bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α
Authors: Rossi Edmund A. , Rossi Diane L. , Cardillo Thomas M. , Chang Chien-Hsing , Goldenberg David M.
Published: March 2024

Abstract
Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell–redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2–targeting Fab using Dock-and-Lock. We show for the first time that bsAb-mediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-α (INFα) on (E1)-3s–mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a—which alone did not increase T-cell activation or raise cytokine levels over baseline—increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFα, 20*-2b, significantly potentiated the activity of (E1)-3s by more than 2.5- or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell–mediated killing of Trop-2–expressing pancreatic and gastric cancers, which was enhanced with INFα. Mol Cancer Ther; 13(10); 2341–51. ©2014 AACR.
Data from Folate Receptor–Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer
Authors: Paulmurugan Ramasamy , Bhethanabotla Rohith , Mishra Kaushik , Devulapally Rammohan , Foygel Kira , Sekar Thillai V. , Ananta Jeyarama S. , Massoud Tarik F. , Joy Abraham
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off-target effects and poor bioavailability of the FDA-approved antiobesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here, we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor–targeted micellar nanoparticles (NP) carrying orlistat, which improved the solubility (70–80 μg/mL) of this water-insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in a nude mouse model. We prepared HEA–EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence-activated cell sorting (FACS) analysis of TNBC cells indicated a dose-dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor–targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase-3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, folate receptor–targeted Fol-DyLight747-orlistat NP–treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. Mol Cancer Ther; 15(2); 221–31. ©2015 AACR.
Data from TWIST1 Polymorphisms Predict Survival in Patients with Metastatic Colorectal Cancer Receiving First-Line Bevacizumab plus Oxaliplatin-Based Chemotherapy
Authors: Matsusaka Satoshi , Zhang Wu , Cao Shu , Hanna Diana L. , Sunakawa Yu , Sebio Ana , Ueno Masashi , Yang Dongyun , Ning Yan , Parekh Anish , Okazaki Satoshi , Berger Martin D. , Ichikawa Wataru , Mizunuma Nobuyuki , Lenz Heinz-Josef
Published: March 2024

Abstract
The epithelial–mesenchymal transition (EMT) is an important mechanism of resistance to angiogenesis inhibition. The ability of EMT pathway genetic variants to predict the efficacy of antiangiogenic therapy is unknown. We analyzed associations between functional SNPs in EMT-related genes and outcomes in metastatic colorectal cancer (mCRC) patients undergoing first-line bevacizumab-based chemotherapy. A total of 220 mCRC patients were included in this study: 143 patients treated with first-line bevacizumab-based chemotherapy (bevacizumab cohort) and 77 patients treated with cetuximab-based chemotherapy (cetuximab cohort). SNPs in TWIST1 (rs2285682, rs2285681), ZEB1 (rs10826943, rs2839658), SNAIL (rs1543442, rs4647958), and E-cadherin (rs16260) genes were analyzed by PCR-based direct sequencing. Patients carrying a TWIST1 rs2285682 G allele had a significantly longer median progression-free survival (PFS) of 18.1 months and overall survival (OS) of 44.1 months compared with those with the T/T genotype, who had a median PFS of 13.3 months (HR, 0.57; P = 0.003) and OS of 29.2 months (HR, 0.53; P = 0.001) in the bevacizumab cohort. In multivariate analysis, associations between TWIST1 rs2285682 and PFS and OS remained significant. Among women, the G allele of TWIST1 rs2285682 (PFS HR, 0.39; P = 0.007; OS HR, 0.30; P = 0.001) and TWIST1 rs2285681 (PFS HR, 0.27; P < 0.001; OS HR, 0.25; P < 0.001) was associated with improved survival. No significant associations were found in the cetuximab cohort. Our findings suggest that TWIST1 polymorphisms are associated with survival in mCRC patients treated with first-line bevacizumab-based chemotherapy and may serve as clinically useful biomarkers for antiangiogenic therapy. Mol Cancer Ther; 15(6); 1405–11. ©2016 AACR.
Data from Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer
Authors: Hassan Saima , Esch Amanda , Liby Tiera , Gray Joe W. , Heiser Laura M.
Published: March 2024

Abstract
Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose–response measures of cell viability, an EC50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle–associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892–901. ©2017 AACR.
Data from Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth
Authors: Abu Aboud Omran , Chen Ching-Hsien , Senapedis William , Baloglu Erkan , Argueta Christian , Weiss Robert H.
Published: March 2024

