bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas
Authors: Kim Jennifer E. , Patel Mira A. , Mangraviti Antonella , Kim Eileen S. , Theodros Debebe , Velarde Esteban , Liu Ann , Sankey Eric W. , Tam Ada , Xu Haiying , Mathios Dimitrios , Jackson Christopher M. , Harris-Bookman Sarah , Garzon-Muvdi Tomas , Sheu Mary , Martin Allison M. , Tyler Betty M. , Tran Phuoc T. , Ye Xiaobu , Olivi Alessandro , Taube Janis M. , Burger Peter C. , Drake Charles G. , Brem Henry , Pardoll Drew M. , Lim Michael
Published: April 2023

Abstract
Purpose: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS.

Experimental Design: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed.

Results: Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples.

Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124–36. ©2016 AACR.
Data from Evaluation of a 5-Marker Blood Test for Colorectal Cancer Early Detection in a Colorectal Cancer Screening Setting
Authors: Werner Simone , Krause Friedemann , Rolny Vinzent , Strobl Matthias , Morgenstern David , Datz Christian , Chen Hongda , Brenner Hermann
Published: April 2023

Abstract
Purpose: In initial studies that included colorectal cancer patients undergoing diagnostic colonoscopy, we had identified a serum marker combination able to detect colorectal cancer with similar diagnostic performance as fecal immunochemical test (FIT). In this study, we aimed to validate the results in participants of a large colorectal cancer screening study conducted in the average-risk, asymptomatic screening population.

Experimental Design: We tested serum samples from 1,200 controls, 420 advanced adenoma patients, 4 carcinoma in situ patients, and 36 colorectal cancer patients with a 5-marker blood test [carcinoembryonic antigen (CEA)+anti-p53+osteopontin+seprase+ferritin]. The diagnostic performance of individual markers and marker combinations was assessed and compared with stool test results.

Results: AUCs for the detection of colorectal cancer and advanced adenomas with the 5-marker blood test were 0.78 [95% confidence interval (CI), 0.68–0.87] and 0.56 (95% CI, 0.53–0.59), respectively, which now is comparable with guaiac-based fecal occult blood test (gFOBT) but inferior to FIT. With cutoffs yielding specificities of 80%, 90%, and 95%, the sensitivities for the detection of colorectal cancer were 64%, 50%, and 42%, and early-stage cancers were detected as well as late-stage cancers. For osteopontin, seprase, and ferritin, the diagnostic performance in the screening setting was reduced compared with previous studies in diagnostic settings while CEA and anti-p53 showed similar diagnostic performance in both settings.

Conclusions: Performance of the 5-marker blood test under screening conditions is inferior to FIT even though it is still comparable with the performance of gFOBT. CEA and anti-p53 could contribute to the development of a multiple marker blood-based test for early detection of colorectal cancer. Clin Cancer Res; 22(7); 1725–33. ©2015 AACR.
Data from c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer
Authors: Nebbioso Angela , Carafa Vincenzo , Conte Mariarosaria , Tambaro Francesco Paolo , Abbondanza Ciro , Martens Joost , Nees Matthias , Benedetti Rosaria , Pallavicini Isabella , Minucci Saverio , Garcia-Manero Guillermo , Iovino Francesco , Lania Gabriella , Ingenito Concetta , Belsito Petrizzi Valeria , Stunnenberg Hendrik G. , Altucci Lucia
Published: April 2023

Abstract
Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood.

Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials.

Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.
Data from Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3–FOXO1-Positive Alveolar Rhabdomyosarcoma
Authors: Kephart Julie J.G. , Tiller Rosanne G.J. , Crose Lisa E.S. , Slemmons Katherine K. , Chen Po-Han , Hinson Ashley R. , Bentley Rex C. , Chi Jen-Tsan Ashley , Linardic Corinne M.
Published: April 2023

Abstract
Purpose: Rhabdomyosarcoma (RMS) is a soft tissue sarcoma associated with the skeletal muscle lineage. Of the two predominant subtypes, known as embryonal (eRMS) and alveolar (aRMS), aRMS has the poorer prognosis, with a five-year survival rate of <50%. The majority of aRMS tumors express the fusion protein PAX3–FOXO1. As PAX3–FOXO1 has proven chemically intractable, this study aims to identify targetable proteins that are downstream from or cooperate with PAX3–FOXO1 to support tumorigenesis.

