bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Novel Inhibitor of AKT1–PDPK1 Interaction Efficiently Suppresses the Activity of AKT Pathway and Restricts Tumor Growth In Vivo
Authors: Mäemets-Allas Kristina , Viil Janeli , Jaks Viljar
Published: April 2023

Abstract
The serine/threonine kinase AKT/PKB has a critical role in the regulation of cell proliferation. Because AKT signaling is deregulated in numerous human malignancies, it has become an attractive anticancer drug target. A number of small molecule AKT kinase inhibitors have been developed; however, severe side effects have prevented their use in clinical trials. To find inhibitors of AKT1 signaling with principally novel mechanism of action, we carried out a live cell-based screen for small molecule inhibitors of physical interaction between AKT1 and its primary activator PDPK1. The screen revealed one molecule—NSC156529, which downregulated AKT1 signaling, efficiently decreased the proliferation of human cancer cells in vitro, and substantially inhibited the growth of prostate tumor xenografts in vivo. Interestingly, the treated tumor xenografts exhibited higher expression level of normal prostate differentiation markers but did not show augmented cell death, suggesting that the identified compound primarily enhances the differentiation of malignant cells toward normal prostate epithelium and thus poses as an attractive lead compound for developing novel antitumor agents with less cytotoxic side effects. Mol Cancer Ther; 14(11); 2486–96. ©2015 AACR.
Data from Verticillin A Causes Apoptosis and Reduces Tumor Burden in High-Grade Serous Ovarian Cancer by Inducing DNA Damage
Authors: Salvi Amrita , Amrine Chiraz Soumia M. , Austin Julia R. , Kilpatrick KiAundra , Russo Angela , Lantvit Daniel , Calderon-Gierszal Esther , Mattes Zachary , Pearce Cedric J. , Grinstaff Mark W. , Colby Aaron H. , Oberlies Nicholas H. , Burdette Joanna E.
Published: April 2023

Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy in women worldwide and the fifth most common cause of cancer-related deaths among U.S. women. New therapies are needed to treat HGSOC, particularly because most patients develop resistance to current first-line therapies. Many natural product and fungal metabolites exhibit anticancer activity and represent an untapped reservoir of potential new agents with unique mechanism(s) of action. Verticillin A, an epipolythiodioxopiperazine alkaloid, is one such compound, and our recent advances in fermentation and isolation are now enabling evaluation of its anticancer activity. Verticillin A demonstrated cytotoxicity in HGSOC cell lines in a dose-dependent manner with a low nmol/L IC50. Furthermore, treatment with verticillin A induced DNA damage and caused apoptosis in HGSOC cell lines OVCAR4 and OVCAR8. RNA-Seq analysis of verticillin A–treated OVCAR8 cells revealed an enrichment of transcripts in the apoptosis signaling and the oxidative stress response pathways. Mass spectrometry histone profiling confirmed reports that verticillin A caused epigenetic modifications with global changes in histone methylation and acetylation marks. To facilitate in vivo delivery of verticillin A and to monitor its ability to reduce HGSOC tumor burden, verticillin A was encapsulated into an expansile nanoparticle (verticillin A-eNP) delivery system. In an in vivo human ovarian cancer xenograft model, verticillin A-eNPs decreased tumor growth and exhibited reduced liver toxicity compared with verticillin A administered alone. This study confirmed that verticillin A has therapeutic potential for treatment of HGSOC and that encapsulation into expansile nanoparticles reduced liver toxicity.
Data from RN927C, a Site-Specific Trop-2 Antibody–Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models
Authors: Strop Pavel , Tran Thomas-Toan , Dorywalska Magdalena , Delaria Kathy , Dushin Russell , Wong Oi Kwan , Ho Wei-Hsien , Zhou Dahui , Wu Aidong , Kraynov Eugenia , Aschenbrenner Laura , Han Bora , O'Donnell Christopher J. , Pons Jaume , Rajpal Arvind , Shelton Dave L. , Liu Shu-Hui
Published: April 2023

