bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression
Authors: Chang Te-Sheng , Wu Yu-Chih , Chi Ching-Chi , Su Wei-Chi , Chang Pey-Jium , Lee Kam-Fai , Tung Tao-Hsin , Wang Jui , Liu Jun-Jen , Tung Shui-Yi , Kuo Liang-Mou , Ho Hong-Nerng , Ling Thai-Yen , Huang Yen-Hua
Published: April 2023

Abstract
Purpose: To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC).

Experimental Design: Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan–Meier survival analysis.

Results: A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)–related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo.

Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC. Clin Cancer Res; 21(1); 201–10. ©2014 AACR.
Data from First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors
Authors: Shapiro Geoffrey I. , Kwak Eunice , Dezube Bruce J. , Yule Murray , Ayrton John , Lyons John , Mahadevan Daruka
Published: April 2023

Abstract
Purpose: AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.

Experimental Design: Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies.

Results: Sixty-two patients were treated with doses ranging from 10 to 120 mg/m2 twice weekly and 150 to 310 mg/m2 once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m2, which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m2 as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients.

Conclusion: AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity. Clin Cancer Res; 21(1); 87–97. ©2014 AACR.
Data from Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 In Vivo
Authors: Dibra Denada , Mitra Abhisek , Newman Melisa , Xia Xueqing , Cutrera Jeffry J. , Gagea Mihai , Kleinerman Eugenie S. , Lozano Guillermina , Li Shulin
Published: April 2023

Abstract
Purpose: p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. IL27 is an important immunomodulatory cytokine, but its impact on mutant p53-driven tumorigenesis has not been reported.

Experimental Design: IL27RA−/− mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA−/−p53H/+ and IL27RA−/−p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via IHC and Western blot analysis.

Results: This study unraveled that lack of IL27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL27 signaling is closely associated with increased mutant p53 stability in vivo from early age.

Conclusions: These results suggest that IL27 signaling modulates the oncogenic properties of mutant p53 in vivo. Clin Cancer Res; 22(15); 3876–83. ©2016 AACR.
Data from Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma
Authors: Kim Edward J. , Sahai Vaibhav , Abel Ethan V. , Griffith Kent A. , Greenson Joel K. , Takebe Naoko , Khan Gazala N. , Blau John L. , Craig Ronald , Balis Ulysses G. , Zalupski Mark M. , Simeone Diane M.
Published: April 2023

Abstract
Purpose: The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma and is upregulated in pancreatic adenocarcinoma cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of the HH pathway. This study assessed the effect of GDC-0449–mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic pancreatic adenocarcinoma.

Experimental Design: Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity.

Results: On pretreatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On posttreatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22, and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and postbiopsy. The median progression-free and overall survival for all treated patients were 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki-67, GLI1, PTCH1 (baseline values or relative change on posttreatment biopsy), and survival. Grade ≥3 adverse events were noted in 56% of patients.

Conclusion: We show that GDC-0449 for 3 weeks leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer. Clin Cancer Res; 20(23); 5937–45. ©2014 AACR.
Data from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
Authors: Sabbatini Paul , Tsuji Takemasa , Ferran Luis , Ritter Erika , Sedrak Christine , Tuballes Kevin , Jungbluth Achim A. , Ritter Gerd , Aghajanian Carol , Bell-McGuinn Katherine , Hensley Martee L. , Konner Jason , Tew William , Spriggs David R. , Hoffman Eric W. , Venhaus Ralph , Pan Linda , Salazar Andres M. , Diefenbach Catherine Magid , Old Lloyd J. , Gnjatic Sacha
Published: April 2023

Abstract
Purpose: Long peptides are efficiently presented to both CD4+ and CD8+ T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.

Experimental Design: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).

Results: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1–specific antibody and CD8+ T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1–specific CD4+ T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1–specific immune responses.

Conclusions: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants. Clin Cancer Res; 18(23); 6497–508. ©2012 AACR.
Data from Personalized Medicine for Patients with Advanced Cancer in the Phase I Program at MD Anderson: Validation and Landmark Analyses
Authors: Tsimberidou Apostolia-Maria , Wen Sijin , Hong David S. , Wheler Jennifer J. , Falchook Gerald S. , Fu Siqing , Piha-Paul Sarina , Naing Aung , Janku Filip , Aldape Kenneth , Ye Yang , Kurzrock Razelle , Berry Donald
Published: April 2023

Abstract
Purpose: The purpose of this study was to confirm our previous results that targeted agents matched with tumor molecular alterations were associated with improved outcomes compared with nonmatched therapy in patients with advanced cancer.

