TY  - JOUR
AB  - A recent phase I clinical study tested anti-ROR1 chimeric antigen receptor (CAR) T cells in patients with chronic lymphocytic leukemia, non–small cell lung cancer, and triple-negative breast cancer. The product could be safely administered and had activity in chronic lymphocytic leukemia but less so in non–small cell lung cancer and triple-negative breast cancer.
AU  - Kobold, S.
C1  - 73362
C2  - 57025
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 437-438
TI  - RORing CAR T cells in solid and hematologic cancers: Same but different.
JO  - Clin. Cancer Res.
VL  - 31
IS  - 3
PB  - Amer Assoc Cancer Research
PY  - 2025
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in the brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated. EXPERIMENTAL DESIGN: We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n = 41), astrocytoma WHO grade 2 (n = 7), and healthy controls (n = 20) and compared TSPO-PET signals of the non-lesion (i.e., contralateral) hemisphere. Back-translation into syngeneic SB28 glioblastoma mice was used to characterize Pet alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain. RESULTS: Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions. CONCLUSIONS: Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression.
AU  - Bartos, L.M.*
AU  - Quach, S.*
AU  - Zenatti, V.*
AU  - Kirchleitner, S.V.*
AU  - Blobner, J.*
AU  - Wind-Mark, K.*
AU  - Kolabas, Z.I.
AU  - Ulukaya, S.
AU  - Holzgreve, A.*
AU  - Ruf, V.C.*
AU  - Kunze, L.H.*
AU  - Kunte, S.T.*
AU  - Hoermann, L.*
AU  - Härtel, M.*
AU  - Park, H.E.*
AU  - Groß, M.*
AU  - Franzmeier, N.*
AU  - Zatcepin, A.*
AU  - Zounek, A.*
AU  - Kaiser, L.*
AU  - Riemenschneider, M.J.*
AU  - Perneczky, R.*
AU  - Rauchmann, B.S.*
AU  - Stöcklein, S.*
AU  - Ziegler, S.*
AU  - Herms, J.*
AU  - Ertürk, A.
AU  - Tonn, J.C.*
AU  - Thon, N.*
AU  - von Baumgarten, L.*
AU  - Prestel, M.*
AU  - Tahirovic, S.*
AU  - Albert, N.L.*
AU  - Brendel, M.*
C1  - 72062
C2  - 56360
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 4618-4634
TI  - Remote neuroinflammation in newly diagnosed glioblastoma correlates with unfavorable clinical outcome.
JO  - Clin. Cancer Res.
VL  - 30
IS  - 20
PB  - Amer Assoc Cancer Research
PY  - 2024
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Esophageal cancer (EC) carries a poor prognosis with 5-year overall survival of less than 20%. Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). The aim of this study was to investigate the ability of EMI-137, a mesenchymal-epithelial transition factor (c-MET)-targeting optical imaging tracer, to detect dysplasia in BE. EXPERIMENTAL DESIGN: c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus (GEO) datasets, tissue microarrays and BE biopsies. EMI-137 was tested in a dual xenograft mouse model bearing OE33 (c-MET high expression) and FLO-1 (c-MET low expression) tumors. Fluorescence molecular endoscopy (FME) was performed in a mouse model of Barrett's-like metaplasia and dysplasia (L2-IL1β). Tumors and organs-of-interest were evaluated through ex vivo fluorescence imaging. RESULTS: MET mRNA expression analyses and c-MET immunostaining confirmed upregulation of c-MET in BE and EAC compared to normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 h post injection decreasing by more than 50% on co-injection of a 10-fold molar excess of unlabeled EMI-137. The target-to background ratio (TBR) at 3 h p.i. for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. FME of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within BE with a TBR of 1.9 in vivo, and greater than 2 in ex vivo fluorescence imaging. CONCLUSIONS: EMI-137 accumulates in dysplastic lesions within BE and in c-MET positive EAC. EMI-137 imaging has potential as a screening and surveillance tool for patients with BE and as a means to detecting dysplasia and EAC.
AU  - Huang, Y.J.*
AU  - Rieder, J.*
AU  - Tan, K.V.*
AU  - Tenditnaya, A.
AU  - Vojnovic, B.*
AU  - Gorpas, D.
AU  - Quante, M.*
AU  - Vallis, K.A.*
C1  - 72318
C2  - 56595
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 98-109
TI  - Targeting c-MET for endoscopic detection of dysplastic lesions within Barrett's esophagus using EMI-137 fluorescence imaging.
JO  - Clin. Cancer Res.
VL  - 31
IS  - 1
PB  - Amer Assoc Cancer Research
PY  - 2024
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia. Experimental Design: A DNA-methylome–based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression–based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)–negative patients with HNSCC treated with primary radiochemotherapy (RCHT). Results: Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P ¼ 0.001) and overall survival (HR, 2.34; P ¼ 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P ¼ 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. Conclusions: Our findings highlight an unexplored avenue for DNA methylation–based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors.
AU  - Tawk, B.*
AU  - Rein, K.*
AU  - Schwager, C.*
AU  - Knoll, M.*
AU  - Wirkner, U.*
AU  - Hörner-Rieber, J.*
AU  - Liermann, J.*
AU  - Kurth, I.*
AU  - Balermpas, P.*
AU  - Rödel, C.*
AU  - Linge, A.*
AU  - Löck, S.*
AU  - Lohaus, F.*
AU  - Tinhofer, I.*
AU  - Krause, M.*
AU  - Stuschke, M.*
AU  - Grosu, A.L.*
AU  - Zips, D.*
AU  - Combs, S.E.*
AU  - Belka, C.
AU  - Stenzinger, A.*
AU  - Herold-Mende, C.*
AU  - Baumann, M.*
AU  - Schirmacher, P.*
AU  - Debus, J.*
AU  - Abdollahi, A.*
C1  - 68352
C2  - 53634
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 3051-3064
TI  - DNA-methylome–based tumor hypoxia classifier identifies HPV-negative head and neck cancer patients at risk for locoregional recurrence after primary radiochemotherapy.
JO  - Clin. Cancer Res.
VL  - 29
IS  - 16
PB  - Amer Assoc Cancer Research
PY  - 2023
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Current systems of gastric cancer (GC) molecular classification include genomic, molecular, and morphological features. GC classification based on tissue metabolomics remains lacking. This study aimed to define metabolically distinct GC subtypes and identify their clinicopathological and molecular characteristics. EXPERIMENTAL DESIGN: Spatial metabolomics by high mass resolution imaging mass spectrometry was performed in 362 GC patients. K-means clustering was used to define tumor and stroma-related subtypes based on tissue metabolites. The identified subtypes were linked with clinicopathological characteristics, molecular features, and metabolic signatures. Responses to trastuzumab treatment were investigated across the subtypes by introducing an independent patient cohort with HER2-positive GC from a multicenter observational study. RESULTS: Three tumor- and three stroma-specific subtypes with distinct tissue metabolite patterns were identified. Tumor-specific subtype T1(HER2+MIB+CD3+) positively correlated with HER2, MIB1, DEFA-1, CD3, CD8, FOXP3, but negatively correlated with MMR. Tumor-specific subtype T2(HER2-MIB-CD3-) negatively correlated with HER2, MIB1, CD3, FOXP3, but positively correlated with MMR. Tumor-specific subtype T3(pEGFR+) positively correlated with pEGFR. Patients with tumor subtype T1(HER2+MIB+CD3+) had elevated nucleotide levels, enhanced DNA metabolism, and a better prognosis than T2(HER2-MIB-CD3-) and T3(pEGFR+). An independent validation cohort confirmed that the T1 subtype benefited from trastuzumab therapy. Stroma-specific subtypes had no association with clinicopathological characteristics, however linked to distinct metabolic pathways and molecular features. CONCLUSIONS: Patient subtypes derived by tissue-based spatial metabolomics are a valuable addition to existing GC molecular classification systems. Metabolic differences between the subtypes and their associations with molecular features could provide a valuable tool to aid in selecting specific treatment approaches.
AU  - Wang, J.
AU  - Kunzke, T.
AU  - Prade, V.M.
AU  - Shen, J.
AU  - Buck, A.
AU  - Feuchtinger, A.
AU  - Haffner, I.*
AU  - Luber, B.*
AU  - Liu, D.H.W.*
AU  - Langer, R.*
AU  - Lordick, F.*
AU  - Sun, N.
AU  - Walch, A.K.
C1  - 64802
C2  - 51903
SP  - 2865-2877
TI  - Spatial metabolomics identifies distinct tumor-specific subtypes in gastric cancer patients.
JO  - Clin. Cancer Res.