Abstract
Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2–targeting antibody–drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2–expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2–expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non–dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698–708. ©2016 AACR.
Data from Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience
Authors: Schwaederle Maria , Parker Barbara A. , Schwab Richard B. , Daniels Gregory A. , Piccioni David E. , Kesari Santosh , Helsten Teresa L. , Bazhenova Lyudmila A. , Romero Julio , Fanta Paul T. , Lippman Scott M. , Kurzrock Razelle
Published: April 2023

Abstract
By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a “matched” versus “unmatched” therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a “matched” therapy, 93 (26.8%) with an “unmatched” therapy. More patients in the matched group achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P ≤ 0.020 multivariable or propensity score methods). Matched patients had a longer median progression-free survival (PFS; 4.0 vs. 3.0 months, P = 0.039 in the Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P = 0.009); however, this shortening was not observed in the matched patients (P = 0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/PFS1 ratio ≥1.3 compared with 19.3% of patients (11/57) in the unmatched group (P = 0.004 univariable and P ≥ 0.057 in multivariable/propensity score analysis). Patients with a “matching-score” (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) > 0.2 had a median overall survival (OS) of 15.7 months compared with 10.6 months when their matching-score was ≤ 0.2, (P = 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD ≥ 6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis. Mol Cancer Ther; 15(4); 743–52. ©2016 AACR.
Data from Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response
Authors: Cramer Dina , Mazur Johanna , Espinosa Octavio , Schlesner Matthias , Hübschmann Daniel , Eils Roland , Staub Eike
Published: April 2023

Abstract
In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent. We asked whether the association of cancer driver mutations with drug response is modulated by other driver mutations or the tissue of origin. We developed an analytic framework based on linear regression to study interactions in pharmacogenomic data from two large cancer cell line panels. Starting from a model with only covariates, we included additional variables only if they significantly improved simpler models. This allows to systematically assess interactions in small, easily interpretable models. Our results show that including mutation–mutation interactions in drug response prediction models tends to improve model performance and robustness. For example, we found that TP53 mutations decrease sensitivity to BRAF inhibitors in BRAF-mutated cell lines and patient tumors, suggesting a therapeutic benefit of combining inhibition of oncogenic BRAF with reactivation of the tumor suppressor TP53. Moreover, we identified tissue-specific mutation–drug associations and synthetic lethal triplets where the simultaneous mutation of two genes sensitizes cells to a drug. In summary, our interaction-based approach contributes to a holistic view on the determining factors of drug response.
Data from Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations
Authors: Larrue Clément , Saland Estelle , Vergez François , Serhan Nizar , Delabesse Eric , Mansat-De Mas Véronique , Hospital Marie-Anne , Tamburini Jérôme , Manenti Stéphane , Sarry Jean Emmanuel , Récher Christian
Published: April 2023

Abstract
We assessed the antileukemic activity of 2-deoxy-d-glucose (2-DG) through the modulation of expression of receptor tyrosine kinases (RTK) commonly mutated in acute myeloid leukemia (AML). We used human leukemic cell lines cells, both in vitro and in vivo, as well as leukemic samples from AML patients to demonstrate the role of 2-DG in tumor cell growth inhibition. 2-DG, through N-linked glycosylation inhibition, affected the cell-surface expression and cellular signaling of both FTL3-ITD and mutated c-KIT and induced apoptotic cell death. Leukemic cells harboring these mutated RTKs (MV4-11, MOLM-14, Kasumi-1, and TF-1 c-KIT D816V) were the most sensitive to 2-DG treatment in vitro as compared with nonmutated cells. 2-DG activity was also demonstrated in leukemic cells harboring FLT3-TKD mutations resistant to the tyrosine kinase inhibitor (TKI) quizartinib. Moreover, the antileukemic activity of 2-DG was particularly marked in c-KIT–mutated cell lines and cell samples from core binding factor–AML patients. In these cells, 2-DG inhibited the cell-surface expression of c-KIT, abrogated STAT3 and MAPK–ERK pathways, and strongly downregulated the expression of the receptor resulting in a strong in vivo effect in NOD/SCID mice xenografted with Kasumi-1 cells. Finally, we showed that 2-DG decreases Mcl-1 protein expression in AML cells and induces sensitization to both the BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w, ABT-737, and cytarabine. In conclusion, 2-DG displays a significant antileukemic activity in AML with FLT3-ITD or KIT mutations, opening a new therapeutic window in a subset of AML with mutated RTKs. Mol Cancer Ther; 14(10); 2364–73. ©2015 AACR.
Data from Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin
Authors: Roh Jong-Lyel , Kim Eun Hye , Park Jin Young , Kim Ji Won
Published: April 2023

