bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor
Authors: Ganaie Arsheed A. , Mansini Adrian P. , Hussain Tabish , Rao Arpit , Siddique Hifzur R. , Shabaneh Ashraf , Ferrari Marina G. , Murugan Paari , Klingelhöfer Jörg , Wang Jinhua , Ambartsumian Noona , Warlick Christopher A. , Konety Badrinath R. , Saleem Mohammad
Published: March 2024

Abstract
S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.
Data from Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody–Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function
Authors: Jin Rui , Liu Liang , Xing Yun , Meng Tao , Ma Lanping , Pei Jinpeng , Cong Ying , Zhang Xuesai , Ren Zhiqiang , Wang Xin , Shen Jingkang , Yu Ker
Published: March 2024

Abstract
Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50<0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors, including the RAS-mutant models [minimum effective dose <1 mg/kg]. Treatment with CD73–ADC triggered a robust intratumoral accumulation of proinflammatory macrophages and activated dendritic cells (DC), which were not observed with naked CD73 antibody or standard chemotherapy. Studies with human PBMC-derived systems confirmed CD73-ADC as fully functional in protecting effector T cells and stimulating DCs thus providing dual benefits in killing CD73-high tumors and improving cancer immunity response. These results warrant clinical investigation of CD73-targeted antibody and ADC for treating advanced lung cancer.
Data from Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer
Authors: Kawai Yoshihisa , Imada Kenjiro , Akamatsu Shusuke , Zhang Fan , Seiler Roland , Hayashi Tetsutaro , Leong Jeffrey , Beraldi Eliana , Saxena Neetu , Kretschmer Alexander , Oo Htoo Zarni , Contreras-Sanz Alberto , Matsuyama Hideyasu , Lin Dong , Fazli Ladan , Collins Colin C. , Wyatt Alexander W. , Black Peter C. , Gleave Martin E.
Published: March 2024

Abstract
Paternally expressed gene 10 (PEG10) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G1–S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of PEG10 in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.
Data from Circulating Tumor Cells and Biomarker Modulation with Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin: Phase Ib Study in Patients with Soft-Tissue Sarcoma
Authors: Martín-Broto Javier , Pousa Antonio López , Brohl Andrew S. , Van Tine Brian A. , Powers Benjamin , Stacchiotti Silvia , Blay Jean-Yves , Hu James S. , Oakley Gerard J. , Wang Hong , Szpurka Anna M. , Levy Donna E. , Mo Gary , Ceccarelli Matteo , Jones Robin L.
Published: March 2024

Abstract
This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1–2; 15 mg/kg, cycles 3–7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRβ [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRβ, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.
Data from Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody–drug Conjugate (ARX788) for Breast Cancer Treatment
Authors: Nagaraja Shastri Prathap , Zhu Jingjing , Skidmore Lillian , Liang Xuejun , Ji Yanping , Gu Yi , Tian Feng , Yao Sulan , Xia Gang
Published: March 2024

Abstract
Conventional antibody–drug conjugates (ADC) utilize native surface-exposed lysines or cysteines on the antibody of interest to conjugate cytotoxic payload. The nonspecific conjugation results in a mixture with variable drug-to-antibody ratios (DAR), conjugation sites, and ADCs that are often unstable in systemic circulation. ARX788 is an ADC consisting of a HER2-targeting antibody site-specifically conjugated with a potent antitubulin cytotoxic drug-linker, AS269. The site-specific conjugation is achieved by first incorporating the nonnatural amino acid, para-acetyl phenylalanine (pAF), into the antibody, followed by covalent conjugation of AS269 to the pAF to form a highly stable oxime bond resulting in a DAR 2 ADC. ARX788 exhibits significant, dose-dependent antitumor activity against HER2- expressing breast and gastric xenograft tumors. Pharmacokinetic (PK) studies in multiple species showed the highly stable nature of ARX788 with overlapping PK profiles for the intact ADC and total antibody. Metabolism studies demonstrated that pAF-AS269 was the sole major metabolite of ARX788, with no evidence for the release of free drug often observed in conventional ADCs and responsible for adverse side effects. Furthermore, ARX788 demonstrated a favorable safety profile in monkeys with a highest nonseverely toxic dose of 10 mg/kg, which was well above the efficacious dose level observed in preclinical tumor models, thus supporting clinical development of ARX788.
Data from A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer
Authors: Sullivan Ryan J. , Hollebecque Antoine , Flaherty Keith T. , Shapiro Geoffrey I. , Rodon Ahnert Jordi , Millward Michael J. , Zhang Wei , Gao Ling , Sykes Amanda , Willard Melinda D. , Yu Danni , Schade Andrew E. , Crowe KrisAnne , Flynn Daniel L. , Kaufman Michael D. , Henry James R. , Peng Sheng-Bin , Benhadji Karim A. , Conti Ilaria , Gordon Michael S. , Tiu Ramon V. , Hong David S.
Published: March 2024