VL  - 28
IS  - 13
PY  - 2022
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations. EXPERIMENTAL DESIGN: From 150 tumors, 74 primary HNSCCs were RNA-sequenced and 38 matched primary/recurrent tumor pairs were both, whole-exome and RNA-sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA) and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data. RESULTS: While CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-emt) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Gene set enrichment analysis identified upregulation of Hypoxia, p-emt and radiation resistance signatures and downregulation of tumor inflammation in recurrences compared to index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin. CONCLUSIONS: Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.
AU  - Weber, P.
AU  - Künstner, A.*
AU  - Hess J.
AU  - Unger, K.
AU  - Marschner, S.
AU  - Idel, C.*
AU  - Ribbat-Idel, J.*
AU  - Walz, C.*
AU  - Rietzler, S.*
AU  - Valeanu, L.*
AU  - Herkommer, T.
AU  - Kreutzer, L.
AU  - Klymenko, O.*
AU  - Kirchner, T.*
AU  - Ganswindt, U.
AU  - Walch, A.K.
AU  - Sterr, M.
AU  - Lickert, H.
AU  - Canis, M.*
AU  - Rades, D.*
AU  - Perner, S.*
AU  - Berriel Diaz, M.
AU  - Herzig, S.
AU  - Wollenberg, B.*
AU  - Busch, H.*
AU  - Zitzelsberger, H.
C1  - 64025
C2  - 51660
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 1038-1052
TI  - Therapy-related transcriptional subtypes in matched primary and recurrent head and neck cancer.
JO  - Clin. Cancer Res.
VL  - 28
IS  - 5
PB  - Amer Assoc Cancer Research
PY  - 2022
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.Experimental Design: We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.Results: We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.Conclusions: Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.
AU  - Anande, G.*
AU  - Deshpande, N.P.*
AU  - Mareschal, S.*
AU  - Batcha, A.M.N.*
AU  - Hampton, H.R.*
AU  - Herold, T.
AU  - Lehmann, S.*
AU  - Wilkins, M.R.*
AU  - Wong, J.W.H.*
AU  - Unnikrishnan, A.*
AU  - Pimanda, J.E.*
C1  - 59860
C2  - 49078
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 3597-3607
TI  - RNA splicing alterations induce a cellular stress response associated with poor prognosis inAcute Myeloid Leukemia.
JO  - Clin. Cancer Res.
VL  - 26
IS  - 14
PB  - Amer Assoc Cancer Research
PY  - 2020
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Hulstaert, E.*
AU  - Morlion, A.*
AU  - Cobos, F.A.*
AU  - Verniers, K.*
AU  - Nuytens, J.*
AU  - Eynde, E.V.*
AU  - Yigit, N.*
AU  - Anckaert, J.*
AU  - Geerts, A.*
AU  - Hindryckx, P.*
AU  - Jacques, P.*
AU  - Brusselle, G.*
AU  - Bracke, K.*
AU  - Maes, T.*
AU  - Malfait, T.*
AU  - Derveaux, T.*
AU  - Ninclaus, V.*
AU  - Van Cauwenbergh, C.*
AU  - Roelens, K.*
AU  - Roets, E.*
AU  - Hemelsoet, D.*
AU  - Tilleman, K.*
AU  - Brochez, L.*
AU  - Kuersten, S.*
AU  - Simon, L.
AU  - Karg, S.*
AU  - Nohammer, C.*
AU  - Kautzky-Willers, A.*
AU  - Leutner, M.*
AU  - Slaby, O.*
AU  - Schroth, G.*
AU  - Vandesompele, J.*
AU  - Mestdagh, P.*
C1  - 59404
C2  - 48787
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 33-34
TI  - Charting extracellular transcriptomes in The Human Biofluid RNA Atlas.
JO  - Clin. Cancer Res.
VL  - 26
IS  - 11
PB  - Amer Assoc Cancer Research
PY  - 2020
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Non-small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. Amembrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo-activated NK cells in patients with NSCLC after radiochemotherapy (RCT).Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60-70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses.Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%-90%] for the INT arm and 33% (95% CI, 5%-68%) for the CTRL arm (P = 0.36, 1-sided logrank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood.Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.
AU  - Multhoff, G.*
AU  - Seier, S.*
AU  - Stangl, S.*
AU  - Sievert, W.*
AU  - Shevtsov, M.*
AU  - Werner, C.*
AU  - Pockley, A.G.*
AU  - Blankenstein, C.*
AU  - Hildebrandt, M.*
AU  - Offner, R.*
AU  - Ahrens, N.*
AU  - Kokowski, K.*
AU  - Hautmann, M.*
AU  - Roedel, C.*
AU  - Fietkau, R.*
AU  - Lubgan, D.*
AU  - Huber, R.*
AU  - Hautmann, H.*
AU  - Duell, T.*
AU  - Molls, M.*
AU  - Specht, H.*
AU  - Haller, B.*
AU  - Devecka, M.*
AU  - Sauter, A.*
AU  - Combs, S.E.
C1  - 60517
C2  - 49342
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 5368-5379
TI  - Targeted natural killer cell-based adoptive immunotherapy for the treatment of patients with NSCLC after radiochemotherapy: A randomized phase II clinical trial.
JO  - Clin. Cancer Res.
VL  - 26
IS  - 20
PB  - Amer Assoc Cancer Research
PY  - 2020
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined.Experimental Design: We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursivepartitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed.Results: For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsamiR- 6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, P < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, P < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, P < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive- partitioning analysis of both samples combined classified patients into low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < 0.001).Conclusions: The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC.
AU  - Hess J.
AU  - Unger, K.
AU  - Maihoefer, C.
AU  - Schüttrumpf, L.
AU  - Wintergerst, L.
AU  - Heider, T.
AU  - Weber, P.
AU  - Marschner, S.
AU  - Braselmann, H.
AU  - Samaga, D.
AU  - Kuger, S.
AU  - Pflugradt, U.
AU  - Baumeister, P.
AU  - Walch, A.K.
AU  - Woischke, C.*
AU  - Kirchner, T.*
AU  - Werner, M.*
AU  - Werner, K.*
AU  - Baumann, M.*
AU  - Budach, V.*
AU  - Combs, S.E.
AU  - Debus, J.*
AU  - Grosu, A.-L.*
AU  - Krause, M.*
AU  - Linge, A.*
AU  - Rödel, C.*
AU  - Stuschke, M.*
AU  - Zips, D.*
AU  - Zitzelsberger, H.
AU  - Ganswindt, U.
AU  - Henke, M.*
AU  - Belka, C.
C1  - 54217
C2  - 45362
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 1505-1516
TI  - A five-microRNA signature predicts survival and disease control of patients with head and neck cancer negative for HPV-infection.
JO  - Clin. Cancer Res.
VL  - 25
IS  - 5
PB  - Amer Assoc Cancer Research
PY  - 2019
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.Experimental Design: BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo.Results: Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3 zeta signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII x anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo.Conclusions: We describe a novel ACT platform with antitumor activity inmurine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.
AU  - Karches, C.H.*
AU  - Benmebarek, M.R.*
AU  - Schmidbauer, M.L.*
AU  - Kurzay, M.*
AU  - Klaus, R.*
AU  - Geiger, M.*
AU  - Rataj, F.*
AU  - Cadilha, B.L.*
AU  - Lesch, S.*
AU  - Heise, C.*
AU  - Murr, R.*
AU  - vom Berg, J.*
AU  - Jastroch, M.
AU  - Lamp, D.
AU  - Ding, J.*
AU  - Duewell, P.*
AU  - Niederfellner, G.*
AU  - Sustmann, C.*
AU  - Endres, S.*
AU  - Klein, C.*
AU  - Kobold, S.*
C1  - 56542
C2  - 47083
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 5890-5900
TI  - Bispecific antibodies enable synthetic agonistic receptor-transduced T cells for tumor immunotherapy.
JO  - Clin. Cancer Res.
VL  - 25
IS  - 19
PB  - Amer Assoc Cancer Research
PY  - 2019
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Hensel, T.*
AU  - Giorgi, C.*
AU  - Becker-Dettling, F.*
AU  - Calzada-Wack, J.
AU  - Schmidt, O.*
AU  - Wang, S.*
AU  - Schaefer, B.W.*
AU  - Burdach, S.*
AU  - Richter, G.H.S.*
C1  - 52849
C2  - 44406
CY  - Philadelphia
SP  - 56-56
TI  - Combined targeting of the Ewing sarcoma transcriptional program by blocking epigenetic readers and transcription initiation via EWS-FLI1.
JO  - Clin. Cancer Res.
VL  - 24
IS  - 2
PB  - Amer Assoc Cancer Research
PY  - 2018
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio (chemo)therapy (PORT-C). Experimental Design: Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms. Results: We identified a 7-gene signature consisting of the three individual genes HILPDA, CD24, TCF3, and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2, and ACTN1. The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci ¼ 0.82), which was successfully validated (ci ¼ 0.71). The signature showed improved performance compared with clinical parameters alone (ci ¼ 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci ¼ 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (P < 0.001). Conclusions: We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification.