Abstract
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and one of the relatively few whose incidence is increasing. Because of the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth. We now show, using the dual PAK4/NAMPT inhibitor KPT-9274, that interference with these signaling pathways results in reduction of G2–M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. Furthermore, NAPRT1 downregulation, which we show occurs in all RCC cell lines tested, makes this tumor highly dependent on NAMPT for its NAD requirements, such that inhibition of NAMPT by KPT-9274 leads to decreased survival of these rapidly proliferating cells. When KPT-9274 was administered in vivo to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with no apparent toxicity; KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC. Mol Cancer Ther; 15(9); 2119–29. ©2016 AACR.
Data from The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance
Authors: Venetsanakos Eleni , Brameld Ken A. , Phan Vernon T. , Verner Erik , Owens Timothy D. , Xing Yan , Tam Danny , LaStant Jacob , Leung Kwan , Karr Dane E. , Hill Ronald J. , Gerritsen Mary E. , Goldstein David M. , Funk Jens Oliver , Bradshaw J. Michael
Published: March 2024

Abstract
An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668–76. ©2017 AACR.
Data from Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer
Authors: Ishida Michihiro , Kagawa Shunsuke , Shimoyama Kyoko , Takehara Kiyoto , Noma Kazuhiro , Tanabe Shunsuke , Shirakawa Yasuhiro , Tazawa Hiroshi , Kobayashi Hisataka , Fujiwara Toshiyoshi
Published: March 2024

Abstract
Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. We hypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)–mediated PIT induced selective cell death of HER2-ECD–transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700–mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. Mol Cancer Ther; 15(3); 402–11. ©2016 AACR.
Data from Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma
Authors: Amodio Nicola , Stamato Maria Angelica , Gullà Anna Maria , Morelli Eugenio , Romeo Enrica , Raimondi Lavinia , Pitari Maria Rita , Ferrandino Ida , Misso Gabriella , Caraglia Michele , Perrotta Ida , Neri Antonino , Fulciniti Mariateresa , Rolfo Christian , Anderson Kenneth C. , Munshi Nikhil C. , Tagliaferri Pierosandro , Tassone Pierfrancesco
Published: March 2024

Abstract
Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b–based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364–75. ©2016 AACR.
Data from Synergy between Androgen Receptor Antagonism and Inhibition of mTOR and HER2 in Breast Cancer
Authors: Gordon Michael A. , D'Amato Nicholas C. , Gu Haihua , Babbs Beatrice , Wulfkuhle Julia , Petricoin Emanuel F. , Gallagher Isela , Dong Ting , Torkko Kathleen , Liu Bolin , Elias Anthony , Richer Jennifer K.
Published: March 2024

Abstract
The androgen receptor (AR) is widely expressed in breast cancer, and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in preclinical models and clinical trials of prostate cancer and are currently being evaluated in breast cancer. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit breast cancer growth. HER2+ and triple-negative breast cancer cell lines were treated with AR antagonist plus anti-HER2 mAb trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation, and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, Western blot, and reverse phase protein array. In vivo, HER2+ breast cancer xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2+ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2+ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved breast cancer therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ breast cancer cells in vivo. Mol Cancer Ther; 16(7); 1389–400. ©2017 AACR.
Data from Reversible Action of Diaminothiazoles in Cancer Cells Is Implicated by the Induction of a Fast Conformational Change of Tubulin and Suppression of Microtubule Dynamics
Authors: Thomas Nisha E. , Thamkachy Reshma , Sivakumar Krishnankutty C. , Sreedevi Krishnakumar J. , Louis Xavier Lieben , Thomas Sannu A. , Kumar Rohith , Rajasekharan Kallikat N. , Cassimeris Lynne , Sengupta Suparna
Published: March 2024