Experimental Design: Outcomes of patients who were referred for treatment on phase I clinical trials at The University of Texas MD Anderson Cancer Center (Houston, TX) from March 2011 to January 2012 were compared between those who had received targeted therapy and those for whom no targeted therapy was available. Two-month landmark analyses for overall and progression-free survival (PFS) combining previously published and validation cohort patient data were performed.

Results: In patients with one alteration, matched therapy (n = 143) compared with treatment without matching (n = 236) was associated with a higher objective response rate (12% vs. 5%; P < 0.0001), longer PFS (median, 3.9 vs. 2.2 months; P = 0.001), and longer survival (median, 11.4 vs. 8.6 months; P = 0.04). In multivariate analysis, matched therapy was an independent factor predicting response (P < 0.015) and PFS (P < 0.004). Two-month landmark analyses in the matched therapy group demonstrated that the median survival of responders was 30.5 months compared with 11.3 months for nonresponders (P = 0.01); and the median PFS was 38.7 months compared with 5.9 months, respectively (P < 0.0001). The respective values in the nonmatched therapy group were 9.8 and 9.4 months (P = 0.46) and 8.5 and 4.2 months (P = 0.18).

Conclusion: This validation analysis confirms our previous observations. In the matched therapy group, 2-month landmark analyses demonstrated that responders have longer survival and PFS than nonresponders. Clin Cancer Res; 20(18); 4827–36. ©2014 AACR.
Data from MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research
Authors: Chang Wendy , Brohl Andrew S. , Patidar Rajesh , Sindiri Sivasish , Shern Jack F. , Wei Jun S. , Song Young K. , Yohe Marielle E. , Gryder Berkley , Zhang Shile , Calzone Kathleen A. , Shivaprasad Nityashree , Wen Xinyu , Badgett Thomas C. , Miettinen Markku , Hartman Kip R. , League-Pascual James C. , Trahair Toby N. , Widemann Brigitte C. , Merchant Melinda S. , Kaplan Rosandra N. , Lin Jimmy C. , Khan Javed
Published: April 2023

Abstract
Purpose: We undertook a multidimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome-guided precision therapy.

Experimental Design: Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single-nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an amplification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with FDA-approved drugs.

Results: Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7 months to 25 years old. Seventy-three percent of the patients had prior chemotherapy, and the tumors from these patients with relapsed or refractory cancers had a higher mutational burden than that reported in the literature. Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation.

Conclusions: We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations. We demonstrated the clinical feasibility of next-generation sequencing in a diverse population of relapsed and refractory pediatric solid tumors. Clin Cancer Res; 22(15); 3810–20. ©2016 AACR.
Data from First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors
Authors: Sarker Debashis , Ang Joo Ern , Baird Richard , Kristeleit Rebecca , Shah Krunal , Moreno Victor , Clarke Paul A. , Raynaud Florence I. , Levy Gallia , Ware Joseph A. , Mazina Kathryn , Lin Ray , Wu Jenny , Fredrickson Jill , Spoerke Jill M. , Lackner Mark R. , Yan Yibing , Friedman Lori S. , Kaye Stan B. , Derynck Mika K. , Workman Paul , de Bono Johann S.
Published: April 2023

Abstract
Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).

Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.

Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.

Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.
Data from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer
Authors: Julien Sylvia , Merino-Trigo Ana , Lacroix Ludovic , Pocard Marc , Goéré Diane , Mariani Pascale , Landron Sophie , Bigot Ludovic , Nemati Fariba , Dartigues Peggy , Weiswald Louis-Bastien , Lantuas Denis , Morgand Loïc , Pham Emmanuel , Gonin Patrick , Dangles-Marie Virginie , Job Bastien , Dessen Philippe , Bruno Alain , Pierré Alain , De Thé Hugues , Soliman Hany , Nunes Manoel , Lardier Guillaume , Calvet Loreley , Demers Brigitte , Prévost Grégoire , Vrignaud Patricia , Roman-Roman Sergio , Duchamp Olivier , Berthet Cyril
Published: April 2023

Abstract
Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.

Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis.

Results: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance.

Conclusions: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients. Clin Cancer Res; 18(19); 5314–28. ©2012 AACR.
Data from CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin
Authors: Guerzoni Clara , Fiori Valentina , Terracciano Mario , Manara Maria Cristina , Moricoli Diego , Pasello Michela , Sciandra Marika , Nicoletti Giordano , Gellini Mara , Dominici Sabrina , Chiodoni Claudia , Fornasari Pier Maria , Lollini Pier-Luigi , Colombo Mario P. , Picci Piero , Cianfriglia Maurizio , Magnani Mauro , Scotlandi Katia
Published: April 2023

Abstract
Purpose: The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application.

Experimental Design:In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7.

Results: The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS.

Conclusions: These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99-triggered cell death. Clin Cancer Res; 21(1); 146–56. ©2014 AACR.
Data from Translational Phase I Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytarabine and Etoposide in Patients with Relapsed, Refractory, or High-Risk Acute Myeloid Leukemia
Authors: Gojo Ivana , Tan Ming , Fang Hong-Bin , Sadowska Mariola , Lapidus Rena , Baer Maria R. , Carrier France , Beumer Jan H. , Anyang Bean N. , Srivastava Rakesh K. , Espinoza-Delgado Igor , Ross Douglas D.
Published: April 2023

Abstract
Purpose: To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts.

Experimental Design: In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m2) and cytarabine (1 or 2 g/m2 twice a day if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design.

Results: Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment.

Conclusions: Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings. Clin Cancer Res; 19(7); 1838–51. ©2013 AACR.
Data from β-1,4-Galactosyltransferase III Enhances Invasive Phenotypes Via β1-Integrin and Predicts Poor Prognosis in Neuroblastoma
Authors: Chang Hsiu-Hao , Chen Chia-Hua , Chou Chih-Hsing , Liao Yung-Feng , Huang Miao-Juei , Chen Ya-Hsin , Wang Wei-Jen , Huang John , Hung Ji-Shiang , Ho Wan-Ling , Jeng Yung-Ming , Che Mei-Ieng , Lee Hsinyu , Lu Meng-Yao , Yang Yung-Li , Jou Shiann-Tarng , Lin Dong-Tsamn , Lin Kai-Hsin , Hsu Wen-Ming , Huang Min-Chuan
Published: April 2023

Abstract
Purpose: Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. β-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly-N-acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB.

Experimental Design: We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies.

Results: We found that B4GALT3 expression correlated with advanced clinical stages (P = 0.040), unfavorable Shimada histology (P < 0.001), and lower survival rate (P < 0.001). Multivariate analysis showed that B4GALT3 expression is an independent prognostic factor for poor survival of NB patients. B4GALT3 overexpression increased migration, invasion, and tumor growth of NB cells, whereas B4GALT3 knockdown suppressed the malignant phenotypes of NB cells. Mechanistic investigation showed that B4GALT3-enhanced migration and invasion were significantly suppressed by β1-integrin blocking antibody. Furthermore, B4GALT3 overexpression increased lactosamine glycans on β1-integrin, increased expression of mature β1-integrin via delayed degradation, and enhanced phosphorylation of focal adhesion kinase. Conversely, these properties were decreased by knockdown of B4GALT3 in NB cells.

Conclusions: Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of β1-integrin in NB cells. Clin Cancer Res; 19(7); 1705–16. ©2013 AACR.
Data from Emerging Treatment Paradigms in Radiation Oncology
Authors: Le Quynh-Thu , Shirato Hiroki , Giaccia Amato J. , Koong Albert C.
Published: April 2023

Abstract
Rapid advancements in radiotherapy and molecularly targeted therapies have resulted in the development of potential paradigm-shifting use of radiotherapy in the treatment of cancer. In this review, we discuss some of the most promising therapeutic approaches in the field of radiation oncology. These strategies include the use of highly targeted stereotactic radiotherapy and particle therapy as well as combining radiotherapy with agents that modulate the DNA damage response, augment the immune response, or protect normal tissues. Clin Cancer Res; 21(15); 3393–401. ©2015 AACR.
Data from Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Hussain Maha , Le Moulec Sylvestre , Gimmi Claude , Bruns Rolf , Straub Josef , Miller Kurt
Published: April 2023

Abstract
Purpose: Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-αv integrin inhibitor abituzumab in chemotherapy-naïve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.