AU  - Schmidt, S.*
AU  - Linge, A.*
AU  - Zwanenburg, A.*
AU  - Leger, S.*
AU  - Lohaus, F.*
AU  - Krenn, C.*
AU  - Appold, S.*
AU  - Gudziol, V.*
AU  - Nowak, A.*
AU  - von Neubeck, C.*
AU  - Tinhofer, I.*
AU  - Budach, V.*
AU  - Sak, A.*
AU  - Stuschke, M.*
AU  - Balermpas, P.*
AU  - Roedel, C.*
AU  - Bunea, H.*
AU  - Grosu, A.*
AU  - Abdollahi, A.*
AU  - Debus, J.*
AU  - Ganswindt, U.
AU  - Belka, C.
AU  - Pigorsch, S.U.*
AU  - Combs, S.E.
AU  - Moennich, D.*
AU  - Zips, D.*
AU  - Baretton, G.B.*
AU  - Buchholz, F.*
AU  - Baumann, M.*
AU  - Krause, M.*
AU  - Loeck, S.*
C1  - 53384
C2  - 44714
CY  - Philadelphia
SP  - 1364-1374
TI  - Development and validation of a gene signature for patients with head and neck squamous cell carcinomas treated by postoperative radio(chemo)therapy.
JO  - Clin. Cancer Res.
VL  - 24
IS  - 6
PB  - Amer Assoc Cancer Research
PY  - 2018
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - von Heyking, K.*
AU  - Calzada-Wack, J.
AU  - Goellner, S.*
AU  - Schmidt, O.*
AU  - Hensel, T.*
AU  - Schirmer, D.*
AU  - Fasan, A.*
AU  - Mueller-Tidow, C.*
AU  - Sorensen, P.*
AU  - Burdach, S.*
AU  - Richter, G.H.S.*
C1  - 52850
C2  - 44407
CY  - Philadelphia
SP  - 57-57
TI  - The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype promoting lung metastasis in Ewing sarcoma.
JO  - Clin. Cancer Res.
VL  - 24
IS  - 2
PB  - Amer Assoc Cancer Research
PY  - 2018
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: In a pilot study, we introduce fast handheld Multi-Spectral Optoacoustic Tomography (MSOT) of the breast at 28 wavelengths, aiming to identify high-resolution optoacoustic (photoacoustic) patterns of breast cancer and non-cancerous breast tissue. EXPERIMENTAL DESIGN: We imaged 10 female patients aged 48-81 years with malignant non-specific breast cancer or invasive lobular carcinoma. Three healthy volunteers aged 31-36 years were also imaged. Fast-MSOT was based on unique single-frame-per-pulse (SFPP) image acquisition employed to improve the accuracy of spectral differentiation over using a small number of wavelengths. Breast tissue was illuminated at the 700 - 970 nm spectral range over 0.56 seconds total scan time. MSOT data were guided by ultrasonography and X-ray mammography or MRI. RESULTS: The extended spectral range allowed the computation of oxygenated hemoglobin (HBO2), deoxygenated hemoglobin (HB), total blood volume (TBV), lipid and water contributions, allowing first insights into in-vivo high-resolution breast tissue MSOT cancer patterns. TBV and Hb/HBO2 images resolved marked differences between cancer and control tissue, manifested as a vessel rich tumor periphery with highly heterogeneous spatial appearance compared to healthy tissue. We observe significant TBV variations between different tumors and between tumors over healthy tissues. Water and fat lipid layers appear disrupted in cancer vs. healthy tissue; however offer weaker contrast compared to TBV images. CONCLUSION: In contrast to optical methods, MSOT resolves physiological cancer features with high resolution and revealed patterns not offered by other radiological modalities. The new features relate to personalized and precision medicine potential.
AU  - Diot, G.*
AU  - Metz, S.*
AU  - Noske, A.*
AU  - Liapis, E.
AU  - Schroeder, B.
AU  - Ovsepian, S.V.
AU  - Meier, R.*
AU  - Rummeny, E.J.*
AU  - Ntziachristos, V.
C1  - 51877
C2  - 43451
CY  - Philadelphia
SP  - 6912-6922
TI  - Multi-spectral optoacoustic tomography (MSOT) of human breast cancer.
JO  - Clin. Cancer Res.
VL  - 23
IS  - 22
PB  - Amer Assoc Cancer Research
PY  - 2017
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: to provide proof of principle of safety, breast tumor-specific uptake and positive tumor margin assessment of the systemically administered near-infrared fluorescent (NIRF) tracer bevacizumab-IRDye800CW targeting vascular endothelial growth factor (VEGF)-A in breast cancer patients. Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and co-registration of tumor tissue and healthy tissue. Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared to those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two out of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level. Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor-margin uptake as evaluated by a systematic validation methodology. The findings are a step towards a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in tumor tissue.
AU  - Lamberts, L.E.*
AU  - Koch, M.
AU  - de Jong, J.S.*
AU  - Adams, A.L.L.*
AU  - Glatz, J.
AU  - Kranendonk, M.E.G.*
AU  - Terwisscha van Scheltinga, A.G.*
AU  - Jansen, L.*
AU  - de Vries, J.*
AU  - Lub-de, Hoog, M.N.*
AU  - Schröder, C.P.*
AU  - Jorritsma-Smit, A.*
AU  - Linssen, M.D.*
AU  - de Boer, E.*
AU  - van der Vegt, B.*
AU  - Nagengast, W.B.*
AU  - Elisas,S.G.*
AU  - Oliveira, S.*
AU  - Witkamp, A.J.*
AU  - Mali, W.P.Th.M.*
AU  - van der Wall, E.*
AU  - van Diest, P.J.*
AU  - de Vries, E.G.*
AU  - Ntziachristos, V.
AU  - van Dam, G.M.*
C1  - 49999
C2  - 41960
CY  - Philadelphia
SP  - 2730-2741
TI  - Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: A phase I feasibility study.
JO  - Clin. Cancer Res.
VL  - 23
IS  - 11
PB  - Amer Assoc Cancer Research
PY  - 2016
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Morphologic intratumor heterogeneity is well known to exist in hepatocellular carcinoma (HCC) but very few systematic analyses of this phenomenon have been performed. The aim of this study was to comprehensively characterize morphological intratumor heterogeneity in HCC. Also taken into account were well-known immunohistochemical markers and molecular changes in liver cells that are considered in proposed classifications of liver cell neoplasms or discussed as molecular therapeutic targets. Experimental Design: In HCC of 23 patients without medical pretreatment, a total of 120 tumor areas were defined. Analyzed were cell and tissue morphology, expression of the liver cell markers CK7, CD44, AFP, EpCAM and glutamine synthetase along with mutations of TP53 and CTNNB1, assayed by both Sanger and next generation sequencing. Results: Overall, intratumor heterogeneity was detectable in the majority of HCC cases (20/23, 87%). Heterogeneity solely on the level of morphology was found in 6/23 cases (26%), morphological heterogeneity combined with immunohistochemical heterogeneity in 9/23 cases (39%), and heterogeneity with respect to morphology, immunohistochemistry and mutational status of TP53 and CTNNB1 in 5/23 cases (22%). Conclusions: Our findings demonstrate that intratumor heterogeneity represents a challenge for the establishment of a robust HCC classification and may contribute to treatment failure and drug resistance in many cases of HCC.
AU  - Friemel, J.*
AU  - Rechsteiner, M.P.*
AU  - Frick, L.*
AU  - Boehm, F.*
AU  - Struckmann, K.*
AU  - Sigg, M.*
AU  - Moch, H.*
AU  - Heikenwälder, M.
AU  - Weber, A.*
C1  - 32373
C2  - 35016
CY  - Philadelphia
SP  - 1951-1961
TI  - Intratumor heterogeneity in hepatocellular carcinoma.
JO  - Clin. Cancer Res.
VL  - 21
IS  - 8
PB  - Amer Assoc Cancer Research
PY  - 2015
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology non-invasively and identify differences between the models. EXPERIMENTAL DESIGN: DEN and McA tumor development was monitored by magnetic resonance imaging (MRI) and positron emission tomography (PET). A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors. RESULTS: Histologically and biochemically confirmed liver damage resulted in increased 18F-fluordeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared to uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared to McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only. CONCLUSION: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.
AU  - Groß, C.*
AU  - Steiger, K.*
AU  - Sayyed, S.*
AU  - Heid, I.*
AU  - Feuchtinger, A.
AU  - Walch, A.K.
AU  - Hess J.