Abstract
Diaminothiazoles are novel cytotoxic compounds that have shown efficacy toward different cancer cell lines. They show potent antimitotic and antiangiogenic activity upon binding to the colchicine-binding site of tubulin. However, the mechanism of action of diaminothiazoles at the molecular level is not known. Here, we show a reversible binding to tubulin with a fast conformational change that allows the lead diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino)thiazole] to cause a reversible mitotic block. DAT1 also suppresses microtubule dynamic instability at much lower concentration than its IC50 value in cancer cells. Both growth and shortening events were reduced by DAT1 in a concentration-dependent way. Colchicine, the long-studied tubulin-binding drug, has previously failed in the treatment of cancer due to its toxicity, even though it generates a strong apoptotic response. The toxicity is attributable to its slow removal from the cell due to irreversible tubulin binding caused by a slow conformational change. DAT1 binds to tubulin at an optimal pH lower than colchicine. Tubulin conformational studies showed that the binding environments of DAT1 and colchicine are different. Molecular dynamic simulations showed a difference in the number of H-bonding interactions that accounts for the different pH optima. This study gives an insight of the action of compounds targeting tubulin's colchicine-binding site, as many such compounds have entered into clinical trials recently. Mol Cancer Ther; 13(1); 179–89. ©2013 AACR.
Data from Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms
Authors: Pinkerneil Maria , Hoffmann Michèle J. , Deenen René , Köhrer Karl , Arent Tanja , Schulz Wolfgang A. , Niegisch Günter
Published: March 2024

Abstract
Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays; flow cytometry, senescence and lactate dehydrogenase cytotoxicity assays; and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80% and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line– and HDAC-dependently reduced, with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors romidepsin and givinostat, significantly reduced proliferation of all UCCs (IC50, 3.36 nmol/L–4.59 μmol/L). Romidepsin and givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on nontumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and nonapoptotic cell death in UCCs. Thus, although both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation, their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for urothelial carcinoma therapy. Mol Cancer Ther; 15(2); 299–312. ©2016 AACR.
Data from Dipyridamole Enhances the Cytotoxicities of Trametinib against Colon Cancer Cells through Combined Targeting of HMGCS1 and MEK Pathway
Authors: Zhou Sheng , Xu Huanji , Tang Qiulin , Xia Hongwei , Bi Feng
Published: March 2024

Abstract
Both the MAPK pathway and mevalonate (MVA) signaling pathway play an increasingly significant role in the carcinogenesis of colorectal carcinoma, whereas the cross-talk between these two pathways and its implication in targeted therapy remains unclear in colorectal carcinoma. Here, we identified that HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1), the rate-limiting enzyme of the MVA pathway, is overexpressed in colon cancer tissues and positively regulates the cell proliferation, migration, and invasion of colon cancer cells. In addition, HMGCS1 could enhance the activity of pERK independent of the MVA pathway, and the suppression of HMGCS1 could completely reduce the EGF-induced proliferation of colon cancer cells. Furthermore, we found that trametinib, a MEK inhibitor, could only partially abolish the upregulation of HMGCS1 induced by EGF treatment, while combination with HMGCS1 knockdown could completely reverse the upregulation of HMGCS1 induced by EGF treatment and increase the sensitivity of colon cancer cells to trametinib. Finally, we combined trametinib and dipyridamole, a common clinically used drug that could suppress the activity of SREBF2 (sterol regulatory element-binding transcription factor 2), a transcription factor regulating HMGCS1 expression, and identified its synergistic effect in inhibiting the proliferation and survival of colon cancer cells in vitro as well as the in vivo tumorigenic potential of colon cancer cells. Together, the current data indicated that HMGCS1 may be a novel biomarker, and the combination of targeting HMGCS1 and MEK might be a promising therapeutic strategy for patients with colon cancer.
Data from Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors
Authors: Mastri Michalis , Lee Christina R. , Tracz Amanda , Kerbel Robert S. , Dolan Melissa , Shi Yuhao , Ebos John M.L.
Published: March 2024

Abstract
The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor “host” treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral “side effects” of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare “off-target” host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or “therasomes”) may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602–12. ©2018 AACR.
Data from Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo
Authors: Lopez Salvatore , Cocco Emiliano , Black Jonathan , Bellone Stefania , Bonazzoli Elena , Predolini Federica , Ferrari Francesca , Schwab Carlton L. , English Diana P. , Ratner Elena , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Terranova Corrado , Angioli Roberto , Santin Alessandro D.
Published: March 2024

Abstract
HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu–amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0–G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent–treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor–resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy. Mol Cancer Ther; 14(11); 2519–26. ©2015 AACR.
Data from The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear β-Catenin
Authors: Shukla Samriddhi , Milewski David , Pradhan Arun , Rama Nihar , Rice Kathryn , Le Tien , Flick Matthew J. , Vaz Sara , Zhao Xueheng , Setchell Kenneth D. , Logarinho Elsa , Kalinichenko Vladimir V. , Kalin Tanya V.
Published: March 2024