Experimental Design: PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS).

Results: The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR = 0.89; 95% confidence interval (CI), 0.57–1.39; abituzumab 1,500 mg, 4.3 months, HR = 0.81; 95% CI, 0.52–1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms.

Conclusions: Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancer–associated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192–200. ©2016 AACR.
Data from Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model
Authors: Bai Ren-Yuan , Staedtke Verena , Wanjiku Teresia , Rudek Michelle A. , Joshi Avadhut , Gallia Gary L. , Riggins Gregory J.
Published: April 2023

Abstract
Purpose: Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different mebendazole polymorphs (A, B, and C) exist, and a detailed assessment of the brain penetration, pharmacokinetics, and antitumor properties of each individual mebendazole polymorph is necessary to improve mebendazole-based brain cancer therapy.

Experimental Design and Results: In this study, various marketed and custom-formulated mebendazole tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in an orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of mebendazole polymorphs and two main metabolites were analyzed by LC/MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Polymorph B and C both reached concentrations in the brain that exceeded the IC50 in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC0–24h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice.

Conclusions: Among mebendazole polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with fewer side effects, and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar. Clin Cancer Res; 21(15); 3462–70. ©2015 AACR.
Data from Expansion of CCR8+ Inflammatory Myeloid Cells in Cancer Patients with Urothelial and Renal Carcinomas
Authors: Eruslanov Evgeniy , Stoffs Taryn , Kim Wan-Ju , Daurkin Irina , Gilbert Scott M. , Su Li-Ming , Vieweg Johannes , Daaka Yehia , Kusmartsev Sergei
Published: April 2023

Abstract
Purpose: Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas.

Experimental Design: We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function.

Results: We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b+CCR8+ cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b+CCR8+ cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1.

Conclusions: This study provides the first evidence that CCR8+ myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8+ myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers. Clin Cancer Res; 19(7); 1670–80. ©2013 AACR.
Data from The Impact of Non–Drug-Related Toxicities on the Estimation of the Maximum Tolerated Dose in Phase I Trials
Authors: Iasonos Alexia , Gounder Mrinal , Spriggs David R. , Gerecitano John F. , Hyman David M. , Zohar Sarah , O'Quigley John
Published: April 2023

Abstract
The rate of observed dose-limiting toxicities (DLT) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non–drug-related toxicities or other-cause toxicities (OCT) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using 2 trial designs—the “3+3” dose-escalation scheme and the continual reassessment method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (type A error) and when an OCT is misclassified as a DLT (type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared with 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time to increase the accuracy of 3+3; otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared with the 3+3 as it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials. Clin Cancer Res; 18(19); 5179–87. ©2012 AACR.
Data from The Novel Organic Arsenical Darinaparsin Induces MAPK-Mediated and SHP1-Dependent Cell Death in T-cell Lymphoma and Hodgkin Lymphoma Cells and Human Xenograft Models
Authors: Ravi Dashnamoorthy , Bhalla Savita , Gartenhaus Ronald B. , Crombie Jennifer , Kandela Irawati , Sharma Jaya , Mazar Andrew , Evens Andrew M.
Published: April 2023

Abstract
Purpose: Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action.

Experimental Design: TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V–based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK.

Results: Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death.

Conclusions: Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms. Clin Cancer Res; 20(23); 6023–33. ©2014 AACR.
Data from Redirecting Gene-Modified T Cells toward Various Cancer Types Using Tagged Antibodies
Authors: Tamada Koji , Geng Degui , Sakoda Yukimi , Bansal Navneeta , Srivastava Ratika , Li Zhaoyang , Davila Eduardo
Published: April 2023

Abstract
Purpose: To develop an adaptable gene-based vector that will confer immune cell specificity to various cancer types.