Experimental Design: Microarray analysis of the transcriptomes of human skeletal muscle myoblasts expressing PAX3–FOXO1 revealed alteration of several Wnt pathway gene members, including secreted frizzled related protein 3 (SFRP3), a secreted Wnt pathway inhibitor. Loss-of-function using shRNAs against SFRP3 was used to interrogate the role of SFRP3 in human aRMS cell lines in vitro and conditional murine xenograft systems in vivo. The combination of SFRP3 genetic suppression and the chemotherapeutic agent vincristine was also examined.

Results: In vitro, suppression of SFRP3 inhibited aRMS cell growth, reduced proliferation accompanied by a G1 arrest and induction of p21, and induced apoptosis. In vivo, doxycycline-inducible suppression of SFRP3 reduced aRMS tumor growth and weight by more than three-fold, in addition to increasing myogenic differentiation and β-catenin signaling. The combination of SFRP3 suppression and vincristine was more effective at reducing aRMS cell growth in vitro than either treatment alone, and ablated tumorigenesis in vivo.

Conclusions: SFRP3 is necessary for the growth of human aRMS cells both in vitro and in vivo and is a promising new target for investigation in aRMS. Clin Cancer Res; 21(21); 4868–80. ©2015 AACR.
Data from Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study
Authors: Dubois Sydney , Viailly Pierre-Julien , Mareschal Sylvain , Bohers Elodie , Bertrand Philippe , Ruminy Philippe , Maingonnat Catherine , Jais Jean-Philippe , Peyrouze Pauline , Figeac Martin , Molina Thierry J. , Desmots Fabienne , Fest Thierry , Haioun Corinne , Lamy Thierry , Copie-Bergman Christiane , Brière Josette , Petrella Tony , Canioni Danielle , Fabiani Bettina , Coiffier Bertrand , Delarue Richard , Peyrade Frédéric , Bosly André , André Marc , Ketterer Nicolas , Salles Gilles , Tilly Hervé , Leroy Karen , Jardin Fabrice
Published: April 2023

Abstract
Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.

Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays.

Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell–like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK–STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.

Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919–28. ©2016 AACR.

See related commentary by Lim and Elenitoba-Johnson, p. 2829
Data from Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma
Authors: Brown Jennifer R. , Davids Matthew S. , Rodon Jordi , Abrisqueta Pau , Kasar Siddha N. , Lager Joanne , Jiang Jason , Egile Coumaran , Awan Farrukh T.
Published: April 2023

Abstract
Purpose: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma.

Patients and Methods: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed.

Results: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival ≥6 months.

Conclusions: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development. Clin Cancer Res; 21(14); 3160–9. ©2015 AACR.
Data from Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma
Authors: Tateishi Kensuke , Iafrate A. John , Ho Quan , Curry William T. , Batchelor Tracy T. , Flaherty Keith T. , Onozato Maristela L. , Lelic Nina , Sundaram Sudhandra , Cahill Daniel P. , Chi Andrew S. , Wakimoto Hiroaki
Published: April 2023

Abstract
Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma.

Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using 13C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.

Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN–amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.

Conclusions: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452–65. ©2016 AACR.
Data from Gain of HIF-1α under Normoxia in Cancer Mediates Immune Adaptation through the AKT/ERK and VEGFA Axes
Authors: Lee Young-Ho , Bae Hyun Cheol , Noh Kyung Hee , Song Kwon-Ho , Ye Sang-kyu , Mao Chih-Ping , Lee Kyung-Mi , Wu T.-C. , Kim Tae Woo
Published: April 2023

Abstract
Purpose: Adaptation to host immune surveillance is now recognized as a hallmark of cancer onset and progression, and represents an early, indispensable event in cancer evolution. This process of evolution is first instigated by an immune selection pressure imposed by natural host surveillance mechanisms and may then be propagated by vaccination or other types of immunotherapy.

Experimental Design: We developed a system to simulate cancer evolution in a live host and to dissect the mechanisms responsible for adaptation to immune selection. Here, we show that the oxygen-sensitive α subunit of hypoxia-inducible factor 1 (HIF-1α) plays a central role in cancer immune adaptation under conditions of normal oxygen tension.

Results: We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice. The effects of HIF-1α on immune adaptation were mediated through VEGFA-dependent activation of the AKT and ERK signaling pathways, which induced an antiapoptotic gene expression network in tumor cells.

Conclusions: Our study therefore establishes a link between immune selection, overexpression of HIF-1α, and cancer immune adaptation under normoxia, providing new opportunities for molecular intervention in patients with cancer. Clin Cancer Res; 21(6); 1438–46. ©2015 AACR.
Data from Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease
Authors: Klintman Marie , Buus Richard , Cheang Maggie Chon U. , Sheri Amna , Smith Ian E. , Dowsett Mitch
Published: April 2023

Abstract
Purpose: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression.