Abstract
Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.
Data from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer
Authors: Furman Craig , Puyang Xiaoling , Zhang Zhaojie , Wu Zhenhua J. , Banka Deepti , Aithal Kiran B. , Albacker Lee A. , Hao Ming-Hong , Irwin Sean , Kim Amy , Montesion Meagan , Moriarty Alyssa D. , Murugesan Karthikeyan , Nguyen Tuong-Vi , Rimkunas Victoria , Sahmoud Tarek , Wick Michael J. , Yao Shihua , Zhang Xun , Zeng Hao , Vaillancourt Frédéric H. , Bolduc David M. , Larsen Nicholas , Zheng Guo Zhu , Prajapati Sudeep , Zhu Ping , Korpal Manav
Published: March 2024

Abstract
Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both  ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089).
Summary:
H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.
Data from Tinengotinib (TT-00420), a Novel Spectrum-Selective Small-Molecule Kinase Inhibitor, Is Highly Active Against Triple-Negative Breast Cancer
Authors: Peng Peng , Qiang Xiaoyan , Li Guoyu , Li Lin , Ni Shumao , Yu Qi , Sourd Laura , Marangoni Elisabetta , Hu Chao , Wang Dong , Wu Di , Wu Frank
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous cancer lacking actionable targets. Using a phenotypic screen of TNBC cells, we discovered a novel multiple kinase inhibitor tinengotinib (TT-00420) that strongly inhibited Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R in biochemical assays. Exposure to tinengotinib specifically inhibited proliferation across all subtypes of TNBC in vitro and in vivo, while leaving luminal breast cancer cells intact. Incubation of HCC1806 with tinengotinib led to dose-dependent downregulation of genes essential for TNBC cell growth and proliferation. Studies revealed that the potential mechanism of action of tinengotinib involved, predominantly, inhibition of Aurora A or B kinase activity, while inhibition of other pathways contributed to suppression of potency and activity. In vitro treatment of TNBC cell lines or in vivo administration in a syngeneic model with tinengotinib resulted in up-regulation of CXCL10 and 11 or diminished tumor-associated macrophage (TAM) infiltration. Tinengotinib represents a novel combinatorial inhibitory mechanism to treat TNBC. The phase I trial of tinengotinib was completed (ClinicalTrials.gov identifier: NCT03654547).
Data from Exploiting Ligand-binding Domain Dimerization for Development of Novel Androgen Receptor Inhibitors
Authors: Helsen Christine , Nguyen Tien T. , Lee Xiao Yin , Eerlings Roy , Louros Nikolaos , Schymkowitz Joost , Rousseau Frederic , Claessens Frank , Voet Arnout
Published: March 2024

