bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer
Authors: Nakagawa Takayuki , Takeuchi Shinji , Yamada Tadaaki , Nanjo Shigeki , Ishikawa Daisuke , Sano Takako , Kita Kenji , Nakamura Takahiro , Matsumoto Kunio , Suda Kenichi , Mitsudomi Tetsuya , Sekido Yoshitaka , Uenaka Toshimitsu , Yano Seiji
Published: April 2023

Abstract
Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. Mol Cancer Ther; 11(10); 2149–57. ©2012 AACR.
Data from MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma
Authors: Asundi Jyoti , Lacap Jennifer A. , Clark Suzanna , Nannini Michelle , Roth Leslie , Polakis Paul
Published: April 2023

Abstract
Therapies targeting the mitogen-activated protein (MAP) kinase pathway in melanoma have produced significant clinical responses; however, duration of response is limited by acquisition of drug resistance. Rational drug combinations may improve outcomes in this setting. We assessed the therapeutic combination of an antibody–drug conjugate (ADC) targeting the endothelin B receptor (EDNRB) with small-molecule inhibitors of the MAP kinase signaling pathway in melanoma. Cell lines and tumor models containing either mutant BRAF or NRAS, or wild-type for both, were exposed to small-molecule inhibitors of BRAF and MEK. Expression of EDNRB was analyzed and the therapeutic impact of combining the anti-EDNRB ADC with the BRAF and MEK inhibitors was assessed. Increased expression of EDNRB in response to inhibition of BRAF and/or MEK was observed and augmented the antitumor activity of the ADC. Enhanced target expression and ADC antitumor activity were realized irrespective of the response of the tumor model to the BRAF or MEK inhibitors alone and could be achieved in melanoma with mutant NRAS, BRAF, or neither mutation. Cells that acquired resistance to BRAF inhibition through long-term culture retained drug-induced elevated levels of EDNRB expression. Expression of EDNRB was not enhanced in normal human melanocytes by inhibition of BRAF and the combination of the ADC with MAPK inhibitors was well-tolerated in mice. The anti-EDNRB ADC combines well with BRAF and MEK inhibitors and could have therapeutic use in the majority of human melanoma cases. Mol Cancer Ther; 13(6); 1599–610. ©2014 AACR.
Data from 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3β Activation
Authors: Kovács Krisztina , Decatur Christina , Toro Marcela , Pham Dien G. , Liu Huaping , Jing Yuqi , Murray Timothy G. , Lampidis Theodore J. , Merchan Jaime R.
Published: April 2023

Abstract
Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2-deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity to 2-DG in endothelial cells is not associated with enhanced drug uptake compared with tumor cells, but with time-dependent, endothelial-selective inhibition of AKT and ERK phosphorylation. Downregulation of these critical survival pathways is shown to be due to 2-DG's interference with N-linked glycosylation, leading to alterations in VEGFR2 (and downstream signaling) as well as induction of endoplasmic reticulum (ER) stress, GSK3β activation, and apoptosis. In vivo, periocular administration of 2-DG in LHBETATAG mice was associated with significant reduction of newly formed (CD105+) tumor capillaries, ER stress (GRP 78 expression), and endothelial apoptosis (TUNEL). These findings uniquely link N-linked glycosylation inhibition, ER stress, and ERK/AKT downregulation in endothelial cells, and provide a novel drug development strategy to overcome resistance mechanisms to currently available antiangiogenic agents. Mol Cancer Ther; 15(2); 264–75. ©2015 AACR.
Data from V-ATPase Inhibition Regulates Anoikis Resistance and Metastasis of Cancer Cells
Authors: Schempp Christina M. , von Schwarzenberg Karin , Schreiner Laura , Kubisch Rebekka , Müller Rolf , Wagner Ernst , Vollmar Angelika M.
Published: April 2023