Abstract
Glucosylceramide synthase (GCS) overexpression is associated with multidrug resistance in several human cancers. GCS blockade, which overcomes multidrug resistance by downregulating P-glycoprotein (P-gp), has not been tested in head and neck cancer (HNC). This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. The effect of genetic or pharmacologic GCS inhibition (using GCS siRNA/shRNA or d,l-threo-PPMP, respectively) on cisplatin sensitivity was assessed in several human HNC cells and acquired cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, ceramide production, and in preclinical tumor xenograft mouse models. GCS and P-gp expression were significantly associated with cisplatin resistance in several HNC cell lines (P = 0.007). Both were significantly increased in HN9-cisR cells, which display acquired cisplatin resistance (P < 0.001). Genetic or pharmacologic inhibition of GCS induced accumulation of increased ceramide levels. GCS inhibition increased cisplatin-induced cell death in HNC cells via P-gp downregulation and proapoptotic protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacologic GCS inhibition sensitized resistant HNC cells to cisplatin in vitro and in vivo. GCS and P-gp overexpression is associated with acquired cisplatin resistance, suggesting a role for these molecules as therapeutic targets for HNC. Genetic or pharmacologic GCS blockade may have therapeutic benefit in cisplatin-resistant HNC. Mol Cancer Ther; 14(8); 1907–15. ©2015 AACR.
Data from In Vitro and In Vivo Studies of a New Class of Anticancer Molecules for Targeted Radiotherapy of Cancer
Authors: Wang Chun-Rong , Mahmood Javed , Zhang Qin-Rong , Vedadi Ali , Warrington Jenny , Ou Ning , Bristow Robert G. , Jaffray David A. , Lu Qing-Bin
Published: April 2023

Abstract
There is a compelling need to develop anticancer therapies that target cancer cells and tissues. Arising from innovative femtomedicine studies, a new class of non–platinum-based halogenated molecules (called FMD molecules) that selectively kill cancer cells and protect normal cells in treatments of multiple cancers has been discovered. This article reports the first observation of the radiosensitizing effects of such compounds in combination with ionizing radiation for targeted radiotherapy of a variety of cancers. We present in vitro and in vivo studies focused on combination with radiotherapy of cervical, ovarian, head and neck, and lung cancers. Our results demonstrate that treatments of various cancer cells in vitro and in vivo mouse xenograft models with such compounds led to enhanced efficiencies in radiotherapy, while the compounds themselves induced no or little radiotoxicity toward normal cells or tissues. These compounds are therefore effective radiosensitizers that can be translated into clinical trials for targeted radiotherapy of multiple types of cancer. This study also shows the potential of femtomedicine to bring breakthroughs in understanding fundamental biologic processes and to accelerate the discovery of novel drugs for effective treatment or prevention of a variety of cancers. Mol Cancer Ther; 15(4); 640–50. ©2016 AACR.
Data from Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs
Authors: Berte Nancy , Piée-Staffa Andrea , Piecha Nadine , Wang Mengwan , Borgmann Kerstin , Kaina Bernd , Nikolova Teodora
Published: April 2023

Abstract
Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First- and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O6-chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement, and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacologic inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes, and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. Mol Cancer Ther; 15(11); 2665–78. ©2016 AACR.
Data from Pralatrexate in Combination with Oxaliplatin in Advanced Esophagogastric Cancer: A Phase II Trial with Predictive Molecular Correlates
Authors: Malhotra Usha , Mukherjee Sarbajit , Fountzilas Christos , Boland Patrick , Miller Austin , Patnaik Santosh , Attwood Kristopher , Yendamuri Sai , Adjei Araba , Kannisto Eric , Opyrchal Mateusz , Bushunow Peter , Loud Peter , Iyer Renuka , Khushalani Nikhil
Published: April 2023