AU  - Unger, K.
AU  - Zitzelsberger, H.
AU  - Settles, M.*
AU  - Schlitter, A.M.*
AU  - Dworniczak, J.*
AU  - Altomonte, J.*
AU  - Ebert, O.*
AU  - Schwaiger, M.*
AU  - Rummeny, E.J.*
AU  - Steingötter, A.*
AU  - Esposito, I.*
AU  - Braren, R.*
C1  - 44919
C2  - 37116
SP  - 4440-4450
TI  - Model matters: Differences in orthotopic rat hepatocellular carcinoma physiology determine therapy response to sorafenib.
JO  - Clin. Cancer Res.
VL  - 21
IS  - 19
PY  - 2015
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPAs), given their high relapse rate. Here, we evaluated the antitumor efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats). EXPERIMENTAL DESIGN: Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored non-invasively by diffusion weighted-magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells. RESULTS: NVP-BEZ235 showed anti-proliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP-BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition. CONCLUSIONS: Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival.
AU  - Lee, M.S.
AU  - Wiedemann, T.
AU  - Gross, C.*
AU  - Leinhäuser, I.
AU  - Roncaroli, F.*
AU  - Braren, R.*
AU  - Pellegata, N.S.
C1  - 44108
C2  - 36747
CY  - Philadelphia
SP  - 3204-3215
TI  - Targeting PI3K/mTOR signaling displays potent antitumor efficacy against nonfunctioning pituitary adenomas.
JO  - Clin. Cancer Res.
VL  - 21
IS  - 14
PB  - Amer Assoc Cancer Research
PY  - 2015
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Due to its heterogeneity, lack of prognostic markers, tumor-escape mechanisms and frequent relapse upon surgical intervention, treatment of hepatocellular carcinoma (HCC) remains challenging. In this issue of Clinical Cancer Research, Groß and colleagues characterize a rodent model, which might help identify novel drugs for combinatorial sorafenib-based therapies for HCC.
AU  - Weber, A.*
AU  - O'Connor, T.*
AU  - Heikenwälder, M.
C1  - 46323
C2  - 37594
SP  - 4254-4256
TI  - Next generation of preclinical liver cancer models.
JO  - Clin. Cancer Res.
VL  - 21
IS  - 19
PY  - 2015
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Targeting of the HER2 protein in human breast cancer represents a major advance in oncology but relies on measurements of total HER2 protein and not HER2 signaling network activation. We used reverse-phase protein microarrays (RPMA) to measure total and phosphorylated HER2 in the context of HER family signaling to understand correlations between phosphorylated and total levels of HER2 and downstream signaling activity.EXPERIMENTAL DESIGN: Three independent study sets, comprising a total of 415 individual patient samples from flash-frozen core biopsy samples and formalin-fixed and paraffin-embedded (FFPE) surgical and core samples, were analyzed via RPMA. The phosphorylation and total levels of the HER receptor family proteins and downstream signaling molecules were measured in laser capture microdissected (LCM) enriched tumor epithelium from 127 frozen pretreatment core biopsy samples and whole-tissue lysates from 288 FFPE samples and these results were compared with FISH and immunohistochemistry (IHC).RESULTS: RPMA measurements of total HER2 were highly concordant (>90% all sets) with FISH and/or IHC data, as was phosphorylation of HER2 in the FISH/IHC(+) population. Phosphorylation analysis of HER family signaling identified HER2 activation in some FISH/IHC(-) tumors and, identical to that seen with FISH/IHC(+) tumors, the HER2 activation was concordant with EGF receptor (EGFR) and HER3 phosphorylation and downstream signaling endpoint activation.CONCLUSIONS: Molecular profiling of HER2 signaling of a large cohort of human breast cancer specimens using a quantitative and sensitive functional pathway activation mapping technique reveals IHC(-)/FISH(-)/pHER2(+) tumors with HER2 pathway activation independent of total HER2 levels and functional signaling through HER3 and EGFR.
AU  - Wulfkuhle, J.D.*
AU  - Berg, D.*
AU  - Wolff, C.*
AU  - Langer, R.*
AU  - Tran, K.*
AU  - Illi, J.*
AU  - Espina, V.*
AU  - Pierobon, M.*
AU  - Deng, J.*
AU  - Demichele, A.*
AU  - Walch, A.K.
AU  - Bronger, H.*
AU  - Becker, I.*
AU  - Waldhör, C.*
AU  - Höfler, H.*
AU  - Esserman, L.*
AU  - Liotta, L.A.*
AU  - Becker, K.F.*
AU  - Petricoin, E.F.*
C1  - 10959
C2  - 30449
SP  - 6426-6435
TI  - Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping.
JO  - Clin. Cancer Res.
VL  - 18
IS  - 23
PB  - American Assoc. for Cancer Research
PY  - 2012
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - To facilitate development of innovative immunotherapy approaches, especially for treatment concepts exploiting the potential benefits of personalized therapy, there is a need to develop and validate tools to identify patients who can benefit from immunotherapy. Despite substantial effort, we do not yet know which parameters of antitumor immunity to measure and which assays are optimal for those measurements.
      The iSBTc-SITC (International Society for Biological Therapy of Cancer-Society for Immunotherapy of Cancer), FDA (Food and Drug Administration), and NCI (National Cancer Institute) partnered to address these issues for immunotherapy of cancer. Here, we review the major challenges, give examples of approaches and solutions, and present our recommendations.
      Although specific immune parameters and assays are not yet validated, we recommend following standardized (accurate, precise, and reproducible) protocols and use of functional assays for the primary immunologic readouts of a trial; consideration of central laboratories for immune monitoring of large, multi-institutional trials; and standardized testing of several phenotypic and functional potential potency assays specific to any cellular product. When reporting results, the full QA (quality assessment)/QC (quality control) should be conducted and selected examples of truly representative raw data and assay performance characteristics should be included. Finally, to promote broader analysis of multiple aspects of immunity, and gather data on variability, we recommend that in addition to cells and serum, RNA and DNA samples be banked (under standardized conditions) for later testing. We also recommend that sufficient blood be drawn to allow for planned testing of the primary hypothesis being addressed in the trial, and that additional baseline and posttreatment blood is banked for testing novel hypotheses (or generating new hypotheses) that arise in the field.
AU  - Butterfield, L.H.*
AU  - Palucka, A.K.*
AU  - Britten, C.M.*
AU  - Dhodapkar, M.V.*
AU  - Håkansson, L.*
AU  - Janetzki, S.*
AU  - Kawakami, Y.*
AU  - Kleen, T.O.*
AU  - Lee, P.P.*
AU  - Maccalli, C.*
AU  - Maecker, H.T.*
AU  - Maino, V.C.*
AU  - Maio, M.*
AU  - Malyguine, A.*
AU  - Masucci, G.*
AU  - Pawelec, G.*
AU  - Potter, D.M.*
AU  - Rivoltini, L.*
AU  - Salazar, L.G.*
AU  - Schendel, D.J.
AU  - Slingluff, C.L. Jr.*
AU  - Song, W.*
AU  - Stroncek, D.F.*
AU  - Tahara, H.*
AU  - Thurin, M.*
AU  - Trinchieri, G.*
AU  - van Der Burg, S.H.*
AU  - Whiteside, T.L.*
AU  - Wigginton, J.M.*
AU  - Marincola, F.*
AU  - Khleif, S.*
AU  - Fox, B.A.*
AU  - Disis, M.L.*
C1  - 6616
C2  - 28977
CY  - Philadelphia, MA
SP  - 3064-3076
TI  - Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers.
JO  - Clin. Cancer Res.
VL  - 17
IS  - 10
PB  - Amer. Assoc. Cancer Res.
PY  - 2011
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Sensitivity of tumor cells towards chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemo-sensitivity remain poorly understood. Here, we aimed at characterizing the role of Caspase-8 for chemo-sensitivity of B- and T-ALL cells. EXPERIMENTAL DESIGN: Primary tumor cells from children with ALL were evaluated for expression levels of the Caspase-8 protein, were amplified in NSG-mice, transfected with siRNA and evaluated for their chemo-sensitivity in vitro. RESULTS: Effective cell death in B- and T-ALL cells depended on the presence of Caspase-8 for the majority of cytotoxic drugs routinely used in anti-leukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of Caspase-8 protein correlated with cell death sensitivity towards defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells with low expression of Caspase-8, methotrexate upregulated the expression of Caspase-8 mediated by the transcription factor p53 suggesting epigenetic silencing of Caspase-8. RNA interference in patient-derived B- and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving methotrexate depended on the presence of Caspase-8. CONCLUSION: Our results indicate that Caspase-8 is crucial for the high anti-leukemic efficiency of numerous routine cytotoxic drugs. Re-expression of epigenetically downregulated Caspase-8 represents a promising approach to increase efficiency of anti-leukemic therapy.