Abstract
Fighting metastasis is a major challenge in cancer therapy and novel therapeutic targets and drugs are highly appreciated. Resistance of invasive cells to anoikis, a particular type of apoptosis induced by loss of cell–matrix contact, is a major prerequisite for their metastatic spread. Inducing anoikis in metastatic cancer cells is therefore a promising therapeutic approach. The vacuolar-ATPase (V-ATPase), a proton pump located at the membrane of acidic organelles, has recently come to focus as an antimetastatic cancer target. As V-ATPase inhibitors have shown to prevent invasion of tumor cells and are able to induce apoptosis, we proposed that V-ATPase inhibition induces anoikis-related pathways in invasive cancer cells. We used the V-ATPase inhibitor archazolid to investigate the mechanism of anoikis induction in various metastatic cancer cells (T24, MDA-MB-231, 4T1, 5637) in vitro. Anoikis induction by archazolid was characterized by decreased c-FLIP expression and caspase-8 activation as well as reduction of active integrin-β1 and an early increase of the proapoptotic protein BIM. However, we observed that archazolid also induces mechanisms opposing anoikis such as degradation of BIM mediated by extracellular signal-regulated kinase (ERK), Akt and Src kinases at later time points and induction of reactive oxygen species. Still, intravenous injection of archazolid-treated 4T1-Luc2 mouse breast cancer cells resulted in reduced metastasis in mouse lungs. Thus, V-ATPase inhibition is not only an interesting option to reduce cancer metastasis, but also to better understand anoikis resistance and to find choices to fight against it. Mol Cancer Ther; 13(4); 926–37. ©2014 AACR.
Data from PP2A Inhibition Is a Common Event in Colorectal Cancer and Its Restoration Using FTY720 Shows Promising Therapeutic Potential
Authors: Cristóbal Ion , Manso Rebeca , Rincón Raúl , Caramés Cristina , Senin Clara , Borrero Aurea , Martínez-Useros Javier , Rodriguez María , Zazo Sandra , Aguilera Oscar , Madoz-Gúrpide Juan , Rojo Federico , García-Foncillas Jesús
Published: April 2023

Abstract
Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. Mol Cancer Ther; 13(4); 938–47. ©2014 AACR.
Data from Drug Repurposing for Gastrointestinal Stromal Tumor
Authors: Pessetto Ziyan Y. , Weir Scott J. , Sethi Geetika , Broward Melinda A. , Godwin Andrew K.
Published: April 2023

Abstract
Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning,” has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. Mol Cancer Ther; 12(7); 1299–309. ©2013 AACR.
Data from Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody
Authors: Leonard John E. , Fisher Terrence L. , Winter Laurie A. , Cornelius Chad A. , Reilly Christine , Smith Ernest S. , Zauderer Maurice
Published: April 2023

Abstract
The humanized IgG4 monoclonal antibody VX15/2503 bound with 1 to 5 nmol/L affinity to purified recombinant semaphorin 4D (SEMA4D; CD100) produced using murine, rat, cynomolgus macaque, and human sequences. The affinity for native SEMA4D expressed on macaque T lymphocytes was approximately 0.6 nmol/L. Tissues from rats and cynomolgus macaques demonstrated specific staining only with resident lymphocytes. Single-dose and one-month toxicology/PK studies used VX15/2503 dose levels of 0 to 100 mg/kg. No toxicity was observed with either species in these studies, thus the no observed adverse effect level (NOAEL) was 100 mg/kg. Cmax, exposure, and half-life values were similar for both rats and macaques. The NOAEL in a primate maximum feasible dose study was 200 mg/kg. Saturation of T-cell–associated SEMA4D occurred following administration of single doses of 0.1 mg/kg and above; five weekly injections of VX15/2503 at a dose level of 100 mg/kg produced saturation lasting for more than 120 and 130 days, respectively, for rats and primates. Macaques administered five weekly doses of VX15/2503 showed dose-dependent reductions of 2- to 3-fold in T-cell SEMA4D (cSEMA4D) expression levels compared with controls. Reduced cSEMA4D expression levels continued until serum antibody concentrations were 2 to 5 μg/mL, and thereafter normal cSEMA4D levels were restored. On the basis of these data, a phase I clinical study of the safety and tolerability of VX15/2503 was conducted, enrolling adult patients with advanced solid tumor diseases; a single-dose, dose escalation, phase I safety study was also initiated with subjects with multiple sclerosis. Mol Cancer Ther; 14(4); 964–72. ©2015 AACR.
Data from Small Molecule Inhibition of PAX3-FOXO1 through AKT Activation Suppresses Malignant Phenotypes of Alveolar Rhabdomyosarcoma
Authors: Jothi Mathivanan , Mal Munmun , Keller Charles , Mal Asoke K.
Published: April 2023