Abstract
The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.
Data from Gene Knockdown by EpCAM Aptamer–siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells
Authors: Gilboa-Geffen Adi , Hamar Peter , Le Minh T.N. , Wheeler Lee Adam , Trifonova Radiana , Petrocca Fabio , Wittrup Anders , Lieberman Judy
Published: April 2023

Abstract
Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (TIC, also known as cancer stem cells). Here, we show that aptamer–siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knock down gene expression in EpCAM+ cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and mammosphere formation (in vitro TIC assays) and tumor initiation by EpCAM+ luminal and basal-A triple-negative breast cancer (TNBC) cell lines, but not EpCAM− mesenchymal basal-B TNBCs, in nude mice. Subcutaneously administered EpCAM-AsiCs concentrate in EpCAM+ Her2+ and TNBC tumors and suppress their growth. Thus, EpCAM-AsiCs provide an attractive approach for treating epithelial cancer. Mol Cancer Ther; 14(10); 2279–91. ©2015 AACR.
Data from Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity
Authors: Roche Francis P. , Pietilä Ilkka , Kaito Hiroshi , Sjöström Elisabet O. , Sobotzki Nadine , Noguer Oriol , Skare Tor Persson , Essand Magnus , Wollscheid Bernd , Welsh Michael , Claesson-Welsh Lena
Published: April 2023

Abstract
The plasma–protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and antitumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T-cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction–decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and colocalization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG–treated gliomas displayed decreased numbers of IL35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control antitumor immunity. Mol Cancer Ther; 17(9); 1961–72. ©2018 AACR.
Data from In Vivo ERK1/2 Reporter Predictively Models Response and Resistance to Combined BRAF and MEK Inhibitors in Melanoma
Authors: Sanchez Ileine M. , Purwin Timothy J. , Chervoneva Inna , Erkes Dan A. , Nguyen Mai Q. , Davies Michael A. , Nathanson Katherine L. , Kemper Kristel , Peeper Daniel S. , Aplin Andrew E.
Published: April 2023

Abstract
Combined BRAF and MEK inhibition is a standard of care in patients with advanced BRAF-mutant melanoma, but acquired resistance remains a challenge that limits response durability. Here, we quantitated in vivo ERK1/2 activity and tumor response associated with resistance to combined BRAF and MEK inhibition in mutant BRAF xenografts. We found that ERK1/2 pathway reactivation preceded the growth of resistant tumors. Moreover, we detected a subset of cells that not only persisted throughout long-term treatment but restored ERK1/2 signaling and grew upon drug removal. Cell lines derived from combination-resistant tumors (CRT) exhibited elevated ERK1/2 phosphorylation, which were sensitive to ERK1/2 inhibition. In some CRTs, we detected a tandem duplication of the BRAF kinase domain. Monitoring ERK1/2 activity in vivo was efficacious in predicting tumor response during intermittent treatment. We observed maintained expression of the mitotic regulator, polo-like kinase 1 (Plk1), in melanoma resistant to BRAF and MEK inhibitors. Plk1 inhibition induced apoptosis in CRTs, leading to slowed growth of BRAF and MEK inhibitor–resistant tumors in vivo. These data demonstrate the utility of in vivo ERK1/2 pathway reporting as a tool to optimize clinical dosing schemes and establish suppression of Plk1 as potential salvage therapy for BRAF inhibitor and MEK inhibitor–resistant melanoma.
Data from Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer
Authors: Santoro Raffaela , Zanotto Marco , Simionato Francesca , Zecchetto Camilla , Merz Valeria , Cavallini Chiara , Piro Geny , Sabbadini Fabio , Boschi Federico , Scarpa Aldo , Melisi Davide
Published: April 2023

Abstract
YAP and TAZ are central determinants of malignancy; however, their functions remain still undruggable. We identified TGFβ-activated kinase 1 (TAK1) as a central hub integrating the most relevant signals sustaining pancreatic cancer aggressiveness and chemoresistance. Glycogen synthase kinase (GSK)3 is known to stabilize TAK1, and its inhibition causes a reduction in TAK1 levels. Here, we hypothesized that TAK1 could sustain YAP/TAZ program, and thus, modulation of TAK1 expression through the inhibition of GSK3 could impair YAP/TAZ functions in pancreatic cancer.