Abstract
Currently, all clinically used androgen receptor (AR) antagonists target the AR ligand-binding pocket and inhibit T and dihydrotestosterone (DHT) binding. Resistance to these inhibitors in prostate cancer frequently involves AR-dependent mechanisms resulting in a retained AR dependence of the tumor. More effective or alternative AR inhibitors are therefore required to limit progression in these resistant stages. Here, we applied the structural information of the ligand-binding domain (LBD) dimerization interface to screen in silico for inhibitors. A completely new binding site, the Dimerisation Inhibiting Molecules (DIM) pocket, was identified at the LBD dimerization interface. Selection of compounds that fit the DIM pocket via virtual screening identified the DIM20 family of compounds which inhibit AR transactivation and dimerization of the full-length AR as well as the isolated LBDs. Via biolayer interferometry, reversible dose-dependent binding to the LBD was confirmed. While DIM20 does not compete with 3H-DHT for binding in the LBP, it limits the maximal activity of the AR indicative of a noncompetitive binding to the LBD. DIM20 and DIM20.39 specifically inhibit proliferation of AR-positive prostate cancer cell lines, with only marginal effects on AR-negative cell lines such as HEK 293 and PC3. Moreover, combination treatment of DIM compounds with enzalutamide results in synergistic antiproliferative effects which underline the specific mechanism of action of the DIM compounds.
Data from Genomic Analysis of Head and Neck Squamous Cell Carcinoma Cell Lines and Human Tumors: A Rational Approach to Preclinical Model Selection
Authors: Li Hua , Wawrose John S. , Gooding William E. , Garraway Levi A. , Lui Vivian Wai Yan , Peyser Noah D. , Grandis Jennifer R.
Published: March 2024

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. The increasing amount of genomic information on human tumors and cell lines provides more biologic data to design preclinical studies. We and others previously reported whole-exome sequencing data of 106 HNSCC primary tumors. In 2012, high-throughput genomic data and pharmacologic profiling of anticancer drugs of hundreds of cancer cell lines were reported. Here, we compared the genomic data of 39 HNSCC cell lines with the genomic findings in 106 HNSCC tumors. Amplification of eight genes (PIK3CA, EGFR, CCND2, KDM5A, ERBB2, PMS1, FGFR1, and WHSCIL1) and deletion of five genes (CDKN2A, SMAD4, NOTCH2, NRAS, and TRIM33) were found in both HNSCC cell lines and tumors. Seventeen genes were only mutated in HNSCC cell lines (>10%), suggesting that these mutations may arise through immortalization in tissue culture. Conversely, 11 genes were only mutated in >10% of human HNSCC tumors. Several mutant genes in the EGF receptor (EGFR) pathway are shared both in cell lines and in tumors. Pharmacologic profiling of eight anticancer agents in six HNSCC cell lines suggested that PIK3CA mutation may serve as a predictive biomarker for the drugs targeting the EGFR/PI3K pathway. These findings suggest that a correlation of gene mutations between HNSCC cell lines and human tumors may be used to guide the selection of preclinical models for translational research.

Implications: These findings suggest that a correlation of gene mutations between HNSCC cell lines and human tumors may be used to guide the selection of preclinical models for translational research.

Visual Overview: http://mcr.aacrjournals.org/content/12/4/571/F1.large.jpg.

Mol Cancer Res; 12(4); 571–82. ©2014 AACR.
Data from miR-155–Deficient Bone Marrow Promotes Tumor Metastasis
Authors: Yu Fang , Jia Xuemei , Du Fen , Wang Junfeng , Wang Yuzhen , Ai Walden , Fan Daping
Published: March 2024

Abstract
Infiltration of immune cells in primary tumors and metastatic sites is known to influence tumor progression and metastasis. Macrophages represent the most abundant immune cells in the tumor microenvironment, and evidence has shown that macrophages promote seeding, extravasation, and persistent growth of tumor cells at metastatic sites. miR-155 plays an essential role in immune cell development/function, and its aberrant expression is associated with lymphomas and several solid tumor types. However, it is unknown how miR-155 expression in immune cells affects solid tumor growth and metastasis. To this end, bone marrow transplantation was performed using miR-155–deficient mice as bone marrow donors and wild-type (WT) mice as recipients, and the chimeric mice were inoculated with tumor cells. We demonstrate that bone marrow lacking miR-155 significantly enhanced lung metastasis without a substantial effect on primary tumor growth. Relative to mice with WT bone marrow, miR-155–deficient bone marrow accumulated more macrophages in the spleen and lungs. Further analysis revealed that miR-155–deficient macrophages in metastatic sites exhibited a tumor-promoting M2 phenotype. In vitro study suggested that miR-155–null macrophages were prone to M2 polarization upon incubation with tumor cell–conditioned medium, due to elevated expression of C/EBPβ, an identified miR-155 target. These data, for the first time, demonstrate that miR-155 in host immune cells plays a vital role in modulating solid tumor metastasis by affecting the recruitment and polarization of bone marrow–derived macrophages.