Abstract
Alveolar rhabdomyosarcoma comprises a rare highly malignant tumor presumed to be associated with skeletal muscle lineage in children. The hallmark of the majority of alveolar rhabdomyosarcoma is a chromosomal translocation that generates the PAX3-FOXO1 fusion protein, which is an oncogenic transcription factor responsible for the development of the malignant phenotype of this tumor. Alveolar rhabdomyosarcoma cells are dependent on the oncogenic activity of PAX3-FOXO1, and its expression status in alveolar rhabdomyosarcoma tumors correlates with worst patient outcome, suggesting that blocking this activity of PAX3-FOXO1 may be an attractive therapeutic strategy against this fusion-positive disease. In this study, we screened small molecule chemical libraries for inhibitors of PAX3-FOXO1 transcriptional activity using a cell-based readout system. We identified the Sarco/endoplasmic reticulum Ca2+-ATPases (SERCA) inhibitor thapsigargin as an effective inhibitor of PAX3-FOXO1. Subsequent experiments in alveolar rhabdomyosarcoma cells showed that activation of AKT by thapsigargin inhibited PAX3-FOXO1 activity via phosphorylation. Moreover, this AKT activation appears to be associated with the effects of thapsigargin on intracellular calcium levels. Furthermore, thapsigargin inhibited the binding of PAX3-FOXO1 to target genes and subsequently promoted its proteasomal degradation. In addition, thapsigargin treatment decreases the growth and invasive capacity of alveolar rhabdomyosarcoma cells while inducing apoptosis in vitro. Finally, thapsigargin can suppress the growth of an alveolar rhabdomyosarcoma xenograft tumor in vivo. These data reveal that thapsigargin-induced activation of AKT is an effective mechanism to inhibit PAX3-FOXO1 and a potential agent for targeted therapy against alveolar rhabdomyosarcoma. Mol Cancer Ther; 12(12); 2663–74. ©2013 AACR.
Data from Targeted Cytolysins Synergistically Potentiate Cytoplasmic Delivery of Gelonin Immunotoxin
Authors: Pirie Christopher M. , Liu David V. , Wittrup K. Dane
Published: April 2023

Abstract
Targeted endocytic uptake is a first step toward tissue-specific cytoplasmic macromolecular delivery; however, inefficient escape from the endolysosomal compartment makes this generally impractical at present. We report here a targeted cytolysin approach that dramatically potentiates endosomal release of an independently targeted potent gelonin immunotoxin. Fibronectin domains engineered for affinity to EGF receptor or carcinoembryonic antigen were fused to the plant toxin gelonin or bacterial pore-forming cytolysins. These fusion proteins display synergistic activity in both antigen-specific cytotoxicity in vitro, enhancing potency by several orders of magnitude, and in tumor growth inhibition in vivo. In addition, the number of internalized gelonin molecules required to induce apoptosis is reduced from approximately 5 × 106 to less than 103. Targeted potentiation shows promise for enhancing cytoplasmic delivery of other macromolecular payloads such as DNA, siRNA, and miRNA. Mol Cancer Ther; 12(9); 1774–82. ©2013 AACR.
Data from Dual Targeting of Integrin αvβ3 and Matrix Metalloproteinase-2 for Optical Imaging of Tumors and Chemotherapeutic Delivery
Authors: Crisp Jessica L. , Savariar Elamprakash N. , Glasgow Heather L. , Ellies Lesley G. , Whitney Michael A. , Tsien Roger Y.
Published: April 2023

