Catherine J. , Getz Gad 
Published: September 2020

Abstract
Chronic lymphocytic leukemia (CLL) accounts for one third of all diagnosed leukemias. It exhibits tremendous clinical variability, ranging from indolent disease kinetics to a fast progressing aggressive disease. Two large-scale studies by our groups, each analyzing more than 500 CLL subjects, have shown that a large part of this clinical variability can be explained by underlying molecular features of the cancerous B-cells, including genetic and epigenetic alterations. Despite this progress, patients do not yet fully benefit from these discoveries in their treatment plans, and prognosis is not tailored to them based on the molecular features of their cancer. To achieve precision medicine, we compile a large dataset of multi-omic and clinical data from over 1100 CLL patients. Our extensive cohort confers power to detect novel driver genes, doubling the number of known drivers (114 total) and identifying drivers specific to major CLL subtypes, such as IGHV-mutated and IGHV-unmutated. The analysis identifies recurrent copy number alterations, order-of-event timing and mutational processes acting in CLL. We integrate these with expression data from 700 CLL RNA-seqs and epigenetic data to define molecular subtypes that present differential clinical outcomes. Altogether, this work delineates the molecular landscape of CLL and sets the stage for improved classification, prognostics and treatment of CLL patients.
Citation Format: Binyamin A. Knisbacher, Ziao Lin, Chip Stewart, Cynthia K. Hahn, Kristen E. Stevenson, Donna S. Neuberg, José I. Martín-Subero, Xose S. Puente, Elias Campo, Catherine J. Wu, Gad Getz. Discovery of clinically distinct CLL subgroups by integrative mapping of large-scale genetic, epigenetic, expression and clinical data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 169.
Abstract 1690: Blockade of antitumor milieu-induced tumor cell PIM2 expression potently synergizes with anti-PD-L1 therapy in hepatocellular carcinoma
Authors: Wang Juncheng , Lu Shi-Xun , Chen Jinbin , Chen Dongping , Chen Minshan , Zhou Zhongguo 
Published: September 2020

Abstract
Background & Aims: Despite being a typical oncogene, PIM kinase has been reported to suggest a favorable prognosis in some solid tumors, but no research has yet explored the underlying mechanisms. Furthermore, an inconsistent prognosis also hinders the clinical application of PIM inhibitors. We aimed to explore the clinical significance and regulatory mechanism of PIM2, as well as the potential clinical application of PIM2 inhibitor in hepatocellular carcinoma (HCC).
Methods: PIM2 expression was assessed in 464 HCC patients who underwent curative resection, and its correlations with prognosis, immune status, and tumor infiltrating leukocytes (TILs) were investigated. Moreover, the underlying regulatory mechanisms of PIM2 and the clinical application of PIM2 inhibitor were also studied.
Results: We found that PIM2 primarily displayed an oncogenic function in HCC. However, elevated PIM2 expression in tumor cells predicted a favorable prognosis. Mechanistically, high PIM2 expression in tumors was associated with an adaptive immune response elicited by TILs, and IL-1β, together with TNF-α and IFN-γ, derived from TILs induced the expression of PIM2 by activating the p38/Erk/MAPK and NF-κB signaling pathways in tumor cells. Specifically, high PIM2 expression in tumors was significantly correlated with a high density of T cells and monocytes, and activated T cell-secreting IFN-γ-polarized monocytes induced the tumor cell PIM2 expression in the tumor milieu. Moreover, blockade of antitumor milieu-induced tumor cell PIM2 expression potently augmented the therapeutic efficacy of anti-PD-L1 therapy in HCC.
Conclusions: Our study provides important insights into a possible adaptive immune resistance mechanism by which the antitumor milieu induces oncogenic PIM2 expression in tumor cells. Moreover, specific inhibition of PIM2 in tumor cells augments the therapeutic efficacy of anti-PD-L1 therapy in HCC.
Citation Format: Juncheng Wang, Shi-Xun Lu, Jinbin Chen, Dongping Chen, Minshan Chen, Zhongguo Zhou. Blockade of antitumor milieu-induced tumor cell PIM2 expression potently synergizes with anti-PD-L1 therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1690.
Abstract 1721: Hypoxia penetrating ultra-small nanoparticle for anti-cancer effect in Glioblastoma
Authors: Rauf Mohd A. , Tatiparti Katyayani , Sau Samaresh , Iyer Arun K. 
Published: September 2020