Differentially expressed transcripts between pancreatic cancer cells expressing scramble or TAK1-specific shRNA were annotated for functional interrelatedness by ingenuity pathway analysis. TAK1 expression was modulated by using different GSK3 inhibitors, including LY2090314. In vivo activity of LY2090314 alone or in combination with nab-paclitaxel was evaluated in an orthotopic nude mouse model.

Differential gene expression profiling revealed significant association of TAK1 expression with HIPPO and ubiquitination pathways. We measured a significant downregulation of YAP/TAZ and their regulated genes in shTAK1 cells. TAK1 prevented YAP/TAZ proteasomal degradation in a kinase independent manner, through a complex with TRAF6, thereby fostering their K63-ubiquitination versus K48-ubiquitination. Pharmacologic modulation of TAK1 by using GSK3 inhibitors significantly decreased YAP/TAZ levels and suppressed their target genes and oncogenic functions. In vivo, LY2090314 plus nab-paclitaxel significantly prolonged mice survival duration.

Our study demonstrates a unique role for TAK1 in controlling YAP/TAZ in pancreatic cancer. LY2090314 is a novel agent that warrants further clinical development in combination with nab-paclitaxel for the treatment of pancreatic cancer.
Data from A Novel Salicylanilide Derivative Induces Autophagy Cell Death in Castration-Resistant Prostate Cancer via ER Stress-Activated PERK Signaling Pathway
Authors: Hsieh Chia-Ling , Huang Hsu-Shan , Chen Kuan-Chou , Saka Teigi , Chiang Chih-Ying , Chung Leland W.K. , Sung Shian-Ying
Published: April 2023

Abstract
Metastatic castration-resistant prostate cancer (CRPC) is currently incurable. Cancer growth and progression is intimately affected by its interaction with host microenvironment. Cotargeting of the stroma and prostate cancer is therefore an emerging therapeutic strategy for metastatic CRPC. Cancer-induced osteoclastogenesis is known to contribute to CRPC bone metastasis. This study is to extend pharmacologic value of our synthesized LCC03, a derivative of 5-(2′,4′-difluorophenyl)-salicylanilide that has previously testified for its osteoclastogenesis activity, by exploring its additional cytotoxic properties and underlying mechanism in CRPC cells. LCC03 was chemically synthesized and examined for cell growth inhibition in a serial of CRPC cell lines. We demonstrated that LCC03 dose-dependently suppressed proliferation and retarded cell-cycle progression in CRPC cells. The classical autophagy features, including autophagosome formation and LC3-II conversion, 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 endoplasmic reticulum (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 LCC03-induced autophagy. Furthermore, treatment of tumor-bearing mice with intraperitoneal administered LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity. The dual action of 5-(2′,4′-difluorophenyl)-salicylanilide on targeting both the osteoclasts and the tumor cells strongly indicates that LCC03 is a promising anticancer candidate for preventing and treating metastatic CRPC.
Data from Nanoparticle Delivery of miR-708 Mimetic Impairs Breast Cancer Metastasis
Authors: Ramchandani Divya , Lee Seung Koo , Yomtoubian Shira , Han Myung Shin , Tung Ching-Hsuan , Mittal Vivek
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) patients exhibit the worst clinical outcome due to its aggressive clinical course, higher rate of recurrence, and a conspicuous lack of FDA-approved targeted therapies. Here, we show that multilayered nanoparticles (NPs) carrying the metastasis suppressor microRNA miR-708 (miR708-NP) localize to orthotopic primary TNBC, and efficiently deliver the miR-708 cargo to reduce lung metastasis. Using a SOX2/OCT4 promoter reporter, we identified a population of miR-708low cancer cells with tumor-initiating properties, enhanced metastatic potential, and marked sensitivity to miR-708 treatment. In vivo, miR708-NP directly targeted the SOX2/OCT4-mCherry+ miR-708low tumor cells to impair metastasis. Together, our preclinical findings provide a mechanism-based antimetastatic therapeutic approach for TNBC, with a marked potential to generate miR-708 replacement therapy for high-risk TNBC patients in the clinic. To our knowledge, this gold nanoparticle-based delivery of microRNA mimetic is the first oligonucleotide-based targeted therapy for TNBC.
Data from Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA
Authors: Strobl Carolin Dorothea , Schaffer Stefanie , Haug Tabea , Völkl Simon , Peter Katrin , Singer Katrin , Böttcher Martin , Mougiakakos Dimitrios , Mackensen Andreas , Aigner Michael
Published: April 2023