Abstract
Activatable cell-penetrating peptides (ACPP) provide a general strategy for molecular targeting by exploiting the extracellular protease activities associated with disease. Previous work used a matrix metalloproteinase (MMP-2 and 9)-cleavable sequence in the ACPP to target contrast agents for tumor imaging and fluorescence-guided surgery. To improve specificity and sensitivity for MMP-2, an integrin αvβ3-binding domain, cyclic-RGD, was covalently linked to the ACPP. This co-targeting strategy relies on the interaction of MMP-2 with integrin αvβ3, which are known to associate via the hemopexin domain of MMP-2. In U87MG glioblastoma cells in culture, dual targeting greatly improved ACPP uptake compared with either MMP or integrin αvβ3 targeting alone. In vivo, dual-targeted ACPP treatment resulted in tumor contrast of 7.8 ± 1.6, a 10-fold higher tumor fluorescence compared with the negative control peptide, and increased probe penetration into the core of MDA-MB-231 tumors. This platform also significantly improved efficacy of the chemotherapeutic monomethylauristatin E (MMAE) in both MDA-MB-231 orthotopic human and syngeneic Py230 murine breast tumors. Treatment with cyclic-RGD-PLGC(Me)AG-MMAE-ACPP resulted in complete tumor regression in one quarter of MDA-MB-231 tumor–bearing mice, compared with no survival in the control groups. This rational mechanism for amplified delivery of imaging and potent chemotherapeutic agents avoids the use of antibodies and may be of considerable generality. Mol Cancer Ther; 13(6); 1514–25. ©2014 AACR.
Data from A Meta-analysis of Somatic Mutations from Next Generation Sequencing of 241 Melanomas: A Road Map for the Study of Genes with Potential Clinical Relevance
Authors: Xia Junfeng , Jia Peilin , Hutchinson Katherine E. , Dahlman Kimberly B. , Johnson Douglas , Sosman Jeffrey , Pao William , Zhao Zhongming
Published: April 2023

Abstract
Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed “pan negative.” We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS-driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 “pan-negative” melanoma genomes harbored alternate infrequent mutations in the five known driver genes along with many mutations in genes encoding guanine nucleotide binding protein α-subunits. Third, we identified 12 significantly mutated genes in “pan-negative” samples (ALK, STK31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including five genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least two “pan-negative” tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas. Mol Cancer Ther; 13(7); 1918–28. ©2014 AACR.
Data from Downregulation of Hepatoma-Derived Growth Factor Contributes to Retarded Lung Metastasis via Inhibition of Epithelial–Mesenchymal Transition by Systemic POMC Gene Delivery in Melanoma
Authors: Tsai Han-En , Liu Guei-Sheung , Kung Mei-Lang , Liu Li-Feng , Wu Jian-Ching , Tang Chia-Hua , Huang Ching-Hui , Chen San-Cher , Lam Hing-Chung , Wu Chieh-Shan , Tai Ming-Hong
Published: April 2023

Abstract
The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial–mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and α-smooth muscle actin (α-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma. Mol Cancer Ther; 12(6); 1016–25. ©2013 AACR.
Data from Novel Curcumin-Loaded Magnetic Nanoparticles for Pancreatic Cancer Treatment
Authors: Yallapu Murali M. , Ebeling Mara C. , Khan Sheema , Sundram Vasudha , Chauhan Neeraj , Gupta Brij K. , Puumala Susan E. , Jaggi Meena , Chauhan Subhash C.
Published: April 2023

Abstract
Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has showed potent anticancer and cancer prevention activity in a variety of cancers. However, the clinical translation of CUR has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics, and poor bioavailability. To address these clinically relevant issues, we have developed a novel CUR-loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAF-II and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose-dependent manner. As a result, the MNP-CUR formulation effectively inhibited growth of HPAF-II and Panc-1 cells in cell proliferation and colony formation assays. The MNP-CUR formulation suppressed pancreatic tumor growth in an HPAF-II xenograft mouse model and improved the survival of mice by delaying tumor growth. The growth-inhibitory effect of MNP-CUR formulation correlated with the suppression of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-extra large (Bcl-xL), induced myeloid leukemia cell differentiation protein (Mcl-1), cell surface–associated Mucin 1 (MUC1), collagen I, and enhanced membrane β-catenin expression. MNP-CUR formulation did not show any sign of hemotoxicity and was stable after incubation with human serum proteins. In addition, the MNP-CUR formulation improved serum bioavailability of CUR in mice up to 2.5-fold as compared with free CUR. Biodistribution studies show that a significant amount of MNP-CUR formulation was able to reach the pancreatic xenograft tumor(s), which suggests its clinical translational potential. In conclusion, this study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer. Mol Cancer Ther; 12(8); 1471–80. ©2013 AACR.
Data from Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways
Authors: Basu Dipanjan , Lettan Robert , Damodaran Krishnan , Strellec Susan , Reyes-Mugica Miguel , Rebbaa Abdelhadi
Published: April 2023