Experimental Design: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs.

Results: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER−, PgR−, and HER2− status. In ER+/HER2− patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER−/HER2− patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2.

Conclusions: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras–ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405–16. ©2016 AACR.
Data from Clever-1/Stabilin-1 Controls Cancer Growth and Metastasis
Authors: Karikoski Marika , Marttila-Ichihara Fumiko , Elima Kati , Rantakari Pia , Hollmén Maija , Kelkka Tiina , Gerke Heidi , Huovinen Ville , Irjala Heikki , Holmdahl Rikard , Salmi Marko , Jalkanen Sirpa
Published: April 2023

Abstract
Purpose: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown.

Experimental Design: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma.

Results: Clever-1–deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity.

Conclusion: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer. Clin Cancer Res; 20(24); 6452–64. ©2014 AACR.
Data from Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer
Authors: Bonito Nair A. , Borley Jane , Wilhelm-Benartzi Charlotte S. , Ghaem-Maghami Sadaf , Brown Robert
Published: April 2023

Abstract
Purpose: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity.

Experimental Design: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines.

Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P < 0.05, q < 0.05, n = 78), have poor RECIST response (P < 0.05, q < 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR, 0.92; 95% CI, 0.85–0.99; P = 0.029; n = 309). Cisplatin-resistant ovarian cancer cell lines have reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression.

Conclusions: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity. Clin Cancer Res; 22(12); 3097–104. ©2016 AACR.
Data from IgG Glycome in Colorectal Cancer
Authors: Vučković Frano , Theodoratou Evropi , Thaçi Kujtim , Timofeeva Maria , Vojta Aleksandar , Štambuk Jerko , Pučić-Baković Maja , Rudd Pauline M. , Đerek Lovorka , Servis Dražen , Wennerström Annika , Farrington Susan M. , Perola Markus , Aulchenko Yurii , Dunlop Malcolm G. , Campbell Harry , Lauc Gordan
Published: April 2023

Abstract
Purpose: Alternative glycosylation has significant structural and functional consequences on IgG and consequently also on cancer immunosurveillance. Because of technological limitations, the effects of highly heritable individual variations and the differences in the dynamics of changes in IgG glycosylation on colorectal cancer were never investigated before.

Experimental Design: Using recently developed high-throughput UPLC technology for IgG glycosylation analysis, we analyzed IgG glycome composition in 760 patients with colorectal cancer and 538 matching controls. Effects of surgery were evaluated in 28 patients sampled before and three times after surgery. A predictive model was built using regularized logistic regression and evaluated using a 10-cross validation procedure. Furthermore, IgG glycome composition was analyzed in 39 plasma samples collected before initial diagnosis of colorectal cancer.

Results: We have found that colorectal cancer associates with decrease in IgG galactosylation, IgG sialylation and increase in core-fucosylation of neutral glycans with concurrent decrease of core-fucosylation of sialylated glycans. Although a model based on age and sex did not show discriminative power (AUC = 0.499), the addition of glycan variables into the model considerably increased the discriminative power of the model (AUC = 0.755). However, none of these differences were significant in the small set of samples collected before the initial diagnosis.

Conclusions: Considering the functional relevance of IgG glycosylation for both tumor immunosurveillance and clinical efficacy of therapy with mAbs, individual variation in IgG glycosylation may turn out to be important for prediction of disease course or the choice of therapy, thus warranting further, more detailed studies of IgG glycosylation in colorectal cancer. Clin Cancer Res; 22(12); 3078–86. ©2016 AACR.
Data from β-Cryptoxanthin Synergistically Enhances the Antitumoral Activity of Oxaliplatin through ΔNP73 Negative Regulation in Colon Cancer
Authors: San Millán Coral , Soldevilla Beatriz , Martín Paloma , Gil-Calderón Beatriz , Compte Marta , Pérez-Sacristán Belén , Donoso Encarnación , Peña Cristina , Romero Jesús , Granado-Lorencio Fernando , Bonilla Félix , Domínguez Gemma
Published: April 2023

Abstract
Background: The acquired resistance to chemotherapy represents the major limitation in the treatment of cancer. New strategies to solve this failure and improve patients' outcomes are necessary. The cancer preventive effect of β-cryptoxanthin has been widely described in population studies. Few reports support its putative use as an antitumoral compound. Here we focus on the therapeutic potential of β-cryptoxanthin individually or in combination with oxaliplatin in colon cancer and try to decipher the molecular basis underlying its effect.