Abstract
The oncogenic transcription factor FOXM1 has been previously shown to play a critical role in carcinogenesis by inducing cellular proliferation in multiple cancer types. A small-molecule compound, Robert Costa Memorial drug-1 (RCM-1), has been recently identified from high-throughput screen as an inhibitor of FOXM1 in vitro and in mouse model of allergen-mediated lung inflammation. In the present study, we examined antitumor activities of RCM-1 using tumor models. Treatment with RCM-1 inhibited tumor cell proliferation as evidenced by increased cell-cycle duration. Confocal imaging of RCM-1–treated tumor cells indicated that delay in cellular proliferation was concordant with inhibition of FOXM1 nuclear localization in these cells. RCM-1 reduced the formation and growth of tumor cell colonies in the colony formation assay. In animal models, RCM-1 treatment inhibited growth of mouse rhabdomyosarcoma Rd76-9, melanoma B16-F10, and human H2122 lung adenocarcinoma. RCM-1 decreased FOXM1 protein in the tumors, reduced tumor cell proliferation, and increased tumor cell apoptosis. RCM-1 decreased protein levels and nuclear localization of β-catenin, and inhibited protein–protein interaction between β-catenin and FOXM1 in cultured tumor cells and in vivo. Altogether, our study provides important evidence of antitumor potential of the small-molecule compound RCM-1, suggesting that RCM-1 can be a promising candidate for anticancer therapy.
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: March 2024

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 A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy
Authors: Manara Maria Cristina , Valente Sergio , Cristalli Camilla , Nicoletti Giordano , Landuzzi Lorena , Zwergel Clemens , Mazzone Roberta , Stazi Giulia , Arimondo Paola B. , Pasello Michela , Guerzoni Clara , Picci Piero , Nanni Patrizia , Lollini Pier-Luigi , Mai Antonello , Scotlandi Katia
Published: March 2024

Abstract
The identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G1 or G2–M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881–92. ©2018 AACR.
Data from Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers
Authors: Arora Arvind , Parvathaneni Swetha , Aleskandarany Mohammed A. , Agarwal Devika , Ali Reem , Abdel-Fatah Tarek , Green Andrew R. , Ball Graham R. , Rakha Emad A. , Ellis Ian O. , Sharma Sudha , Madhusudan Srinivasan
Published: March 2024

Abstract
RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (P = 0.026), which is characterized by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 [luminal A estrogen receptor–positive (ER+) subgroup; P = 0.0455] and intClust.9 (luminal B ER+ subgroup; P = 0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer–specific survival (P = 0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumor size, lymph node positivity, high tumor grade, high mitotic index, pleomorphism, dedifferentiation, ER negativity, and HER-2 overexpression (P < 0.05). In ER+ tumors that received endocrine therapy, low RECQL1 was associated with poor survival (P = 0.008). However, in ER− tumors that received anthracycline-based chemotherapy, high RECQL1 was associated with poor survival (P = 0.048). In RECQL1-depleted breast cancer cell lines, we confirmed doxorubicin sensitivity, which was associated with DNA double-strand breaks accumulation, S-phase cell-cycle arrest, and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers. Mol Cancer Ther; 16(1); 239–50. ©2016 AACR.
Data from Targeting the MET Receptor Tyrosine Kinase as a Strategy for Radiosensitization in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma
Authors: Nisa Lluís , Francica Paola , Giger Roland , Medo Matúš , Elicin Olgun , Friese-Hamim Manja , Wilm Claudia , Stroh Christopher , Bojaxhiu Beat , Quintin Aurélie , Caversaccio Marco D. , Dettmer Matthias S. , Buchwalder Mélanie , Brodie Tess M. , Aebersold Daniel M. , Zimmer Yitzhak , Carey Thomas E. , Medová Michaela
Published: March 2024