Abstract
Genetic alterations in tumor cells provide promising targets for antitumor therapy. Recently, loss of methylthioadenosine phosphorylase (MTAP), a deletion frequently occurring in cancer, has been shown to create vulnerability to the inhibition of the protein arginine methyltransferase 5 (PRMT5). MTAP deficiency leads to accumulation of methylthioadenosine (MTA), which reduces PRMT5 activity, and thus, sensitizes the tumor cells to selective PRMT5 inhibitors (PRMT5i). PRMT5i are investigated as a new strategy to selectively kill MTAP-deficient tumor cells by blocking residual PRMT5 activity, but also to treat PRMT5-overexpressing tumors. Although many studies investigated the role of PRMT5 in cancer, only little data exist about the effect of PRMT5 inhibition on immune cells. As we could show that the tumor metabolite MTA suppresses T cells, we asked whether selective PRMT5 inhibition is detrimental for T-cell immune responses. Therefore, we examined the effect of the synthetic PRMT5 inhibitor EPZ015666 on human CD8+ T cells in direct comparison with the naturally occurring PRMT5-inhibiting molecule MTA. Both compounds reduced T-cell proliferation, viability, and functionality. In addition, T-cell metabolism was impaired upon PRMT5 inhibition. These effects coincided with the induction of p53 expression and reduced AKT/mTOR signaling. Our data clearly demonstrate that PRMT5 activity is involved in various cellular processes of human CD8+ T cells associated with essential T-cell functions. Therefore, not only tumor cells, but also antitumor immune responses, are compromised by PRMT5 inhibitors. This emphasizes the importance of considering side effects on the immune system when developing new strategies to specifically target not only MTAP-deficient tumors.
Data from Dual mTORC1/2 Inhibition Sensitizes Testicular Cancer Models to Cisplatin Treatment
Authors: Rosas-Plaza Ximena , de Vries Gerda , Meersma Gert Jan , Suurmeijer Albert J.H. , Gietema Jourik A. , van Vugt Marcel A.T.M. , de Jong Steven
Published: April 2023