Implications: Targeted inhibition of miR-155 delays tumor development but inhibition in host immune cells may encourage metastasis. Mol Cancer Res; 11(8); 923–36. ©2013 AACR.
Data from miR-652 Promotes Tumor Proliferation and Metastasis by Targeting RORA in Endometrial Cancer
Authors: Sun Xiaomei , Dongol Samina , Qiu Chunping , Xu Ying , Sun Chenggong , Zhang Zhiwei , Yang Xingsheng , Zhang Qing , Kong Beihua
Published: March 2024

Abstract
Endometrial cancer is the most common gynecologic malignancy, whose incidence rate is on the rise. However, the underlying mechanisms of endometrial cancer are not very clear yet. miRNAs have been considered to be playing important roles in malignant behavior. Here, miR-652 was significantly upregulated in endometrial cancer, which correlated with shorter overall survival and earlier recurrence. Moreover, overexpression of miR-652 in endometrial cancer cells promoted proliferation, migration, and invasion in vitro and facilitated tumor growth and metastasis in vivo. In contrast, downregulation of miR-652 in endometrial cancer cells inhibited these processes both in vitro and in vivo. Mechanistically, miR-652 promotes proliferation and metastasis through directly targeting RORA. Both mRNA and protein level of RORA were negatively related with miR-652 and overexpression of RORA can rescue the promotion effect of miR-652. Further experiments indicated miR-652 overexpression can activate the Wnt/β-catenin pathway and RORA can downregulate β-catenin and function as a tumor suppressor in endometrial cancer. Collectively, these findings demonstrate that miR-652 functions as an oncomir in endometrial cancer.
Implications:
This study suggests that the miR-652 is a critical regulator of proliferation and metastasis in endometrial cancer and may serve as a therapeutic target.
Data from Taxol Induces Brk-dependent Prosurvival Phenotypes in TNBC Cells through an AhR/GR/HIF–driven Signaling Axis
Authors: Regan Anderson Tarah M. , Ma Shihong , Perez Kerkvliet Carlos , Peng Yan , Helle Taylor M. , Krutilina Raisa I. , Raj Ganesh V. , Cidlowski John A. , Ostrander Julie H. , Schwertfeger Kathryn L. , Seagroves Tiffany N. , Lange Carol A.
Published: March 2024

Abstract
The metastatic cascade is a complex process that requires cancer cells to survive despite conditions of high physiologic stress. Previously, cooperation between the glucocorticoid receptor (GR) and hypoxia-inducible factors (HIF) was reported as a point of convergence for host and cellular stress signaling. These studies indicated p38 MAPK-dependent phosphorylation of GR on Ser134 and subsequent p-GR/HIF–dependent induction of breast tumor kinase (PTK6/Brk), as a mediator of aggressive cancer phenotypes. Herein, p-Ser134 GR was quantified in human primary breast tumors (n = 281) and the levels of p-GR were increased in triple-negative breast cancer (TNBC) relative to luminal breast cancer. Brk was robustly induced following exposure of TNBC model systems to chemotherapeutic agents (Taxol or 5-fluorouracil) and growth in suspension [ultra-low attachment (ULA)]. Notably, both Taxol and ULA resulted in upregulation of the Aryl hydrocarbon receptor (AhR), a known mediator of cancer prosurvival phenotypes. Mechanistically, AhR and GR copurified and following chemotherapy and ULA, these factors assembled at the Brk promoter and induced Brk expression in an HIF-dependent manner. Furthermore, Brk expression was upregulated in Taxol-resistant breast cancer (MCF-7) models. Ultimately, Brk was critical for TNBC cell proliferation and survival during Taxol treatment and in the context of ULA as well as for basal cancer cell migration, acquired biological phenotypes that enable cancer cells to successfully complete the metastatic cascade. These studies nominate AhR as a p-GR binding partner and reveal ways to target epigenetic events such as adaptive and stress-induced acquisition of cancer skill sets required for metastatic cancer spread.