AU  - Ehrhardt, H.
AU  - Wachter, F.
AU  - Maurer, M.
AU  - Stahnke, K.*
AU  - Jeremias, I.
C1  - 6768
C2  - 29247
SP  - 7605-7613
TI  - Important role of Caspase-8 for chemo-sensitivity of ALL cells.
JO  - Clin. Cancer Res.
VL  - 17
IS  - 24
PB  - American Assoc. for Cancer Research
PY  - 2011
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Adoptive therapy with genetically engineered T cells carrying redirected antigen specificity is a new option for the treatment of cancer. This approach is not yet available for metastatic renal cell carcinoma (RCC), due to the scarcity of therapeutically useful reagents. We analyzed tumor-infiltrating lymphocytes (TIL) from RCC to identify T-cell specificities with shared tumor-specific recognition to develop T-cell receptor (TCR)-engineered T lymphocytes for adoptive therapy of RCC. EXPERIMENTAL DESIGN: We established a T-cell clone from TIL that recognized a human leukocyte antigen (HLA)-A2-restricted tumor antigen. The TCR alpha- and beta-chain genes were isolated, modified by codon optimization and murinization, and retrovirally transduced into peripheral blood lymphocytes (PBL). A TCR-expressing indicator line (B3Z-TCR53) was established to screen for antigen prevalence in RCC, other malignancies, and normal cell counterparts. RESULTS: TCR53-engineered PBL recapitulated the specificity of the TIL and showed tumor-specific HLA-A2-restricted effector activities (IFN-gamma, tumor necrosis factor-alpha, interleukin-2, macrophage inflammatory protein-1beta, cytotoxicity). PBL-TCR53 of healthy donors and RCC patients exhibited similar transduction efficiency, expansion, and polyfunctional profile. Using B3Z-TCR53 cells, 130 tumor and normal cells were screened and shared TCR53 peptide: MHC expression was found in >60% of RCC and 25% of tumor lines of other histology, whereas normal tissue cells were not recognized. CONCLUSIONS: To date, TCR53 is the only TCR with shared HLA-A2-restricted recognition of RCC. It fulfills the criteria for utilization in TCR gene therapy and advances T cell-based immunotherapy to patients with RCC and other malignancies expressing the TCR ligand.
AU  - Leisegang, M.*
AU  - Turqueti-Neves, A.
AU  - Engels, B.*
AU  - Blankenstein, T.*
AU  - Schendel, D.J.
AU  - Uckert, W.*
AU  - Nössner, E.
C1  - 5979
C2  - 27731
SP  - 2333-2343
TI  - T-cell receptor gene-modified T cells with shared renal cell carcinoma specificity for adoptive T-cell therapy.
JO  - Clin. Cancer Res.
VL  - 16
IS  - 8
PB  - American Assoc. for Cancer Research
PY  - 2010
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - PURPOSE: Osteosarcoma, the most common primary malignant tumor of the bone, is characterized by complex karyotypes with numerous structural and numerical alterations. Despite attempts to establish molecular prognostic markers at the time of diagnosis, the most accepted predictive factor remains the histologic evaluation of necrosis after neoadjuvant chemotherapy. The present approach was carried out to search for genome-wide recurrent loss of heterozygosity and copy number variations that could have prognostic and therapeutic impact for osteosarcoma patients. EXPERIMENTAL DESIGN: Pretherapeutic biopsy samples of 45 osteosarcoma patients were analyzed using Affymetrix 10K2 high-density single nucleotide polymorphism arrays. Numerical aberrations and allelic imbalances were correlated with the histologically assessed response to therapy and clinical follow-up. RESULTS: The most frequent genomic alterations included amplifications of chromosome 6p21 (15.6%), 8q24 (15.6%, harboring MYC), and 12q14 (11.1%, harboring CDK4), as well as loss of heterozygosity of 10q21.1 (44.4%). All these aberrations and the total degree of heterozygosity of each tumor were significantly associated with an adverse outcome of patients and were used to define a chromosomal alteration staging system with a superior predictive potential compared with the histologic regression grading. CONCLUSIONS: Structural chromosomal alterations detected by single nucleotide polymorphism analysis provide a simple but robust parameter to anticipate response to chemotherapy. The proposed chromosomal alteration staging system might therefore help to better predict the clinical course of osteosarcoma patients at the time of initial diagnosis and to adapt neoadjuvant treatment in patients resistant to the current protocols.
AU  - Smida, J.
AU  - Baumhoer, D.
AU  - Rosemann, M.
AU  - Walch, A.K.
AU  - Bielack, S.*
AU  - Poremba, C.*
AU  - Remberger, K.*
AU  - Korsching, E.*
AU  - Scheurlen, W.*
AU  - Dierkes, C.*
AU  - Burdach, S.*
AU  - Jundt, G.*
AU  - Atkinson, M.J.
AU  - Nathrath, M.
C1  - 5932
C2  - 27524
SP  - 4256-4267
TI  - Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma.
JO  - Clin. Cancer Res.
VL  - 16
IS  - 16
PB  - American Assoc. for Cancer Research
PY  - 2010
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: CBL is a negative regulator of activated receptor tyrosine kinases (RTK). In this study, we determined the frequency of CBL mutations in acute leukemias and evaluated the oncogenic potential of mutant CBL. Experimental Design: The cDNA of 300 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and 82 human leukemic cell lines was screened for aberrations in the linker and RING finger domain of CBL. The oncogenic potential of identified mutants was evaluated in hematopoietic cells. Results: We identified 3 of 279 AML/MDS patients expressing CBL exon 8/9 deletion mutants. Three of four cases at diagnosis expressed deleted transcripts missing exon 8 or exon 8/9. In remission samples a weak or no expression of mutant CBL was detected. No aberrations were found in normal hematopoietic tissues, One of 116 sequenced AML/MDS cases carried a R420G missense mutation. All AML/MDS patients with identified CBL mutants belonged to the core binding factor and 11q deletion AML subtypes. Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. Expression of CBL Delta exon8 and CBL Delta exon8+9 in FLT3-WT-Ba/F3 cells induced growth factor - independent proliferation associated with autophosphorylation of FILT3 and activated the downstream targets signal transducer and activator of transcription 5 (STAT5) and protein kinase B (AKT). FLT3 ligand - dependent hyperproliferation of CBL mutant cells could be abrogated by treatment with the FLT3 PTK inhibitor PKC412 (mid-ostaurin). Conclusion: CBL exon8/9 mutants occur in genetically defined AML/MDS subtypes and transform hematopoietic cells by constitutively activating the FLT3 pathway. This phenotype resembles the one of mutated RTKs and suggests that CBL mutant AML patients might benefit from treatment with FLT3 PTK inhibitors.
AU  - Reindl, C.
AU  - Quentmeier, H.*
AU  - Petropoulos, K.
AU  - Greif, P.A.
AU  - Benthaus, T.*
AU  - Argiropoulos, B.*
AU  - Mellert, G.*
AU  - Vempati, S.
AU  - Duyster, J.*
AU  - Buske, C.
AU  - Bohlander, S.K.
AU  - Humphries, K.R.*
AU  - Hiddemann, W.
AU  - Spiekermann, K.
C1  - 1617
C2  - 26108
SP  - 2238-2247
TI  - CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes.
JO  - Clin. Cancer Res.
VL  - 15
IS  - 7
PB  - Amer Assoc Cancer Research
PY  - 2009
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Peptide receptor radionuclide therapy (PRRT) using somatostatin analogues labeled with beta-particle-emitting isotopes such as 90Y or 177Lu has been a promising treatment strategy for metastasized neuroendocrine tumors. Although remission can be accomplished in a high percentage of neuroendocrine tumors, some tumors do not respond to this treatment. alpha-Emitting isotopes-such as the 10-day half-life alpha-emitting generator nuclide Actinum-225 (225Ac)-are characterized by extremely high cytotoxic activity on the cellular level, and may be superior in the treatment of neuroendocrine tumors not responding to PRRT using beta-emitting isotopes. EXPERIMENTAL DESIGN: Radiolabeling of 225Ac 1,4,7,10-tetra-azacylododecane N,N',N'',N'''-J-tetraacetic acid-Tyr3-octreotide (DOTATOC) was done at pH 5 (60 minutes at 70 degrees C) without further purification. Biodistribution in nude mice bearing AR42J rat pancreas neuroendocrine tumor xenografts were measured for up to 24 hours. Toxicity was tested by weight changes, retention variables (blood urea nitrogen and creatine), and histopathology in mice 7 months after treatment with 10 to 130 kBq (n = 4-5). Therapeutic efficacy was assessed by tumor weighing in animals treated 4 days after xenotransplantation and compared with 177Lu-DOTATOC as a reference. RESULTS: Activities up to 20 kBq had no significant toxic effects in mice. In contrast, activities higher than 30 kBq induced tubular necrosis. Biodistribution studies revealed that 225Ac-DOTATOC effectively accumulated in neuroendocrine xenograft tumors. 225Ac-DOTATOC activities were shown to be nontoxic (12-20 kBq), reduced the growth of neuroendocrine tumors, and showed improved efficacy compared with 177Lu-DOTATOC. CONCLUSIONS: 225Ac might be suitable to improve PRRT in neuroendocrine tumors.