Abstract
Testicular cancer is the most common cancer type among young men. Despite highly effective cisplatin-based chemotherapy, around 20% of patients with metastatic disease will still die from the disease. The aim of this study was to explore the use of kinase inhibitors to sensitize testicular cancer cells to cisplatin treatment. Activation of kinases, including receptor tyrosine kinases and downstream substrates, was studied in five cisplatin-sensitive or -resistant testicular cancer cell lines using phospho-kinase arrays and Western blotting. The phospho-kinase array showed AKT and S6 to be among the top phosphorylated proteins in testicular cancer cells, which are part of the PI3K/AKT/mTORC pathway. Inhibitors of most active kinases in the PI3K/AKT/mTORC pathway were tested using apoptosis assays and survival assays. Two mTORC1/2 inhibitors, AZD8055 and MLN0128, strongly enhanced cisplatin-induced apoptosis in all tested testicular cancer cell lines. Inhibition of mTORC1/2 blocked phosphorylation of the mTORC downstream proteins S6 and 4E-BP1. Combined treatment with AZD8055 and cisplatin led to reduced clonogenic survival of testicular cancer cells. Two testicular cancer patient-derived xenografts (PDX), either from a chemosensitive or -resistant patient, were treated with cisplatin in the absence or presence of kinase inhibitor. Combined AZD8055 and cisplatin treatment resulted in effective mTORC1/2 inhibition, increased caspase-3 activity, and enhanced tumor growth inhibition. In conclusion, we identified mTORC1/2 inhibition as an effective strategy to sensitize testicular cancer cell lines and PDX models to cisplatin treatment. Our results warrant further investigation of this combination therapy in the treatment of patients with testicular cancer with high-risk relapsed or refractory disease.
Data from Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071
Authors: Piperno-Neumann Sophie , Larkin James , Carvajal Richard D. , Luke Jason J. , Schwartz Gary K. , Hodi F. Stephen , Sablin Marie-Paule , Shoushtari Alexander N. , Szpakowski Sebastian , Chowdhury Niladri Roy , Brannon A. Rose , Ramkumar Thiruvamoor , de Koning Leanne , Derti Adnan , Emery Caroline , Yerramilli-Rao Padmaja , Kapiteijn Ellen
Published: April 2023

Abstract
Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n = 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1,400 mg. First-cycle dose-limiting toxicities were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses ≥700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM.

In conclusion, the protein kinase C inhibitor AEB071 was well tolerated, and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of protein kinase C inhibitors with other compounds in metastatic UM.
Data from Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma
Authors: Singh Alok R. , Joshi Shweta , Burgoyne Adam M. , Sicklick Jason K. , Ikeda Sadakatsu , Kono Yuko , Garlich Joseph R. , Morales Guillermo A. , Durden Donald L.
Published: April 2023

Abstract
Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK, and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI3K/BRD4 inhibitors, which can be used either alone or in combination with sorafenib to treat patients with advanced HCC. Herein, we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with sorafenib inhibited proliferation, cell cycle, apoptosis, and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep3B, HepG2, SK-Hep1, and Huh7 HCC cell lines. We demonstrate that the active moiety of the SF1126 prodrug LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaced BRD4 coactivator protein from the transcriptional start site of MYC in Huh7 and SK-Hep1 HCC cell lines. Moreover, SF1126 blocked expression levels of c-Myc in HCC cells. Treatment of SF1126 either alone or in combination with sorafenib showed significant antitumor activity in vivo. Our results establish that SF1126 is a dual PI3K/BRD4 inhibitor. This agent has completed a phase I clinical trial in humans with good safety profile. Our data support the potential future consideration of a phase II clinical trial of SF1126, a clinically relevant dual “first-in-class” PI3K/BRD4 inhibitor in advanced HCC, and a potential combination with sorafenib. Mol Cancer Ther; 15(11); 2553–62. ©2016 AACR.
Data from Development of Anti-CD32b Antibodies with Enhanced Fc Function for the Treatment of B and Plasma Cell Malignancies
Authors: Lu Haihui , Molony Ryan D. , Chen Dongshu , Jang Sunyoung , Wolf Babette , Ewert Stefan , Flaherty Meghan , Xu Fangmin , Isim Sinan , Shim Yeonju , Dornelas Christina , Balke Nicole , Leber Xavier Charles , Scharenberg Meike , Koelln Johanna , Choi Eugene , Ward Rebecca , Johnson Jennifer , Calzascia Thomas , Isnardi Isabelle , Williams Juliet A. , Lindenbergh Pieter L. , van de Donk Niels W.C.J. , Mutis Tuna , Huet Heather , Lees Emma , Meyer Matthew J.
Published: April 2023