Experimental Design: Human and mouse T cells were genetically engineered to express a chimeric antigen receptor (CAR) that binds a fluorescein isothiocyanate (FITC) molecule, termed anti-FITC CAR T cells. Various antibodies (Ab) currently in clinical use including cetuximab (Ctx), trastuzumab (Her2), and rituximab (Rtx) were conjugated with FITC and tested for their ability to bind tumor cells, activate T cells, and induce antitumor effects in vitro and in vivo.

Results: Anti-FITC CAR T cells recognize various cancer types when bound with FITC-labeled Abs resulting in efficient target lysis, T-cell proliferation, and cytokine/chemokine production. The treatment of immunocompromised mice with human anti-FITC CAR T cells plus FITC-labeled cetuximab (FITC-Ctx) delayed the growth of colon cancer but unexpectedly led to the outgrowth of EGF receptor (EGFR)-negative tumor cells. On the other hand, in a human pancreatic cancer cell line with uniform EGFR expression, anti-FITC CAR T cells plus FITC-Ctx eradicated preestablished late-stage tumors. In immunocompetent mice, anti-FITC CAR T cells exhibited potent antitumor activity against syngeneic mouse breast cancer expressing Her2 and B-cell lymphoma expressing CD20 by combining with FITC-Her2 and FITC-Rtx, respectively. In addition, the activity of anti-FITC CAR T cells could be attenuated by subsequent injections of nonspecific FITC-IgG.

Conclusion: These studies highlight an applicability of anti-tag CAR technology to treat patients with different types of cancers and a possibility to regulate CAR T-cell functions with competing FITC molecules. Clin Cancer Res; 18(23); 6436–45. ©2012 AACR.
Data from Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004
Authors: Somlo George , Atzori Francesco , Strauss Lewis C. , Geese William J. , Specht Jennifer M. , Gradishar William J. , Rybicki Alissa , Sy Oumar , Vahdat Linda T. , Cortes Javier
Published: April 2023

Abstract
Purpose: Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis.

Experimental Design: Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m2 twice daily (DL1 and DL2) or 1,000 mg/m2 twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis.

Results: Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor–positive. Most common adverse events (AE) were any grade nausea (58%), hand–foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand–foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m2 twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed.

Conclusions: Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m2 twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect. Clin Cancer Res; 19(7); 1884–93. ©2013 AACR.
Data from ABO Blood Group IgM Isoagglutinins Interact with Tumor-Associated O-Glycan Structures in Pancreatic Cancer
Authors: Hofmann Bianca T. , Stehr Anne , Dohrmann Thorsten , Güngör Cenap , Herich Lena , Hiller Jens , Harder Sönke , Ewald Florian , Gebauer Florian , Tachezy Michael , Precht Clarissa , Izbicki Jakob R. , Bockhorn Maximilian , Wagener Christoph , Wolters-Eisfeld Gerrit
Published: April 2023

Abstract
Purpose: The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC.

Experimental Design: Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis.

Results: We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody.

Conclusion: Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer. Clin Cancer Res; 20(23); 6117–26. ©2014 AACR.
Data from Limited Induction of Tumor Cross-Reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen Class I–Modified Peptides
Authors: Filipazzi Paola , Pilla Lorenzo , Mariani Luigi , Patuzzo Roberto , Castelli Chiara , Camisaschi Chiara , Maurichi Andrea , Cova Agata , Rigamonti Gianluigi , Giardino Felicetta , Di Florio Annabella , Asioli Marco , Frati Paola , Sovena Gloria , Squarcina Paola , Maio Michele , Danielli Riccardo , Chiarion-Sileni Vanna , Villa Antonello , Lombardo Claudia , Tragni Gabrina , Santinami Mario , Parmiani Giorgio , Rivoltini Licia
Published: April 2023

Abstract
Purpose: The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III).

Experimental Design: Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201–restricted modified peptides (Melan-A/MART-1[27L], gp100[210M], NY-ESO-1[165V], and Survivin[97M]) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m2) and low-dose IL-2 (3 × 106 IU). The immune responses were monitored using ex vivo IFN-γ–ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays.

Results: Vaccination induced a rapid and persistent increase in specific effector memory CD8+ T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells.

Conclusions: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8+ T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease. Clin Cancer Res; 18(23); 6485–96. ©2012 AACR.