AU  - Miederer, M.*
AU  - Henriksen, G.*
AU  - Alke, A.*
AU  - Mossbrugger, I.
AU  - Quintanilla-Martinez, L.
AU  - Senekowitsch-Schmidtke, R.*
AU  - Essler, M.*
C1  - 3271
C2  - 25380
SP  - 3555-3561
TI  - Preclinical evaluation of the alpha-particle generator nuclide 225Ac for somatostatin receptor radiotherapy of neuroendocrine tumors.
JO  - Clin. Cancer Res.
VL  - 14
IS  - 11
PB  - American Assoc. for Cancer Research
PY  - 2008
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Mutations in the receptor tyrosine kinase FLT3 are found in up to 30% of acute myelogenous leukemia patients and are associated with an inferior prognosis. In this study, we characterized critical tyrosine residues responsible for the transforming potential of active FLT3-receptor mutants and ligand-dependent activation of FLT3-WT. EXPERIMENTAL DESIGN: We performed a detailed structure-function analysis of putative autophosphorylation tyrosine residues in the FLT3-D835Y tyrosine kinase domain (TKD) mutant. All tyrosine residues in the juxtamembrane domain (Y566, Y572, Y589, Y591, Y597, and Y599), interkinase domain (Y726 and Y768), and COOH-terminal domain (Y955 and Y969) of the FLT3-D835Y construct were successively mutated to phenylalanine and the transforming activity of these mutants was analyzed in interleukin-3-dependent Ba/F3 cells. Tyrosine residues critical for the transforming potential of FLT3-D835Y were also analyzed in FLT3 internal tandem duplication mutants (FLT3-ITD)and the FLT3 wild-type (FLT3-WT) receptor. RESULT: The substitution of the tyrosine residues by phenylalanine in the juxtamembrane, interkinase, and COOH-terminal domains resulted in a complete loss of the transforming potential of FLT3-D835Y-expressing cells which can be attributed to a significant reduction of signal tranducer and activator of transcription 5 (STAT5) phosphorylation at the molecular level. Reintroduction of single tyrosine residues revealed the critical role of Y589 and Y591 in reconstituting interleukin-3-independent growth of FLT3-TKD-expressing cells. Combined mutation of Y589 and Y591 to phenylalanine also abrogated ligand-dependent proliferation of FLT3-WT and the transforming potential of FLT3-ITD-with a subsequent abrogation of STAT5 phosphorylation. CONCLUSION: We identified two tyrosine residues, Y589 and Y591, in the juxtamembrane domain that are critical for the ligand-dependent activation of FLT3-WT and the transforming potential of oncogenic FLT3 mutants.
AU  - Vempati, S.
AU  - Reindl, C.
AU  - Wolf, U.
AU  - Kern, R.
AU  - Petropoulos, K.
AU  - Naidu, V.M.
AU  - Buske, C.
AU  - Hiddemann, W.
AU  - Kohl, T.M.
AU  - Spiekermann, K.
C1  - 392
C2  - 25789
SP  - 4437-4445
TI  - Transformation by oncogenic mutants and ligand-dependent activation of FLT3 wild-type requires the tyrosine residues 589 and 591.
JO  - Clin. Cancer Res.
VL  - 14
IS  - 14
PB  - American Assoc. for Cancer Research
PY  - 2008
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - To investigate the expression and regulation of the centrosomal kinase Aurora-A/STK15 (AURKA) in epithelial ovarian cancers and to determine the prognostic and predictive value of this marker for patients with late stage epithelial ovarian cancer treated by distinct adjuvant chemotherapies.Experimental Design: Archival resection specimens of epithelial ovarian cancers (n = 115) and nonneoplastic ovaries (n = 28) were analyzed for AURKA mRNA and protein expression by microdissection and quantitative reverse transcriptase-PCR and immunohistochemistry. AURKA DNA copy numbers were measured by fluorescence in situ hybridization in 37 cases. Statistical evaluation was done with respect to clinicopathologic variables, disease-free survival, and overall survival. AURKA mRNA expression was significantly elevated in cancers (P < 0.001) and correlated with AURKA protein expression (P = 0.0134). Overexpression of AURKA protein was detected in 68 of 107 (63.5%) cases and was linked with increased AURKA DNA copy numbers (P = 0.0141) and centromere 20 aneusomy (P = 0.0137). Moreover, AURKA overexpression was associated with improved overall survival in optimal debulked patients receiving taxol/carboplatin therapy (n = 43, P = 0.018). Finally, in an exploratory approach, patients receiving non–taxane-based therapy, AURKA overexpression was predictive for worse overall survival (n = 30, P = 0.049).AURKA overexpression is seen in the majority of late stage epithelial ovarian cancers, most likely due to increased AURKA DNA copy numbers and/or chromosome 20 aneusomy. Importantly, AURKA overexpression may differentially affect taxane and non–taxane-based adjuvant therapy responses. The study sheds new light on AURKA expression and regulation in epithelial cancers in vivo and specifically shows its value as a clinically relevant marker and as a potential therapeutic target per se.
AU  - Lassmann, S.*
AU  - Shen, Y.*
AU  - Jütting, U.
AU  - Wiehle, P.*
AU  - Walch, A.K.
AU  - Gitsch, G.*
AU  - Hasenburg, A.*
AU  - Werner, M.*
C1  - 4012
C2  - 24544
SP  - 4083-4091
TI  - Predictive value of aurora-A/STK15 expression for late stage epithelial ovarian cancer patients treated by adjuvant chemotherapy.
JO  - Clin. Cancer Res.
VL  - 13
PB  - AACR-American Assoc. for Cancer Research
PY  - 2007
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - The objective of this study was to analyze the hypermethylation of tumor-related gene promoters for an association with therapy response and clinicopathologic features of neoadjuvant-treated gastric cancer patients. Furthermore, we analyzed the relationship of promoter hypermethylation with microsatellite instability and loss of heterozygosity (LOH) of the tumors. Experimental Design: Pretherapeutic biopsies of 61 patients, subsequently treated with cisplatin and 5-fluorouracil, were studied. Methylation analysis of six gene promoters was done using MethyLight technology. Microsatellite analysis was mainly done in previous studies. The methylation frequencies for the analyzed genes were MGMT, 44%; LOX, 53%; p16, 46%, E-cadherin, 30%; 14-3-3{sigma}, 69%; and HPP1, 82%. Concordant methylation of more than three genes was found in 46% of the tumors and was inversely correlated with the LOH rate (P = 9 x 10–5) and associated with female gender (P = 0.049), nonintestinal type tumors (P = 0.04), and a nonproximal tumor location (P = 0.003). No statistically significant association between the methylation of a single gene or the concordant methylation of multiple genes was found with response or survival. However, patients with none or only one methylated gene showed a trend for an increase in survival (5-year survival rate, 83% versus 35%; P = 0.067). Conclusion: The highly significant inverse correlation of promoter methylation and LOH rate reflects major alternative molecular pathways in gastric carcinogenesis. Methylation was not statistically significantly associated with the response to cisplatin/5-fluorouracil–based therapy. However, a concordant methylation of more than three genes defines subgroups of gastric cancer with distinct biological and genetic characteristics.
AU  - Napieralski, R.*
AU  - Ott, K.*
AU  - Kremer, M.*
AU  - Becker, K.*
AU  - Boulesteix, A.-L.*
AU  - Lordick, F.*
AU  - Siewert, J.R.*
AU  - Höfler, H.
AU  - Keller, G.*
C1  - 1923
C2  - 24564
SP  - 5095-5102
TI  - Methylation of tumor-related genes in neoadjuvant-treated gastric cancer: Relation to therapy response and clinicopathologic and molecular features.
JO  - Clin. Cancer Res.
VL  - 13
IS  - 17
PB  - Amer. Assoc. Cancer Res.
PY  - 2007
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Nößner, E.
AU  - Schleypen, J.S.*
C1  - 3654
C2  - 25634
SP  - S. 1621
TI  - The complexity of natural killer cells.
JO  - Clin. Cancer Res.