Abstract
Embryonic signaling pathways, in particular those mediated by Wnt and TGF-β, are known to play key roles in tumor progression through the induction of epithelial–mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-β–associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-β pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-β–mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence. Mol Cancer Ther; 13(6); 1457–67. ©2014 AACR.
Data from Blocking IL1β Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis
Authors: Voloshin Tali , Alishekevitz Dror , Kaneti Limor , Miller Valeria , Isakov Elina , Kaplanov Irena , Voronov Elena , Fremder Ella , Benhar Moran , Machluf Marcelle , Apte Ron N. , Shaked Yuval
Published: April 2023

Abstract
Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here, we show that the proinflammatory cytokine IL1β is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL1β, or its receptor, using either genetic or pharmacologic approach, results in slight retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL1 receptor antagonist anakinra exhibit increased number of M2 macrophages and vessel leakiness when compared with paclitaxel monotherapy-treated mice, indicating a prometastatic role of M2 macrophages in the IL1β-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL1 pathway on tumor growth. Accordingly, treatments using “add-on” drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases. Mol Cancer Ther; 14(6); 1385–94. ©2015 AACR.
Data from Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2
Authors: Soares Heloisa P. , Ming Ming , Mellon Michelle , Young Steven H. , Han Liang , Sinnet-Smith James , Rozengurt Enrique
Published: April 2023

Abstract
The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser240/244), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at Thr37/46), and mTORC2-mediated AKT phosphorylation at Ser473, in a concentration-dependent manner. Strikingly, BEZ235 markedly enhanced the MEK/ERK pathway in a dose-dependent manner. Maximal ERK overactivation coincided with complete inhibition of phosphorylation of AKT and 4E-BP1. ERK overactivation was induced by other PI3K/TOR-KIs, including PKI-587 and GDC-0980. The MEK inhibitors U126 or PD0325901 prevented ERK overactivation induced by PI3K/TOR-KIs. The combination of BEZ235 and PD0325901 caused a more pronounced inhibition of cell growth than that produced by each inhibitor individually. Mechanistic studies assessing PI3K activity in single PDAC cells indicate that PI3K/TOR-KIs act through a PI3K-independent pathway. Doses of PI3K/TOR-KIs that enhanced MEK/ERK activation coincided with those that inhibited mTORC2-mediated AKT phosphorylation on Ser473, suggesting a role of mTORC2. Knockdown of RICTOR via transfection of siRNA markedly attenuated the enhancing effect of BEZ235 on ERK phosphorylation. We propose that dual PI3K/mTOR inhibitors suppress a novel negative feedback loop mediated by mTORC2, thereby leading to enhanced MEK/ERK pathway activity in pancreatic cancer cells. Mol Cancer Ther; 14(4); 1014–23. ©2015 AACR.
Data from Therapeutic Potential of the Poly(ADP-ribose) Polymerase Inhibitor Rucaparib for the Treatment of Sporadic Human Ovarian Cancer
Authors: Ihnen Maike , zu Eulenburg Christine , Kolarova Teodora , Qi Jing Wei , Manivong Kanthinh , Chalukya Meenal , Dering Judy , Anderson Lee , Ginther Charles , Meuter Alexandra , Winterhoff Boris , Jones Siân , Velculescu Victor E. , Venkatesan Natarajan , Rong Hong-Mei , Dandekar Sugandha , Udar Nitin , Jänicke Fritz , Los Gerrit , Slamon Dennis J. , Konecny Gottfried E.
Published: April 2023

Abstract
Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer. Mol Cancer Ther; 12(6); 1002–15. ©2013 AACR.
Data from Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells
Authors: Happold Caroline , Roth Patrick , Silginer Manuela , Florea Ana-Maria , Lamszus Katrin , Frei Karl , Deenen Rene , Reifenberger Guido , Weller Michael
Published: April 2023