Abstract
Glioblastoma multiforme (GBM) is a lethal brain tumor currently without successful treatment options. Chemotherapeutic agents are the frontline in the management of GBM. Nonetheless, accessibility of the brain tumor is greatly impeded by the poor blood-brain barrier (BBB) penetration of drugs, which needs immediate attention. Ultra-small multifunctional nanoparticle offers a great promise in overcoming the delivery barriers to GBM. The primary goal of our research is to develop BBB targeted nanoparticle that can selectively deliver drugs to GBM and trigger cell death. We developed Anti-GBM drug, such as temozolomide (TMZ) encapsulated biocompatible, ultra-small nanoparticle using Lactoferrin (LAC) protein. Further, we chemically conjugated LAC with tumor hypoxia biomarker homing molecule, Acetazolamide (ATZ) to obtain LAC-ATZ nanoparticle. To validate our hypothesis of hypoxia targeting, we evaluated the carbonic anhydrase-IX (CAIX) receptor expression in human brain tumor section. The IHC data demonstrated significant overexpression of CAIX in tumor tissue compared to healthy human brain tissue section. Literatures have reported overexpression of LRP-1 in endothelial blood vessel of GBM tumor. Thus, use of LAC-ATZ will enhance its penetration across the BBB and delivery of TMZ in hypoxic core of GBM. To achieve the effective BBB penetration, we engineered LAC-ATZ@TMZ nanoparticle that demonstrated homogenous ultra-small particle size of average diameter of 20-30 nm using TEM analysis. The SDS-PAGE analysis demonstrated the conjugation of LAC with ATZ. Our preliminary data in GBM cells, U87MG suggested the dose dependent cell uptake of DiD-fluorescence labeled LAC-ATZ nanoparticle. The nanoparticles are selective in targeting the U87MG cell when compared to healthy microglial BV2 cells. Thus, it is supporting the potential of LAC-ATZ nanoparticle for targeting the GBM tumor with limited effect in healthy brain tissue. We developed conditioned BBB cell culture model to demonstrate the penetration of LAC-ATZ across the BBB. Based on the exciting preliminary outcome in this study builds a strong rational of using LAC-ATZ nanoparticle for overcoming the bottle neck barrier of BBB with improved anti-GBM response.
Keywords:
Glioblastoma multiforme (GBM), blood-brain barrier (BBB), Lactoferrin (LAC), Acetazolamide (ATZ)
Citation Format: Mohd A. Rauf, Katyayani Tatiparti, Samaresh Sau, Arun K. Iyer. Hypoxia penetrating ultra-small nanoparticle for anti-cancer effect in Glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1721.
Abstract 1740: Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption and cisplatin sensitization in non-small cell lung cancer
Authors: Baehr Christopher M. , Zhang Lu , Lam Kit 
Published: September 2020

Abstract
In the United States, non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality. Traditional chemotherapies are toxic, and drug-resistance development is common. Recently, several drug candidates were shown to selectively induce lysosomal membrane permeabilization in aggressive tumors. One of these agents, chloroquine and its derivatives, has been shown to sensitize NSCLCs to cisplatin in human clinical trials. This has led to the interest in lysosome dysregulation as a cancer therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low lysosomal specificity and low potency. Here, we report on the development of a transformable nanomaterial which may be triggered to induce the mechanical lysosomal membrane permeabilization in vitro and in mouse xenograft models. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and due to lysosomal pH shift switch conformation to nanofibrils, leading to mechanical disruption of the lysosome, cisplatin sensitization and cell death. We show that the nanomaterial is cytotoxic to NSCLC cells in the low-micromolar range, but is able to sensitize NSCLC cells to cisplatin in the nanomolar range. Moreover, we demonstrate promising antitumor effect in mouse xenograft models with limited toxicity. This is the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy.
Citation Format: Christopher M. Baehr, Lu Zhang, Kit Lam. Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption and cisplatin sensitization in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1740.
Abstract 1782: N-myristoyltransferase proteins in breast cancer: Prognostic relevance and validation as a new drug target
Authors: Mackey John R. , Lai Justine , Chauhan Utkarsh , Dong Wei-Feng , Glubrect Darryl , Ghosh Sunita , Bigras Gilbert , Lai Raymond , Berthiaume Luc G. 
Published: September 2020