VL  - 13
IS  - 5
PB  - AACR
PY  - 2007
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - HER2 may be a relevant biomarker in Barrett's cancer. We compared three HER2 laboratory methods, standard fluorescence in situ hybridization (FISH), image-based three-dimensional FISH in thick (16 µm) sections, and immunohistochemistry, to predict patient outcome.Experimental Design: Tissue microarray sections from 124 Barrett's cancer patients were analyzed by standard FISH on thin (4 µm) sections and by image-based three-dimensional FISH on thick (16 µm) sections for HER2 and chromosome-17, as well for p185HER2 by immunohistochemistry. Correlations with clinical and follow-up data were examined. Only three-dimensional FISH on thick (16 µm) sections revealed HER2 gene copy gain to be associated with increased disease-specific mortality (relative risk, 2.1; 95% confidence interval, 1.06-4.26; P = 0.033). In contrast, standard FISH on thin (4 µm) sections and immunohistochemistry failed to predict clinical outcome. Low-level gain of HER2 occurred frequently in Barrett's cancer (?2.5-4.0 HER2 copies, 59.7%; HER2-to-chromosome-17 ratio, ?1.1-2.0; 61.2%) and defined a subpopulation for patient outcome as unfavorable as HER2 gene amplification [disease-free survival, P = 0.017 (HER2 copies)]. This low-level group was neither definable by standard FISH nor immunohistochemistry. No prognostic significance was found for chromosome-17 aneusomy. Low-level copy gains of HER2 define a biologically distinct subpopulation of Barrett's cancer patients. Importantly, these subtle copy number changes are not reliably detected by standard FISH in thin (4 µm) tissue sections, highlighting a thus far unrecognized weakness in HER2 FISH testing. These results should be taken into account for accurate evaluation of biomarkers by FISH and for HER2 FISH testing in tissue sections.
AU  - Rauser, S.
AU  - Weis, R.*
AU  - Braselmann, H.
AU  - Feith, M.*
AU  - Stein, H.J.*
AU  - Langer, R.*
AU  - Hutzler, P.
AU  - Hausmann, M.*
AU  - Lassmann, S.*
AU  - Siewert, J.R.*
AU  - Höfler, H.
AU  - Werner, M.*
AU  - Walch, A.K.
C1  - 3194
C2  - 24548
SP  - 5115-5123
TI  - Significance of HER2 low-level copy gain in Barrett's cancer: Implications for fluorescence in situ hybridization testing in tissues.
JO  - Clin. Cancer Res.
VL  - 13
IS  - 17
PB  - AACR
PY  - 2007
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer. EXPERIMENTAL DESIGN: We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG -1000 bp 5'-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were assessed by multivariate logistic regression. RESULTS: We identified five new germ line variants -815 A>T, -782 G>T, -638 insTC, -267 C>G, and -219 del10bp. Two variants showed in vitro functional effects. The -782T allele showed lower protein binding affinity and lower promoter activity compared with the -782G allele, however, the -815T allele showed higher protein binding affinity and higher promoter activity. The -782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% CI, 1.06-2.34 and OR, 2.21; 95% CI, 1.22-3.99, respectively). CONCLUSION: The ERBB4 -782 G>T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer.
AU  - Rokavec, M.*
AU  - Justenhoven, C.*
AU  - Schroth, W.*
AU  - Istrate, M.A.*
AU  - Haas, S.*
AU  - Fischer, H.P.*
AU  - Vollmert, C.
AU  - Illig, T.
AU  - Hamann, U.*
AU  - Ko, Y.D.*
AU  - Glavac, D.*
AU  - Brauch, H.*
C1  - 4253
C2  - 25008
SP  - 7506-7514
TI  - A novel polymorphism in the promoter region of ERBB4 is associated with breast and colorectal cancer risk.
JO  - Clin. Cancer Res.
VL  - 13
IS  - 24
PB  - AACR
PY  - 2007
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Buters, J.T.M.
C1  - 4081
C2  - 24220
SP  - 7203-7204
TI  - Effective strategies for tumors affecting chemopreventive metabolism.
JO  - Clin. Cancer Res.
VL  - 12
PY  - 2006
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Petrich, T.*
AU  - Quintanilla-Martinez, L.
AU  - Korkmaz, Z.*
AU  - Samson, E.
AU  - Helmeke, H.-J.*
AU  - Meyer, G.J.*
AU  - Knapp, W.H.*
AU  - Pötter, E.*
C1  - 1407
C2  - 23544
SP  - 1342-1348
TI  - Effective cancer therapy with the alpha-particle ermitter [211At]astatine in a mouse model of genetically modified sodium/iodide symporter-expressing tumors.
JO  - Clin. Cancer Res.
VL  - 12
PY  - 2006
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Reiter, R.*
AU  - Gais, P.
AU  - Jütting, U.
AU  - Steuer-Vogt, M.K.*
AU  - Pickhard, A.*
AU  - Bink, K.
AU  - Rauser, S.
AU  - Lassmann, S.*
AU  - Höfler, H.
AU  - Werner, M.*
AU  - Walch, A.K.
C1  - 3676
C2  - 23763
SP  - 5136-5141
TI  - Aurora kinase A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma.
JO  - Clin. Cancer Res.
VL  - 12
PY  - 2006
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - Schleypen, J.S.
AU  - Baur, N.
AU  - Kammerer, R.
AU  - Nelson, P.J.*
AU  - Rohrmann, K.*
AU  - Gröne, E.F.*
AU  - Hohenfellner, M.*
AU  - Haferkamp, A.*
AU  - Pohla, H.
AU  - Schendel, D.J.
AU  - Falk, C.S.
C1  - 5328
C2  - 23940
SP  - 718-725
TI  - Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma.
JO  - Clin. Cancer Res.
VL  - 12
PY  - 2006
SN  - 1078-0432
ER  - 

TY  - JOUR
AU  - von Luettichau, I.*
AU  - Nathrath, M.
AU  - Burdach, S.*
AU  - Huss, R.*
AU  - Segerer, S.*
AU  - Nelson, P.J.*
C1  - 833
C2  - 23964
SP  - 5253-5254
TI  - Mononuclear infiltrates in osteosarcoma and chemokine receptor expression.
JO  - Clin. Cancer Res.
VL  - 12
PY  - 2006
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: A renal cell carcinoma (RCC) line, RCC-26, has been identified as a suitable candidate for development of an allogeneic tumor cell vaccine based on its expression of a variety of tumor-associated antigens (TAA). To improve immunogenicity, RCC-26 cells were genetically engineered to express CD80 alone or in combination with interleukin (IL)-2 or IL-7. The effect of these modifications on proliferation, function, and survival of autologous and allogeneic tumor-specific CTLs was assessed.
      
      	Experimental Design: RCC-26 sublines expressing different transgenes were tested for their capacity to reactivate cytokine secretion and cytotoxicity in autologous tumor-infiltrating lymphocytes, to improve proliferation and survival of tumor-associated T cells present in autologous peripheral blood, and to induce tumor-associated responses in naive allogeneic lymphocytes. The expression of several common TAA was quantitated in the RCC-26 sublines using reverse transcription-PCR to identify surrogate markers for immune monitoring in clinical trials.
      
      	Results: Gene-modified RCC-26 cells showed enhanced immunogenicity. CD80 expression was necessary to induce RCC-associated CTL in blood of healthy allogeneic donors. It also improved proliferation of autologous effector-memory T cells. Further enhancement was achieved with IL-2 through induction of the antiapoptosis protein Bcl-xL. The candidate vaccine lines overexpressed several common TAA that are suitable markers for immune monitoring.
      
      	Conclusions: RCC-26 cells coexpressing CD80 and cytokine transgenes display improved immunogenic characteristics, supporting their use as allogeneic tumor cell vaccines for HLA-A2-matched patients with metastatic RCC.
AU  - Frankenberger, B.
AU  - Pohla, H.
AU  - Nößner, E.
AU  - Willimsky, G.*
AU  - Papier, B.
AU  - Pezzutto, A.*
AU  - Kopp, J.*
AU  - Oberneder, R.
AU  - Blankenstein, T.
AU  - Schendel, D.J.
C1  - 2277
C2  - 23079
SP  - 1733-1742
TI  - Influence of CD80 Interleukin2, and Interleukin-7 Expression in Human Renal Cell Carcinoma on the Expression, Function, and Survival of Tumor-Specific CTLs.
JO  - Clin. Cancer Res.
VL  - 11
IS  - 5
PY  - 2005
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Metastases in distant organs are the major cause of death for cancer patients, and bone marrow is a prominent homing organ for early disseminated cancer cells. However, it remains still unclear which of these cells evolve into overt metastases. We therefore established a new approach based on the analysis of viable and proliferating cancer cells by single-cell comparative genomic hybridization.