Methods: Apoptosis, viability and proliferation assays, mouse models, and an intervention study in 20 healthy subjects were performed. A PCR array was carried out to unravel the molecular putative basis of the β-cryptoxanthin effect, and further signaling experiments were conducted. Comet Assay was completed to evaluate the genotoxicity of the treatments.

Results: β-Cryptoxanthin differentially regulates the expression of the P73 variants in vitro, in vivo, and in a human intervention study. This carotenoid decreases the proliferation of cancer cells and cooperates with oxaliplatin to induce apoptosis through the negative regulation of ΔNP73. The antitumoral concentrations of oxaliplatin decrease in the presence of β-cryptoxanthin to achieve same percentage of growth inhibition. The genotoxicity in peripheral blood mononuclear cells of mice decreased in the combined treatment.

Conclusions: We propose a putative novel therapeutic strategy for the treatment of colon cancer based on the combination of β-cryptoxanthin and oxaliplatin. The combined regimen produced more benefit than either individual modality without increasing side effects. In addition, the concentration-limiting toxicity of oxaliplatin is reduced in the presence of the carotenoid. Clin Cancer Res; 21(19); 4398–409. ©2015 AACR.
Data from Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
Authors: Gréen Henrik , Hasmats Johanna , Kupershmidt Ilya , Edsgärd Daniel , de Petris Luigi , Lewensohn Rolf , Blackhall Fiona , Vikingsson Svante , Besse Benjamin , Lindgren Andrea , Brandén Eva , Koyi Hirsh , Peterson Curt , Lundeberg Joakim
Published: April 2023

Abstract
Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression.

Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy–Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis.

Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients' myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8–18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17–0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia.

Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/carboplatin chemotherapy. Clin Cancer Res; 22(2); 366–73. ©2015 AACR.
Data from Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/or BRCA Mutation–Associated Breast Cancer
Authors: Rodler Eve T. , Kurland Brenda F. , Griffin Melissa , Gralow Julie R. , Porter Peggy , Yeh Rosa F. , Gadi Vijayakrishna K. , Guenthoer Jamie , Beumer Jan H. , Korde Larissa , Strychor Sandra , Kiesel Brian F. , Linden Hannah M. , Thompson John A. , Swisher Elizabeth , Chai Xiaoyu , Shepherd Stacie , Giranda Vincent , Specht Jennifer M.
Published: April 2023

Abstract
Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.

Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.

Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).

Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.
Data from A Novel Anti-CD22 Anthracycline-Based Antibody–Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs
Authors: Yu Shang-Fan , Zheng Bing , Go MaryAnn , Lau Jeff , Spencer Susan , Raab Helga , Soriano Robert , Jhunjhunwala Suchit , Cohen Robert , Caruso Michele , Polakis Paul , Flygare John , Polson Andrew G.
Published: April 2023

Abstract
Purpose: We are interested in identifying mechanisms of resistance to the current generation of antibody–drug conjugates (ADC) and developing ADCs that can overcome this resistance.

Experimental Design: Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs.

Results: We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE–based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines.

Conclusions: These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates. Clin Cancer Res; 21(14); 3298–306. ©2015 AACR.
Data from A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation
Authors: Arai Sally , Pidala Joseph , Pusic Iskra , Chai Xiaoyu , Jaglowski Samantha , Khera Nandita , Palmer Jeanne , Chen George L. , Jagasia Madan H. , Mayer Sebastian A. , Wood William A. , Green Michael , Hyun Teresa S. , Inamoto Yoshihiro , Storer Barry E. , Miklos David B. , Shulman Howard M. , Martin Paul J. , Sarantopoulos Stefanie , Lee Stephanie J. , Flowers Mary E.D.
Published: April 2023

Abstract
Purpose: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.

Experimental design: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m2 i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.

Results: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%–43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%–44%) randomized to rituximab. Six (17%; 95% CI, 7%–34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%–29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27+) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.

Conclusions: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab. Clin Cancer Res; 22(2); 319–27. ©2015 AACR.
Data from Development of Circulating Tumor Cell-Endocrine Therapy Index in Patients with Hormone Receptor–Positive Breast Cancer
Authors: Paoletti Costanza , Muñiz Maria C. , Thomas Dafydd G. , Griffith Kent A. , Kidwell Kelley M. , Tokudome Nahomi , Brown Martha E. , Aung Kimberly , Miller M. Craig , Blossom Dorothy L. , Schott Anne F. , Henry N. Lynn , Rae James M. , Connelly Mark C. , Chianese David A. , Hayes Daniel F.
Published: April 2023

Abstract
Background: Endocrine therapy (ET) fails to induce a response in one half of patients with hormone receptor (HR)–positive metastatic breast cancer (MBC), and almost all will eventually become refractory to ET. Circulating tumor cells (CTC) are associated with worse prognosis in patients with MBC, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multiparameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR-positive MBC.