Implication: Breast cancer cells enlist intracellular stress response pathways that evade chemotherapy by increasing cancer cell survival and promoting migratory phenotypes. Mol Cancer Res; 16(11); 1761–72. ©2018 AACR.
Data from Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb
Authors: Yang Zhe , Maciejowski John , de Lange Titia
Published: March 2024

Abstract
The mammalian nuclear envelope (NE) forms a stable physical barrier between the nucleus and the cytoplasm, normally breaking down only during mitosis. However, spontaneous transient NE rupture in interphase can occur when NE integrity is compromised, such as when the nucleus experiences mechanical stress. For instance, deficiencies in the nuclear lamins and their associated proteins can cause NE rupture that is promoted by forces exerted by actin filaments. NE rupture can allow cytoplasmic nucleases to access chromatin, potentially compromising genome integrity. Importantly, spontaneous NE rupture was noted in several human cancer cell lines, but the cause of this defect is not known. Here, we investigated the mechanistic contributions of two major tumor suppressors, p53 (TP53) and Rb (RB1), to the repression of NE rupture. NE rupture was induced in normal human epithelial RPE-1 cells upon impairment of either Rb or p53 achieved by shRNA knockdown and CRISPR/Cas9 gene editing. NE rupture did not involve diminished expression of NE components or greater cell motility. However, cells that underwent NE rupture displayed a larger nuclear projection area. In conclusion, the data indicate that NE rupture in cancer cells is likely due to loss of either the Rb or the p53 pathway.

Implications: These findings imply that tumor suppression by Rb and p53 includes the ability to prevent NE rupture, thereby protecting against genome alterations. Mol Cancer Res; 15(11); 1579–86. ©2017 AACR.
Data from Proteomic Characterization of Head and Neck Cancer Patient–Derived Xenografts
Authors: Li Hua , Wheeler Sarah , Park Yongseok , Ju Zhenlin , Thomas Sufi M. , Fichera Michele , Egloff Ann M. , Lui Vivian W. , Duvvuri Umamaheswar , Bauman Julie E. , Mills Gordon B. , Grandis Jennifer R.
Published: March 2024

Abstract
Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic, or processing features. Protein expression profiles, from a subset of the PDXs, were characterized by reverse-phase protein array and the data was compared with The Cancer Genome Atlas HNSCC data. Cluster analysis revealed that HNSCC PDXs were more similar to primary HNSCC than to any other tumor type. Interestingly, while a significant fraction of proteins were expressed similarly in both primary HNSCC and PDXs, a subset of proteins/phosphoproteins were expressed at higher (or lower) levels in PDXs compared with primary HNSCC. These findings indicate that the proteome is generally conserved in PDXs, but mechanisms for both positive and negative model selection and/or differences in the stromal components exist.

Implications: Proteomic characterization of HNSCC PDXs demonstrates potential drivers for model selection and provides a framework for improved utilization of this expanding model system. Mol Cancer Res; 14(3); 278–86. ©2015 AACR.
Data from A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance
Authors: Dimberg Lina Y. , Towers Christina G. , Behbakht Kian , Hotz Taylor J. , Kim Jihye , Fosmire Susan , Porter Christopher C. , Tan Aik-Choon , Thorburn Andrew , Ford Heide L.
Published: March 2024

Abstract
TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulators of TRAIL receptor signaling. To identify novel mechanisms of TRAIL resistance in an unbiased way, we performed a genome-wide shRNA screen for genes that regulate TRAIL sensitivity in sublines that had been selected for acquired TRAIL resistance. This screen identified previously unknown mediators of TRAIL resistance including angiotensin II receptor 2, Crk-like protein, T-Box Transcription Factor 2, and solute carrier family 26 member 2 (SLC26A2). SLC26A2 downregulates the TRAIL receptors, DR4 and DR5, and this downregulation is associated with resistance to TRAIL. Its expression is high in numerous tumor types compared with normal cells, and in breast cancer, SLC26A2 is associated with a significant decrease in relapse-free survival.