Abstract
Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O6-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β–mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible to IFN-β sensitization. Gene expression profiling following IFN-β treatment revealed strong upregulation of IFN-β–associated genes, including a proapoptotic gene cluster, but did not alter stemness-associated expression signatures. Caspase activity and inhibition studies revealed the proapoptotic genes to mediate glioma cell sensitization to exogenous death ligands by IFN-β, but not to temozolomide or irradiation, indicating distinct pathways of death sensitization mediated by IFN-β. Thus, IFN-β is a potential adjunct to glioblastoma treatment that may target the GIC population. IFN-β operates independently of MGMT-mediated resistance, classical apoptosis-regulatory networks, and stemness-associated gene clusters. Mol Cancer Ther; 13(4); 948–61. ©2014 AACR.
Data from Triptolide Induces the Expression of miR-142-3p: A Negative Regulator of Heat Shock Protein 70 and Pancreatic Cancer Cell Proliferation
Authors: MacKenzie Tiffany N. , Mujumdar Nameeta , Banerjee Sulagna , Sangwan Veena , Sarver Aaron , Vickers Selwyn , Subramanian Subbaya , Saluja Ashok K.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits PDAC cell growth in vitro and blocks metastatic spread in vivo. Triptolide downregulates HSP70, a molecular chaperone upregulated in several tumor types. This study investigates the mechanism by which triptolide inhibits HSP70. Because microRNAs (miRNA) are becoming increasingly recognized as negative regulators of gene expression, we tested whether triptolide regulates HSP70 via miRNAs. Here, we show that triptolide as well as quercetin, but not gemcitabine, upregulated miR-142-3p in PDAC cells (MIA PaCa-2, Capan-1, and S2-013). Ectopic expression of miR-142-3p inhibited cell proliferation, measured by electric cell-substrate impedance sensing, and decreased HSP70 expression, measured by real-time PCR and immunoblotting, compared with controls. We showed that miR-142-3p directly binds to the 3′UTR of HSP70, and that this interaction is important as HSP70 overexpression rescued miR–142-3p-induced cell death. We found that miR–142-3p regulates HSP70 independently of heat shock factor 1. Furthermore, Minnelide, a water-soluble prodrug of triptolide, induced the expression of miR-142-3p in vivo. This is the first description of an miRNA-mediated mechanism of HSP70 regulation in cancer, making miR-142-3p an attractive target for PDAC therapeutic intervention. Mol Cancer Ther; 12(7); 1266–75. ©2013 AACR.
Data from A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein
Authors: Pop Marius S. , Stransky Nicolas , Garvie Colin W. , Theurillat Jean-Philippe , Hartman Emily C. , Lewis Timothy A. , Zhong Cheng , Culyba Elizabeth K. , Lin Fallon , Daniels Douglas S. , Pagliarini Raymond , Ronco Lucienne , Koehler Angela N. , Garraway Levi A.
Published: April 2023

Abstract
Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins. Mol Cancer Ther; 13(6); 1492–502. ©2014 AACR.
Data from Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth
Authors: Campbell Veronica T. , Nadesan Puviindran , Ali S. Amanda , Wang Chang Ye Yale , Whetstone Heather , Poon Raymond , Wei Qingxia , Keilty John , Proctor Jennifer , Wang Lauren W. , Apte Suneel S. , McGovern Karen , Alman Benjamin A. , Wunder Jay S.
Published: April 2023

Abstract
Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand-dependent settings, where Hh signaling occurs either directly within the cancer cells or within the nonmalignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand-dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI-926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926–treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in downmodulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling, and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathologic changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma. Mol Cancer Ther; 13(5); 1259–69. ©2014 AACR.
Data from Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases
Authors: Kai Kazuharu , Kondo Kimie , Wang Xiaoping , Xie Xuemei , Pitner Mary K. , Reyes Monica E. , Torres-Adorno Angie M. , Masuda Hiroko , Hortobagyi Gabriel N. , Bartholomeusz Chandra , Saya Hideyuki , Tripathy Debu , Sen Subrata , Ueno Naoto T.
Published: April 2023