Methods: The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC.

Results: The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in patients with MBC. CTC-ETI was successfully determined in 44 of 50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Interobserver concordance of CTC-ETI determination was from 94% to 95% (Kappa statistic, 0.90–0.91). Inter- and cell-to-cell intrapatient heterogeneity of expression of each of the CTC markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissues.

Conclusions: CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC biomarker expression, are being evaluated in an ongoing prospective trial. Clin Cancer Res; 21(11); 2487–98. ©2014 AACR.

See related commentary by Mathew et al., p. 2421
Data from The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer
Authors: Zhao Shuang G. , Evans Joseph R. , Kothari Vishal , Sun Grace , Larm Ashley , Mondine Victor , Schaeffer Edward M. , Ross Ashley E. , Klein Eric A. , Den Robert B. , Dicker Adam P. , Karnes R. Jeffrey , Erho Nicholas , Nguyen Paul L. , Davicioni Elai , Feng Felix Y.
Published: April 2023

Abstract
Purpose: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets.

Experimental Design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score.

Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S).

Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes. Clin Cancer Res; 22(7); 1777–86. ©2015 AACR.
Data from NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma
Authors: Cescon David W. , She Desmond , Sakashita Shingo , Zhu Chang-Qi , Pintilie Melania , Shepherd Frances A. , Tsao Ming-Sound
Published: April 2023

Abstract
Purpose: Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of these findings and assessed whether NRF2 activation predicts benefit from adjuvant chemotherapy in SCC.

Experimental Design: Logistic regression (LR) and significance analysis of microarrays (SAM) were applied to all 104 TCGA (The Cancer Genome Atlas) SCC cases that had microarray gene expression and mutation data to identify genes associated with somatic NRF2 pathway alterations. The resulting signature (NRF2ACT) was tested in 3 independent SCC datasets to evaluate its prognostic and predictive effects. IHC and sequencing for NRF2 and KEAP1 were evaluated in one cohort (n = 43) to assess the relationship between gene expression, mutational status, and protein expression.

Results: Twenty-eight genes were identified by overlap between LR (291 genes) and SAM (30 genes), and these consistently separated SCC into 2 groups in all datasets, corresponding to putatively NRF pathway–activated and wild-type (WT) tumors. NRF2ACT was not prognostic. However, improved survival with adjuvant chemotherapy in the JBR.10-randomized trial appears limited to patients with the WT signature (HR 0.32, P = 0.16; NRF2ACT HR 2.28, P = 0.48; interaction P = 0.15). NRF2ACT was highly correlated with mutations in NRF2 and KEAP1, and with high NRF2 protein expression.

Conclusions: A gene expression signature of NRF2 pathway activation is associated with benefit from adjuvant cisplatin/vinorelbine in SCC. Patients with NRF2 pathway–activating somatic alterations may have reduced benefit from this therapy. Clin Cancer Res; 21(11); 2499–505. ©2015 AACR.
Data from Detection, Characterization, and Inhibition of FGFR–TACC Fusions in IDH Wild-type Glioma
Authors: Di Stefano Anna Luisa , Fucci Alessandra , Frattini Veronique , Labussiere Marianne , Mokhtari Karima , Zoppoli Pietro , Marie Yannick , Bruno Aurelie , Boisselier Blandine , Giry Marine , Savatovsky Julien , Touat Mehdi , Belaid Hayat , Kamoun Aurelie , Idbaih Ahmed , Houillier Caroline , Luo Feng R. , Soria Jean-Charles , Tabernero Josep , Eoli Marica , Paterra Rosina , Yip Stephen , Petrecca Kevin , Chan Jennifer A. , Finocchiaro Gaetano , Lasorella Anna , Sanson Marc , Iavarone Antonio
Published: April 2023

Abstract
Purpose: Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency and molecular features of FGFR–TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma.

Experimental Design: Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR–TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3–TACC3–positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3–TACC3–positive GBM received JNJ-42756493 and were assessed for therapeutic response.

Results: Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3–TACC3 fusions. FGFR–TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3–TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3–TACC3 in vitro and in vivo. The two patients with FGFR3–TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.

Conclusions: RT-PCR sequencing is a sensitive and specific method to identify FGFR–TACC–positive patients. FGFR3–TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3–TACC3–positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR–TACC–positive patients. Clin Cancer Res; 21(14); 3307–17. ©2015 AACR.

See related commentary by Ahluwalia and Rich, p. 3105