Abstract
N-myristoyltransferases (NMTs) catalyze the addition of 14-carbon fatty acids to the N-terminus of proteins. This activity regulates numerous membrane-bound signal transduction pathways important in cancer biology, and the pan-NMT inhibitor PCLX-001 is in clinical development as a cancer therapy. The physiologic distribution and relative contributions of the two human NMTs, NMT1 and NMT2, remain poorly understood as previous studies used polyclonal antibodies with potential cross-reactivity. We generated and validated mutually exclusive monoclonal antibodies (mAbs) specific to the human isotypes of NMT1 and NMT2. These mAbs were used to perform an immunohistochemical (IHC) analysis of the abundance and distribution of NMT1 and NMT2 in normal human breast epithelial samples and a large (n=703) cohort of primary breast adenocarcinomas from the BCIRG001 study. While NMT1 protein was readily identifiable in most normal and transformed breast epithelial tissue, NMT1 abundance was associated with higher overall histologic grade, higher Ki67, and lower hormone expression. While NMT2 protein was readily detected in normal breast epithelial tissue, NMT2 protein was undetectable in the majority of malignant breast cancers, but detectable NMT2 protein correlated with significantly poorer overall survival outcomes (hazard ratio for death 1.36; p &lt; 0.029) and significantly worse biological features including younger age, higher histologic grade, lower hormone receptor expression, higher Ki67, and p53 positivity. NMT status was unrelated to HER2 status. NMT1 and NMT2 protein abundances were positively correlated with each other. Treatment of cultured breast cancer cells with the pan-NMT inhibitor PCLX-001 reduced cell viability in vitro. Daily oral administration of PCLX-001 to immunodeficient mice bearing human MDA-MB-231 breast cancer xenografts induced significant dose-dependent tumor growth inhibition in vivo. These results support the further evaluation of NMT immunohistochemistry for selection of patients for NMT inhibitor therapy, and clinical trials of NMT inhibition in breast cancer patients.
Citation Format: John R. Mackey, Justine Lai, Utkarsh Chauhan, Wei-Feng Dong, Darryl Glubrect, Sunita Ghosh, Gilbert Bigras, Raymond Lai, Luc G. Berthiaume. N-myristoyltransferase proteins in breast cancer: Prognostic relevance and validation as a new drug target [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1782.
Abstract 1817: C/EBPβ antagonist peptide, ST101, attenuates oncogenic gene transactivation in cancer cells to drive antitumor activity
Authors: Rotolo Jim A. , Ramirez Rick , Koester Mark , Gallagher Erin , Leong Siok , Ghamsari Lila , Merutka Gene , Kappel Barry J. 
Published: September 2020