Implication: Our results shed light on novel resistance mechanisms that could affect the efficacy of TRAIL agonist therapies and highlight the possibility of using these proteins as biomarkers to identify TRAIL-resistant tumors, or as potential therapeutic targets in combination with TRAIL. Mol Cancer Res; 15(4); 382–94. ©2017 AACR.
Data from R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc
Authors: Lin Tzu-Ping , Li Jingjing , Li Qinlong , Li Xiangyan , Liu Chunyan , Zeng Ni , Huang Jen-Ming , Chu Gina Chia-Yi , Lin Chi-Hung , Zhau Haiyen E. , Chung Leland W.K. , Wu Boyang Jason , Shih Jean C.
Published: March 2024

Abstract
Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc–interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc–targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis.
Implications:
These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.
Data from Intrinsic Resistance to Cixutumumab Is Conferred by Distinct Isoforms of the Insulin Receptor
Authors: Forest Amelie , Amatulli Michael , Ludwig Dale L. , Damoci Christopher B. , Wang Ying , Burns Colleen A. , Donoho Gregory P. , Zanella Nina , Fiebig Heinz H. , Prewett Marie C. , Surguladze David , DeLigio James T. , Houghton Peter J. , Smith Malcolm A. , Novosiadly Ruslan
Published: March 2024

Abstract
Despite a recent shift away from anti–insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IR-B–overexpressing cells is fully reversed by anti–IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti–IGF-IR antibody.

Implications: This study identifies total IR as a biomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression. Mol Cancer Res; 13(12); 1615–26. ©2015 AACR.
Data from Aberrant Methylation-Mediated Silencing of lncRNA MEG3 Functions as a ceRNA in Esophageal Cancer
Authors: Dong Zhiming , Zhang Aili , Liu Shengnan , Lu Fan , Guo Yanli , Zhang Guoqiang , Xu Fenglou , Shi Yabin , Shen Supeng , Liang Jia , Guo Wei
Published: March 2024

Abstract
Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), has tumor-suppressor properties and its expression is lost in several human tumors. However, its biological role in esophageal squamous cell carcinoma (ESCC) tumorigenesis is poorly defined. The present study determined the role and methylation status of MEG3 in esophageal cancer cells and ESCC clinical specimens, and further observed the competing endogenous RNA (ceRNA) activity of MEG3 in the pathogenesis and development of ESCC. Significant downregulation of MEG3 was detected in esophageal cancer cells and ESCC tissues and the expression level of MEG3 was significantly increased in cancer cells after treated with the DNA methyltransferase inhibitor 5-Aza-dC. Upregulation of MEG3 led to the inhibition of proliferation and invasiveness of the cancer cells. The aberrant promoter hypermethylation of MEG3 indicates silencing of its expression. Furthermore, MEG3 acts as a ceRNA to regulate the expression of E-cadherin and FOXO1 by binding hsa-miR-9. Upregulation of miR-9 was detected in esophageal cancer cell lines and ESCC tissues, and miR-9 promoted esophageal cancer cell proliferation and invasion. Finally, downregulation and hypermethylation of MEG3 was associated with ESCC patients' survival.