Abstract
Radiotherapy (RT) along with surgery is the mainstay of treatment in head and neck squamous cell carcinoma (HNSCC). Radioresistance represents a major source of treatment failure, underlining the urgent necessity to explore and implement effective radiosensitization strategies. The MET receptor widely participates in the acquisition and maintenance of an aggressive phenotype in HNSCC and modulates the DNA damage response following ionizing radiation (IR). Here, we assessed MET expression and mutation status in primary and metastatic lesions within a cohort of patients with advanced HNSCC. Moreover, we investigated the radiosensitization potential of the MET inhibitor tepotinib in a panel of cell lines, in vitro and in vivo, as well as in ex vivo patient-derived organotypic tissue cultures (OTC). MET was highly expressed in 62.4% of primary tumors and in 53.6% of lymph node metastases (LNM), and in 6 of 9 evaluated cell lines. MET expression in primaries and LNMs was significantly associated with decreased disease control in univariate survival analyses. Tepotinib abrogated MET phosphorylation and to distinct extent MET downstream signaling. Pretreatment with tepotinib resulted in variable radiosensitization, enhanced DNA damage, cell death, and G2–M-phase arrest. Combination of tepotinib with IR led to significant radiosensitization in one of two tested in vivo models. OTCs revealed differential patterns of response toward tepotinib, irradiation, and combination of both modalities. The molecular basis of tepotinib-mediated radiosensitization was studied by a CyTOF-based single-cell mass cytometry approach, which uncovered that MET inhibition modulated PI3K activity in cells radiosensitized by tepotinib but not in the resistant ones.
Data from Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective Drug for Paclitaxel-Induced Neuropathy
Authors: Chen Li-Hsien , Sun Yuan-Ting , Chen Yih-Fung , Lee Mei-Yi , Chang Lian-Yun , Chang Jang-Yang , Shen Meng-Ru
Published: March 2024

Abstract
Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. This study aimed to discover potential neuroprotective drugs for paclitaxel-induced neurotoxicity. An image-based high-content platform was first developed to screen for potential neuroprotective drugs. The screening system comprised of automated image acquisition and multiparameter analysis, including neuronal viability, neurite outgrowth, and synaptogenesis. By this platform, we obtained a candidate list from compound libraries. In the drug screening from compound libraries of ion channel ligands, REDOX and GABAergic ligands, 5-hydroxydecanoate (5-HD) exhibited the most significant neuroprotective effects against paclitaxel-induced neurotoxicity in both cortical and dorsal root ganglion (DRG) neurons. In mouse behavioral tests, 5-HD restored the thermal sensitivity and alleviated mechanical allodynia induced by paclitaxel. Electron micrographs of sciatic nerve revealed that 5-HD reduced the damages caused by paclitaxel in the nonmyelinated and smaller myelinated fibers. The mechanistic study on DRG neurons suggested that 5-HD rescued the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, 5-HD did not jeopardize the antitumor effect of paclitaxel in tumor xenograft models. In conclusion, we established an imaged-based high-content screening platform and a protocol for verifying the neuroprotective effect in vivo, by which 5-HD was identified and validated as a potential neuroprotective drug for paclitaxel-induced neuropathy. Mol Cancer Ther; 14(10); 2206–14. ©2015 AACR.
Data from Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations, T790M Mutation, and AXL Overexpression
Authors: Tanaka Hiroaki , Sakagami Hideki , Kaneko Naoki , Konagai Satoshi , Yamamoto Hiroko , Matsuya Takahiro , Yuri Masatoshi , Yamanaka Yosuke , Mori Masamichi , Takeuchi Masahiro , Koshio Hiroyuki , Hirano Masaaki , Kuromitsu Sadao
Published: March 2024

Abstract
First- and second-generation EGFR tyrosine kinase inhibitors (TKI) are effective clinical therapies for patients with non–small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, almost all patients develop resistance to these drugs. The EGFR T790M mutation of EGFR is the most predominant mechanism for resistance. In addition, activation of AXL signaling is one of the suggested alternative bypassing pathways for resistance to EGFR-TKIs. Here, we report that naquotinib, a pyrazine carboxamide–based EGFR-TKI, inhibited EGFR with activating mutations, as well as T790M resistance mutation while sparing wild-type (WT) EGFR. In in vivo murine xenograft models using cell lines and a patient-derived xenograft model, naquotinib induced tumor regression of NSCLC with EGFR-activating mutations with or without T790M resistance mutation, whereas it did not significantly inhibit WT EGFR signaling in skin. Furthermore, naquotinib suppressed tumor recurrence during the treatment period of 90 days. In addition, unlike erlotinib and osimertinib, naquotinib inhibited the phosphorylation of AXL and showed antitumor activity against PC-9 cells overexpressing AXL in vitro and in vivo. Our findings suggest that naquotinib has therapeutic potential in patients with NSCLC with EGFR-activating mutations, T790M resistance mutation, and AXL overexpression.
Data from Antitumor Effect of the Atypical Retinoid ST1926 in Acute Myeloid Leukemia and Nanoparticle Formulation Prolongs Lifespan and Reduces Tumor Burden of Xenograft Mice
Authors: El-Houjeiri Leeanna , Saad Walid , Hayar Berthe , Aouad Patrick , Tawil Nadim , Abdel-Samad Rana , Hleihel Rita , Hamie Maguy , Mancinelli Angelo , Pisano Claudio , El Hajj Hiba , Darwiche Nadine
Published: March 2024