Abstract
Transcription factor dysregulation is common in cancer, resulting in aberrant gene expression that drives oncogenesis. Antagonism of oncogenic transcription factor activity, by disrupting essential protein-protein interactions needed for activation of downstream effector molecules or association with DNA, represents a powerful approach to target this previously ‘undruggable' class of proteins. CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is a transcription factor overexpressed in many cancers that regulates expression of factors that promote tumor survival, proliferation and inhibit differentiation. Here, we decribe the anti-tumor activity of ST101, a cell-penetrating peptide antagonist of C/EBPβ. To demonstrate ST101 disruption of the interaction of C/EBPβ with co-factor activating transcription factor 5 (ATF5), a competition ELISA assay was performed. Recombinant ATF5 associated with plate-bound C/EBPβ with a binding affinity of ∼1 nM. Addition of ST101 inhibited this interaction in dose-dependent manner, resulting in an IC50 of 25 nM. To demonstrate ST101 disruption of C/EBPβ phosphorylation and gene transactivation in cancer cells, western blot analysis and quantitative polymerase chain reaction (qPCR) were performed on U251 glioblastoma, MCF7 breast adenocarcinoma and A549 lung adenocarcinoma cells. Administration of ST101 resulted in a dose-dependent decrease in C/EBPβ activation, as evidenced by a decrease in Thr189 phosphorylation. Anatgonism of C/EBPβ activity resulted in a dose-dependent decrease in mRNA expression of genes involved in survival (BCL2 and the baculoviral inhibitor of apoptosis factors BIRC3, BIRC5), inhibition of differentiation (Inhibitor of DNA binding proteins ID1, ID2 and ID3) and proliferation (cyclins CCNB1 and CCNA2 and cyclin-dependent kinases CDK1 and CDK2). Finally, in a mouse xenograft model, 25mg/kg ST101 administered three times per week for three weeks resulted in significant and sustained tumor growth inhibition in U251 subcutaneous tumors, both when ST101 administration was initiated early (day 2, 200 mm3 tumors, p&lt;0.05) or late (day 16, &gt;500mm3 tumors, p&lt;0.05). These data demonstrate the therapeutic potential of systemic administration of ST101 and support clinical development of ST101 as a potent peptide therapeutic for a variety of solid tumor malignancies.
Citation Format: Jim A. Rotolo, Rick Ramirez, Mark Koester, Erin Gallagher, Siok Leong, Lila Ghamsari, Gene Merutka, Barry J. Kappel. C/EBPβ antagonist peptide, ST101, attenuates oncogenic gene transactivation in cancer cells to drive antitumor activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1817.
Abstract 1829: Olaparib antiproliferative effect in pancreatic cancer and correlation with the response to other anticancer agents
Authors: Leo Elisabetta , Illuzzi Giuditta , Bentouati Sabrina 
Published: September 2020

Abstract
AstraZeneca obtained positive results from POLO, the first Phase III randomised, double-blind study that evaluated the efficacy of the PARP inhibitor (PARPi) olaparib, for maintenance monotherapy in patients with gBRCA mutated metastatic pancreatic cancer whose disease has not progressed on first-line platinum-based chemotherapy.
To support the application of olaparib for the proposed indication in these patients, a series of in vitro pharmacological tests were performed and will be here presented.
1. In a panel of pancreatic cancer cell lines, a striking correlation was observed between the responses to platinum and to olaparib. This indicates that it is predictable that olaparib will show efficacy in treatment of platinum-sensitive pancreatic cancer, as it has been previously demonstrated in other cancer indications.
2. Tests in isogenic cell line pairs and non-tumour cell lines revealed that platinum treatments lead to cytotoxic effects that are only ~10-20-fold more selective for BRCAm versus BRCAwt and non-tumour models; in contrast, olaparib is able to selectively kill BRCAm cells, with ~500-1000-fold sensitivity versus the BRCAwt cells.
3. In the panel of pancreatic cancer cells, the sensitivity to other DNA damaging agents used as standard of care, such as irinotecan (and, to some extent, 5FU, other key components of FOLFIRINOX as well as gemcitabine), correlated with sensitivity to olaparib. In contrast, no correlation was observed with paclitaxel (mitotic inhibitor), or with other agents.
4. The antiproliferative effects to olaparib treatments in the cancer cell panel were compared to that of other 5 clinical PARPi. High correlations were observed in the responses to all the PARPi except for veliparib, which inhibits the catalytic activity of PARP but does not act as PARP-trapper, confirming that the efficacy of PARPi in monotherapy depends on their ability to stabilise the interaction between PARP and the DNA.
Citation Format: Elisabetta Leo, Giuditta Illuzzi, Sabrina Bentouati. Olaparib antiproliferative effect in pancreatic cancer and correlation with the response to other anticancer agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1829.
Abstract 1855: Statins decrease the expression of c myc in cancer cell lines
Authors: Rao U.S. , Mullins Randy , Rao Prema 
Published: September 2020