Implications: MEG3 functions as a tumor-suppressive lncRNA and aberrant promoter hypermethylation is critical for MEG3 gene silencing in ESCC. In addition, MEG3 acts as a ceRNA to regulate expression of E-cadherin and FOXO1 by competitively binding miR-9 and may be used as a potential biomarker in predicting ESCC patients' progression and prognosis. Mol Cancer Res; 15(7); 800–10. ©2017 AACR.
Data from Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer
Authors: Balaban Seher , Nassar Zeyad D. , Zhang Alison Y. , Hosseini-Beheshti Elham , Centenera Margaret M. , Schreuder Mark , Lin Hui-Ming , Aishah Atqiya , Varney Bianca , Liu-Fu Frank , Lee Lisa S. , Nagarajan Shilpa R. , Shearer Robert F. , Hardie Rae-Anne , Raftopulos Nikki L. , Kakani Meghna S. , Saunders Darren N. , Holst Jeff , Horvath Lisa G. , Butler Lisa M. , Hoy Andrew J.
Published: March 2024

Abstract
Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased de novo synthesis of fatty acids (FA); however, little is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1). Extracellular FAs are the major source (∼83%) of carbons to the total lipid pool in all cell lines, compared with glucose (∼13%) and glutamine (∼4%), and FA oxidation rates are greater in prostate cancer cells compared with PNT1 cells, which preferentially partitioned extracellular FAs into triacylglycerols. Because of the higher rates of FA oxidation in C4-2B cells, cells remained viable when challenged by the addition of palmitate to culture media and inhibition of mitochondrial FA oxidation sensitized C4-2B cells to palmitate-induced apoptosis. Whereas in PC-3 cells, palmitate induced apoptosis, which was prevented by pretreatment of PC-3 cells with FAs, and this protective effect required DGAT-1–mediated triacylglycerol synthesis. These outcomes highlight for the first-time heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression.
Implications:
Extracellular-derived FAs are primary building blocks for complex lipids and heterogeneity in FA metabolism exists in prostate cancer that can influence tumor cell behavior.
Data from Histone H3.3K27M Mobilizes Multiple Cancer/Testis (CT) Antigens in Pediatric Glioma
Authors: Deng Houliang , Zeng Jianming , Zhang Ting , Gong Longcai , Zhang Hongjie , Cheung Edwin , Jones Chris , Li Gang
Published: March 2024

Abstract
Lysine to methionine mutations at position 27 (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG) that arise in the midline of the central nervous system. H3K27M perturbs the activity of polycomb repressor complex 2 and correlates with DNA hypomethylation; however, the pathways whereby H3K27M drives the development of pediatric HGG remain poorly understood. To understand the mechanism of pediatric HGG development driven by H3.3K27M and discover potential therapeutic targets or biomarkers, we established pediatric glioma cell model systems harboring H3.3K27M and performed microarray analysis. H3.3K27M caused the upregulation of multiple cancer/testis (CT) antigens, such as ADAMTS1, ADAM23, SPANXA1, SPANXB1/2, IL13RA2, VCY, and VCX3A, in pediatric glioma cells. Chromatin immunoprecipitation analysis from H3.3K27M cells revealed decreased H3K27me3 levels and increased H3K4me3 levels on the VCX3A promoter. Knockdown of VCX3A by siRNA significantly inhibited the growth of pediatric glioma cells harboring H3.3K27M. Overexpression of VCX3A/B genes stimulated the expression of several HLA genes, including HLA-A, HLA-B, HLA-E, HLA-F, and HLA-G. The expression of VCX3A in pediatric HGG was confirmed using a tissue microarray. Gene set enrichment analysis revealed that CT antigens are enriched in pediatric HGG clinical specimens with H3.3K27M, with the upregulation of IL13RA2 contributing to the enrichment significantly. These results indicate that the upregulation of CT antigens, such as VCX3A and IL13RA2, correlates with pediatric gliomagenesis. Mol Cancer Res; 16(4); 623–33. ©2018 AACR.
Data from Therapeutic Implications of p53 Status on Cancer Cell Fate Following Exposure to Ionizing Radiation and the DNA-PK Inhibitor M3814
Authors: Sun Qing , Guo Yige , Liu Xiaohong , Czauderna Frank , Carr Michael I. , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T.
Published: March 2024