Abstract
Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and, because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell-cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed, this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition. Mol Cancer Ther; 14(12); 2687–99. ©2015 AACR.
Data from Bisphosphorylated PEA-15 Sensitizes Ovarian Cancer Cells to Paclitaxel by Impairing the Microtubule-Destabilizing Effect of SCLIP
Authors: Xie Xuemei , Bartholomeusz Chandra , Ahmed Ahmed A. , Kazansky Anna , Diao Lixia , Baggerly Keith A. , Hortobagyi Gabriel N. , Ueno Naoto T.
Published: April 2023

Abstract
Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation, autophagy, apoptosis, and glucose metabolism and also mediates AKT-dependent chemoresistance in breast cancer. The functions of PEA-15 are tightly regulated by its phosphorylation status at Ser104 and Ser116. However, the effect of PEA-15 phosphorylation status on chemosensitivity of cancer cells remains unknown. Here, we tested the hypothesis that PEA-15 phosphorylated at both Ser104 and Ser116 (pPEA-15) sensitizes ovarian cancer cells to paclitaxel. We first found that knockdown of PEA-15 in PEA-15–high expressing HEY and OVTOKO ovarian cancer cells resulted in paclitaxel resistance, whereas re-expression of PEA-15 in these cells led to paclitaxel sensitization. We next found that SKOV3.ip1-DD cells (expressing phosphomimetic PEA-15) were more sensitive to paclitaxel than SKOV3.ip1-AA cells (expressing nonphosphorylatable PEA-15). Compared with SKOV3.ip1-vector and SKOV3.ip1-AA cells, SKOV3.ip1-DD cells displayed reduced cell viability, inhibited anchorage-independent growth, and augmented apoptosis when treated with paclitaxel. Furthermore, HEY and OVTOKO cells displayed enhanced paclitaxel sensitivity when transiently overexpressing phosphomimetic PEA-15 and reduced paclitaxel sensitivity when transiently overexpressing nonphosphorylatable PEA-15. These results indicate that pPEA-15 sensitizes ovarian cancer cells to paclitaxel. cDNA microarray analysis suggested that SCLIP (SCG10-like protein), a microtubule-destabilizing protein, is involved in pPEA-15–mediated chemosensitization. We found that reduced expression and possibly posttranslational modification of SCLIP following paclitaxel treatment impaired the microtubule-destabilizing effect of SCLIP, thereby promoting induction of mitotic arrest and apoptosis by paclitaxel. Our findings highlight the importance of pPEA-15 as a promising target for improving the efficacy of paclitaxel-based therapy in ovarian cancer. Mol Cancer Ther; 12(6); 1099–111. ©2013 AACR.
Data from Nuclear Translocation of Hand-1 Acts as a Molecular Switch to Regulate Vascular Radiosensitivity in Medulloblastoma Tumors: The Protein uPAR Is a Cytoplasmic Sequestration Factor for Hand-1
Authors: Asuthkar Swapna , Gogineni Venkateswara Rao , Rao Jasti S. , Velpula Kiran Kumar
Published: April 2023

Abstract
Urokinase-type plasminogen activator receptor (uPAR) is overexpressed in the tumor–stromal invasive microenvironment in many human cancers, including medulloblastoma. The role of uPAR in tumor progression and angiogenesis has been well characterized. Previously, in medulloblastoma cells, we showed that ionizing radiation (IR)–induced uPAR is a potent activator of cancer stem cell (CSC)–like properties and is associated with various transcription factors that are involved during embryonic development and cancer. In the present study, we show that uPAR protein acts as a cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand-1. The Hand-1 protein plays an essential role in the differentiation of trophoblast giant cells and cardiac morphogenesis, and yet its precise cellular function and its contribution to cancer remain mostly unknown. We also observed that the Hand-1 protein is upregulated in uPAR short hairpin RNA–treated medulloblastoma cells and accompanies sustained cell growth and angiogenesis. Furthermore, IR-induced uPAR overexpression negatively regulates Hand-1 activity and results in the stabilization of angiogenesis-promoting molecules, including hypoxia-inducible factor-1α. Finally, uPAR overexpression and its association with Hand-1 after IR treatment indicate that uPAR is capable of regulating Hand-1 and that uPAR has a role in the process of IR-induced tumor angiogenesis. Mol Cancer Ther; 13(5); 1309–22. ©2014 AACR.