Abstract
The widely used statin drugs for the prevention of cardiovascular diseases are envisioned to have the potential to control cancer. Repurposing these cardiovascular drugs for cancer prevention and/or treatment is an attractive proposition as these drugs are commonly prescribed in the clinic. However, there was no clinical evidence for statins being used as chemopreventive agents and the reasons for this are unclear. To further establish the effectiveness of statins as chemopreventive agents, we investigated the effects of three most common statins, simvastatin, atorvastatin and lovastatin on six different cancer cell lines including an ovarian cancer cell line that overexpresses P-glycoprotein, an ABCB1 gene product. Incubation of cells with statins (at both 12.5 microM and 25 microM) resulted in decreased cell growth in a time-dependent manner. The decreased cell growth could be correlated with decreased cellular NADPH levels. Measurement of viable and dead cells in statin treatments indicated that statins induced cell proliferation arrest without inducing cell death. Removal of statins from culture medium resulted in robust cell growth, identical to that observed in controls. Further, cell cycle analysis clearly indicated that statins induced cell cycle arrest at G0/G1 phase without inducing apoptosis. Analysis of the mechanism of statins in these cancer cells indicated that these drugs inhibit HMG CoA reductase, without affecting the transcript of the HMGCR. The HMG CoA reductase inhibition could be relieved with mevalonate. Analysis of key target proteins important for cancer cell proliferation identified that exposure of cancer cells to statins significantly decreased c-Myc protein without affecting its transcription. Importantly, removal of statins reversed the c-Myc expression to the normal level. Finally, incubation of cells with statins increased phosphorylation of H2AX, suggesting that statins promote cellular senescence. These data together suggested that statins are cytostatic, and eliminate c-Myc expression. These observations are consistently observed in the multidrug-resistant cells as well. These data lend strong support that statins could serve as excellent agents for cancer chemoprevention.
Citation Format: U.S. Rao, Randy Mullins, Prema Rao. Statins decrease the expression of c myc in cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1855.
Abstract 1859: Elucidating the role of KMT2D as a novel therapeutic target for resistant HER2+ breast cancer
Authors: MA EMILY , Zlobin Andrei , Wyatt Debra , Ng Jeffrey , Dingwall Andrew , Osipo Clodia 
Published: September 2020

Abstract
HER2 targeted agents have improved clinical outcomes for women with HER2+ breast cancer. However, drug resistance remains a critical challenge for curing HER2+ disease. Cancer stem cells (CSCs)-enriched during anti-HER2 therapy promote resistance and recurrence. Therefore, novel targets that drive survival of CSCs are needed. Recently, the histone-lysine N-methyltransferase 2D (KMT2D) has been shown to be a prognostic marker for poor recurrence free survival in women with HER2+ breast cancer. Preliminary data showed that KMT2D RNA was increased in HER2+ CSC-enriched mammospheres compared to bulk cells. Further, KMT2D protein is increased in resistant compared to sensitive cells. These data suggest that KMT2D is necessary for survival of CSCs and resistance to anti-HER2 therapy. To address this hypothesis, RNAi-mediated knockdown of KMT2D was performed in trastuzumab sensitive and resistant cells. KMT2D depletion in sensitive cells resulted in almost complete blockade of proliferation in 2-D culture and CSC survival in 3-D culture. In contrast, proliferation and CSC survival was only moderately inhibited by KMT2D depletion in resistant cells. ChIP studies confirmed that KMT2D is enriched on the MYC enhancer in sensitive cells but only moderately in resistant cells. Based on these data, KMT2D is necessary for growth of HER2+ breast cancer and is possibly inactivated during acquisition of resistance. To determine the mechanism, RNA sequencing was performed in both sensitive and resistance cells expressing or depleted for KMT2D. Several differentially expressed genes that were positively or negatively regulated by KMT2D were identified. Specifically, transcript levels of ITGB6 and CLIC3 were decreased upon KMT2D knockdown, while PGR and AR transcripts were increased. Initial results showed that ITGB6 depletion resulted in decreased bulk cell proliferation and survival of CSCs similar to KMT2D knockdown. These results suggest that ITGB6 could be a direct target gene of KMT2D and thus mediates the phenotypic effects of KMT2D. Overall, our results suggest that KMT2D is necessary for both proliferation and CSC survival in HER2+ breast cancer sensitive to anti-HER2 therapy and a combination approach of targeting both HER2 and KMT2D could prevent enrichment of CSCs and acquired resistance.
Citation Format: EMILY MA, Andrei Zlobin, Debra Wyatt, Jeffrey Ng, Andrew Dingwall, Clodia Osipo. Elucidating the role of KMT2D as a novel therapeutic target for resistant HER2+ breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1859.