Abstract
Inhibition of DNA double-strand break (DSB) repair in cancer cells has been proposed as a new therapeutic strategy for potentiating the anticancer effects of radiotherapy. M3814 is a novel, selective pharmacologic inhibitor of the serine/threonine kinase DNA-dependent protein kinase (DNA-PK), a key driver of nonhomologous end-joining, one of the main DSB-repair pathways, currently under clinical investigation. Here, we show that M3814 effectively blocks the repair of radiation-induced DSBs and potently enhances p53 phosphorylation and activation. In p53 wild-type cells, ataxia telangiectasia–mutated (ATM) and its targets, p53 and checkpoint kinase 2 (CHK2), were more strongly activated by combination treatment with M3814 and radiation than by radiation alone, leading to a complete p53-dependent cell-cycle block and premature cell senescence. Cancer cells with dysfunctional p53 were unable to fully arrest their cell cycle and entered S and M phases with unrepaired DNA, leading to mitotic catastrophe and apoptotic cell death. Isogenic p53-null/wild-type A549 and HT-1080 cell lines were generated and used to demonstrate that p53 plays a critical role in determining the response to ionizing radiation and M3814. Time-lapse imaging of cell death and measuring apoptosis in panels of p53 wild-type and p53-null/mutant cancer lines confirmed the clear differences in cell fate, dependent on p53 status.
Implications:
Our results identify p53 as a possible biomarker for response of cancer cells to combination treatment with radiation and a DNA-PK inhibitor and suggest that p53 mutation status should be considered in the design of future clinical trials.
Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/17/12/2457/F1.large.jpg.
Data from Distinct Roles for BET Family Members in Estrogen Receptor α Enhancer Function and Gene Regulation in Breast Cancer Cells
Authors: Murakami Shino , Li Rui , Nagari Anusha , Chae Minho , Camacho Cristel V. , Kraus W. Lee
Published: March 2024

Abstract
The bromodomain family member proteins (BRD; BET proteins) are key coregulators for estrogen receptor alpha (ERα)-mediated transcriptional enhancers. The use of BRD-selective inhibitors has gained much attention as a potential treatment for various solid tumors, including ER-positive breast cancers. However, the roles of individual BET family members have largely remained unexplored. Here, we describe the role of BRDs in estrogen (E2)-dependent gene expression in ERα-positive breast cancer cells. We observed that chemical inhibition of BET family proteins with JQ1 impairs E2-regulated gene expression and growth in breast cancer cells. In addition, RNAi-mediated depletion of each BET family member (BRDs 2, 3, and 4) revealed partially redundant roles at ERα enhancers and for target gene transcription. Furthermore, we found a unique role of BRD3 as a molecular sensor of total BET family protein levels and activity through compensatory control of its own protein levels. Finally, we observed that BRD3 is recruited to a subset of ERα-binding sites (ERBS) that are enriched for active enhancer features, located in clusters of ERBSs likely functioning as “super enhancers,” and associated with highly E2-responsive genes. Collectively, our results illustrate a critical and specific role for BET family members in ERα-dependent gene transcription.
Implications:
BRD3 is recruited to and controls the activity of a subset ERα transcriptional enhancers, providing a therapeutic opportunity to target BRD3 with BET inhibitors in ERα-positive breast cancers.
Data from TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease
Authors: Baba Masaya , Furuya Mitsuko , Motoshima Takanobu , Lang Martin , Funasaki Shintaro , Ma Wenjuan , Sun Hong-Wei , Hasumi Hisashi , Huang Ying , Kato Ikuma , Kadomatsu Tsuyoshi , Satou Yorifumi , Morris Nicole , Karim Baktiar O. , Ileva Lilia , Kalen Joseph D. , Wilan Krisna Luh Ade , Hasumi Yukiko , Sugiyama Aiko , Kurahashi Ryoma , Nishimoto Koshiro , Oyama Masafumi , Nagashima Yoji , Kuroda Naoto , Araki Kimi , Eto Masatoshi , Yao Masahiro , Kamba Tomomi , Suda Toshio , Oike Yuichi , Schmidt Laura S. , Linehan W. Marston
Published: March 2024

Abstract
Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC.
Implications:
Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.