Abstract
Acute myeloid leukemia (AML) is one of the most frequent types of blood malignancies. It is a complex disorder of undifferentiated hematopoietic progenitor cells. The majority of patients generally respond to intensive therapy. Nevertheless, relapse is the major cause of death in AML, warranting the need for novel treatment strategies. Retinoids have demonstrated potent differentiation and growth regulatory effects in normal, transformed, and hematopoietic progenitor cells. All-trans retinoic acid (ATRA) is the paradigm of treatment in acute promyelocytic leukemia, an AML subtype. The majority of AML subtypes are, however, resistant to ATRA. Multiple synthetic retinoids such as ST1926 recently emerged as potent anticancer agents to overcome such resistance. Despite its lack of toxicity, ST1926 clinical development was restricted due to its limited bioavailability and rapid excretion. Here, we investigate the preclinical efficacy of ST1926 and polymer-stabilized ST1926 nanoparticles (ST1926-NP) in AML models. We show that sub-μmol/L concentrations of ST1926 potently and selectively inhibited the growth of ATRA-resistant AML cell lines and primary blasts. ST1926 induced-growth arrest was due to early DNA damage and massive apoptosis in AML cells. To enhance the drug's bioavailability, ST1926-NP were developed using Flash NanoPrecipitation, and displayed comparable anti-growth activities to the naked drug in AML cells. In a murine AML xenograft model, ST1926 and ST1926-NP significantly prolonged survival and reduced tumor burden. Strikingly, in vivo ST1926-NP antitumor effects were achieved at four fold lower concentrations than the naked drug. These results highlight the promising use of ST1926 in AML therapy and encourage its further development. Mol Cancer Ther; 16(10); 2047–57. ©2017 AACR.
Data from NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer
Authors: Li Long-Shan , Reddy Srilakshmi , Lin Zhen-Hua , Liu Shuangping , Park Hyunsil , Chun Stephen G. , Bornmann William G. , Thibodeaux Joel , Yan Jingsheng , Chakrabarti Gaurab , Xie Xian-Jin , Sumer Baran D. , Boothman David A. , Yordy John S.
Published: March 2024

Abstract
Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD+, and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap–induced radiosensitization. Mol Cancer Ther; 15(7); 1757–67. ©2016 AACR.
Data from MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival
Authors: Radoul Marina , Chaumeil Myriam M. , Eriksson Pia , Wang Alan S. , Phillips Joanna J. , Ronen Sabrina M.
Published: March 2024

Abstract
The current standard of care for glioblastoma (GBM) is surgical resection, radiotherapy, and treatment with temozolomide (TMZ). However, resistance to current therapies and recurrence are common. To improve survival, agents that target the PI3K signaling pathway, which is activated in approximately 88% of GBM, are currently in clinical trials. A challenge with such therapies is that tumor shrinkage is not always observed. New imaging methods are therefore needed to monitor response to therapy and predict survival. The goal of this study was to determine whether hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and 1H magnetic resonance spectroscopy (MRS) can be used to monitor response to the second-generation dual PI3K/mTOR inhibitor voxtalisib (XL765, SAR245409), alone or in combination with TMZ. We investigated GS-2 and U87-MG GBM orthotopic tumors in mice, and used MRI, hyperpolarized 13C MRSI, and 1H MRS to monitor the effects of treatment. In our study, 1H MRS could not predict tumor response to therapy. However, in both our models, we observed a significantly lower hyperpolarized lactate-to-pyruvate ratio in animals treated with voxtalisib, TMZ, or combination therapy, when compared with controls. This metabolic alteration was observed prior to MRI-detectable changes in tumor size, was consistent with drug action, and was associated with enhanced animal survival. Our findings confirm the potential translational value of the hyperpolarized lactate-to-pyruvate ratio as a biomarker for noninvasively assessing the effects of emerging therapies for patients with GBM. Mol Cancer Ther; 15(5); 1113–22. ©2016 AACR.