Abstract
The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcγRIIIa on immune effector cells. The NVS32b mAbs selectively target CD32b+ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32b+ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc–binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b+ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32b+ malignant cells.
Data from A Rationally Designed Peptide Antagonist of the PD-1 Signaling Pathway as an Immunomodulatory Agent for Cancer Therapy
Authors: Sasikumar Pottayil G. , Ramachandra Raghuveer K. , Adurthi Srinivas , Dhudashiya Amit A. , Vadlamani Sureshkumar , Vemula Koteswararao , Vunnum Sriharibabu , Satyam Leena K. , Samiulla Dodderi S. , Subbarao Krishnaprasad , Nair Rashmi , Shrimali Rajeev , Gowda Nagaraj , Ramachandra Murali
Published: April 2023

Abstract
Pioneering success of antibodies targeting immune checkpoints such as PD-1 and CTLA4 has opened novel avenues for cancer immunotherapy. Along with impressive clinical activity, severe immune-related adverse events (irAE) due to the breaking of immune self-tolerance are becoming increasingly evident in antibody-based approaches. As a strategy to better manage severe adverse effects, we set out to discover an antagonist targeting PD-1 signaling pathway with a shorter pharmacokinetic profile. Herein, we describe a peptide antagonist NP-12 that displays equipotent antagonism toward PD-L1 and PD-L2 in rescue of lymphocyte proliferation and effector functions. In preclinical models of melanoma, colon cancer, and kidney cancers, NP-12 showed significant efficacy comparable with commercially available PD-1–targeting antibodies in inhibiting primary tumor growth and metastasis. Interestingly, antitumor activity of NP-12 in a preestablished CT26 model correlated well with pharmacodynamic effects as indicated by intratumoral recruitment of CD4 and CD8 T cells, and a reduction in PD-1+ T cells (both CD4 and CD8) in tumor and blood. In addition, NP-12 also showed additive antitumor activity in preestablished tumor models when combined with tumor vaccination or a chemotherapeutic agent such as cyclophosphamide known to induce “immunologic cell death.” In summary, NP-12 is the first rationally designed peptide therapeutic targeting PD-1 signaling pathways exhibiting immune activation, excellent antitumor activity, and potential for better management of irAEs.
Data from Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer
Authors: Porru Manuela , Artuso Simona , Salvati Erica , Bianco Armandodoriano , Franceschin Marco , Diodoro Maria Grazia , Passeri Daniela , Orlandi Augusto , Savorani Francesco , D'Incalci Maurizio , Biroccio Annamaria , Leonetti Carlo
Published: April 2023

Abstract
We previously identified EMICORON as a novel G-quadruplex (G4) ligand showing high selectivity for G4 structures over the duplex DNA, causing telomere damage and inhibition of cell proliferation in transformed and tumor cells. Here, we evaluated the antitumoral effect of EMICORON on advanced models of human colon cancer that could adequately predict human clinical outcomes. Our results showed that EMICORON was well tolerated in mice, as no adverse effects were reported, and a low ratio of sensitivity across human and mouse bone marrow cells was observed, indicating a good potential for reaching similar blood levels in humans. Moreover, EMICORON showed a marked therapeutic efficacy, as it inhibited the growth of patient-derived xenografts (PDX) and orthotopic colon cancer and strongly reduced the dissemination of tumor cells to lymph nodes, intestine, stomach, and liver. Finally, activation of DNA damage and impairment of proliferation and angiogenesis are proved to be key determinants of EMICORON antitumoral activity. Altogether, our results, performed on advanced experimental models of human colon cancer that bridge the translational gap between preclinical and clinical studies, demonstrated that EMICORON had an unprecedented antitumor activity warranting further studies of EMICORON-based combination treatments. Mol Cancer Ther; 14(11); 2541–51. ©2015 AACR.
Data from Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept
Authors: Peyrode Caroline , Weber Valérie , Voissière Aurélien , Maisonial-Besset Aurélie , Vidal Aurélien , Auzeloux Philippe , Gaumet Vincent , Borel Michèle , Dauplat Marie-Mélanie , Quintana Mercedes , Degoul Françoise , Rédini Françoise , Chezal Jean-Michel , Miot-Noirault Elisabeth
Published: April 2023

Abstract
To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [3H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo 99mTc-NTP 15-5 scintigraphic imaging of PGs, 1H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575–85. ©2016 AACR.