      
      	Experimental Design: The bone marrow of early-stage breast tumor patients (pN0M0) was screened for tumor cells by immunostaining. By applying special short-term culturing, we selected for viable and proliferative tumor cells. The short-term culturing allowed us to evaluate the proliferative potential of micrometastatic cells, which we had previously shown to represent an independent prognostic marker. We assessed genomic changes in single disseminated cancer cells by single-cell comparative genomic hybridization.
      
      	Results: We found that these viable disseminated cancer cells already had a plethora of copy number changes in their genome. All of these cells showed chromosomal copy number changes with a substantial intercellular heterogeneity and differences to the matching primary tumors.
      
      	Conclusions: The established experimental strategy might pave the way for the identification of metastatic stem cells in cancer patients. Our preliminary results support the new concept that early disseminated cancer cells evolve independently from their primary tumor.
AU  - Gangnus, R.*
AU  - Langer, S.
AU  - Breit, E.*
AU  - Pantel, K.*
AU  - Speicher, M.R.
C1  - 2999
C2  - 21817
SP  - 3457-3464
TI  - Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients.
JO  - Clin. Cancer Res.
VL  - 10
IS  - 10
PY  - 2004
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Modulation of the heat shock protein (HSP) response affects sensitivity to therapeutic agents in cancer. Here, drugs with anti-inflammatory potential (cyclooxygenase 1/2 inhibitors) and peroxidase proliferator-activated receptor-γ agonists were analyzed for their capacity to affect Hsp70 expression in human cancer cells with a divergent Hsp70 membrane expression pattern.
      
      	Experimental Design: In dose kinetics, the nonlethal concentration of acetyl-salicyl acid, celecoxib, rofecoxib, and the insulin-sensitizer pioglitazone was identified for the human adenocarcinoma cell line CX−. With the exception of CLX, which was diluted in DMSO, all reagents were dissolved in water. After treatment with the different compounds at nontoxic concentrations for 6 h, followed by a 1-h recovery period, the cytosolic Hsp70 levels were measured in CX-2 and CX− tumor cells by Western blot analysis. Fold increase was calculated in relation to the housekeeping protein tubulin. Membrane-bound Hsp70 was analyzed by flow cytometry using a FITC-labeled Hsp70-specific monoclonal antibody. Untreated cells and cells incubated with equivalent amounts of the diluting agents served as controls. The immunological function was tested in granzyme B apoptosis assays, standard 51Cr release assays, and antibody blocking studies.
      
      	Results: Compared with aqua dest, the cytoplasmic amount of Hsp70 was equally enhanced in CX-2 and CX− cells by all compounds. An increase in membrane-bound Hsp70, detected selectively in CX− cells, corresponded to an enhanced sensitivity to granzyme B- and natural killer cell-mediated kill that was blockable by using a Hsp70-specific antibody.
      
      	Conclusions: Although increase in cytosolic Hsp70 levels conferred resistance to further stress, membrane-bound Hsp70 rendered tumor cells more sensitive to the immunological attack mediated by granzyme B and natural killer cells. Our data provide a biological rational for combining anti-inflammatory drugs with immunotherapy in cancer therapy.
AU  - Gehrmann, M.*
AU  - Brunner, M.*
AU  - Pfister, K.*
AU  - Reichle, A.*
AU  - Kremmer, E.
AU  - Multhoff, G.*
C1  - 2991
C2  - 22098
SP  - 3354-3364
TI  - Differential up-regulation of cytosolic and membrane-bound heat shock protein 70 in tumor cells by anti-inflammatory drugs.
JO  - Clin. Cancer Res.
VL  - 10
IS  - 10
PY  - 2004
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Hyperthermia increases the efficiency of various chemotherapeutic drugs and is administered as an adjunct to chemotherapy for the treatment of cancer patients. The temperature-dependent effect can be strongly increased by the use of temperature-sensitive liposomes in combination with regional hyperthermia, which specifically releases the entrapped drug in the heated tumor tissue. The novel lipid 1.2-dipaimitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG), which is closely related to the naturally occurring 1.2-dipalmitoyi-sn-glycero-3-phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine and 1.2-distearoyi-sn-glycero-3-phosphocholine provides long-circulating temperature-sensitive liposomes with favorable properties under mildly hyperthermic conditions (41-42degreesC). DPPGOG facilitates temperature-triggered drug release from these liposomes (diameter, 175 nm) and leads to a substantially prolonged plasma half-life for the encapsulated drug with t(1/2) = 9.6 h in hamsters and t(1/2) = 5.0 h in rats. Quantitative fluorescence microscopy of amelanotic melanoma grown in the transparent dorsal skin fold chamber of hamsters demonstrated a favorable drug accumulation in heated tissue after i.v. application of these liposomes (42degreesC for 1 h). The mean area under the curve for tissue drug concentration was increased by more than sixfold by application of the new liposomes compared with nonliposomal drug delivery. In summary, we present a new DPPGOG-based liposomal formulation enabling long circulation time combined with fast and efficient drug release under mild hyperthermia. This adds positively to the results with lipid-grafted polyethylenglycol used thus far in temperature-sensitive liposomes and widens the possibilities for clinical applications.
AU  - Lindner, L.H.*
AU  - Eichhorn, M.E.*
AU  - Eibl, H.*
AU  - Teichert, N.*
AU  - Schmitt-Sody, M.*
AU  - Issels, R.D.
AU  - Dellian, M.*
C1  - 2770
C2  - 21761
SP  - 2168-2178
TI  - Novel temperature-sensitive liposomes with prolonged circulation time.
JO  - Clin. Cancer Res.
VL  - 10
IS  - 6
PY  - 2004
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Trioma cells are lymphoma cells that have been fused to a hybridoma and have thereby been modified to express an immunoglobulin directed against surface receptors of antigen-presenting cells. Trioma cells that potentially include all lymphoma-derived antigens will be targeted to professional antigen-presenting cells in vivo. This allows uptake, processing, and presentation of tumor-derived antigens to T lymphocytes. In a mouse model, vaccination with trioma cells conferred long-lasting, T cell-dependent tumor immunity and was even able to eradicate established lymphomas. Here, we investigated whether this potent approach is effective in the human system.
      
      	Experimental design: Malignant cells from 11 patients with B cell chronic-lymphocytic leukemia (B-CLL) were fused to an anti-Fc receptor hybridoma. The resulting trioma cells were extensively characterized with respect to their clonal origin. The induction of autologous tumor-specific T lymphocytes in the presence of trioma and antigen-presenting cells was examined in vitro by determining cytokine secretion in coculture assays.
      
      	Results: In seven cases, trioma cells could successfully be generated from B-CLL cells. Stimulation of autologous lymphocytes with trioma cells induced a leukemia-specific T-cell response. Immunostimulatory trioma cells were also obtained from two patients with solid B-cell lymphoma.
      
      	Conclusions: Trioma-mediated immunization may be a promising adjuvant treatment of human malignancies of the B-cell lineage, particularly of B-CLL, which has still a very poor prognosis. Our in vitro results pave the way for clinical application.
      
      	 
AU  - Wahl, U.
AU  - Nössner, E.
AU  - Kronenberger, K.
AU  - Gangnus, R.*
AU  - Pohla, H.*
AU  - Staege, M.S.
AU  - Kolb, H.-J.
AU  - Hallek, M.
AU  - Mocikat, R.
C1  - 10267
C2  - 21220
SP  - 4240-4246
TI  - Vaccination against B-cell Chronic Lymphocytic Leukemia with Trioma Cells : Preclinical Evaluation.
JO  - Clin. Cancer Res.
VL  - 9
IS  - 11
PY  - 2003
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Altered and deregulated cyclin-dependent kinase (cdk) activity is now believed to play a major role in the pathogenesis of head and neck squamous cell carcinomas (HNSCC), thus providing a suitable cellular target for therapeutic intervention. UCN-01 (7-hydroxy-staurosporine), a known protein kinase C and cdk modulator, demonstrates antiproliferative and antitumor properties in many experimental tumor models and may represent a potential candidate to test in HNSCC. In this study, UCN-01 displayed potent antiproliferative properties (IC50 of ∼17–80 nm) in HNSCC cells. Cell cycle analysis revealed that UCN-01 treatment of HNSCC cells for 24 h leads to a G1 block with a concomitant loss of cells in S and G2-M and the emerging sub-G1 cell population, confirmed to be apoptotic by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. Additional in vitro studies demonstrated a G1 arrest that was preceded by depletion in cyclin D3, elevation of p21WAF1 and p27KIP1 leading to a loss in activity of G1 cdks (cdk2, cdk4), and reduction in pRb phosphorylation. Antitumor properties of UCN-01 were also assessed in vivo by treating HN12 xenografts (7.5 mg/kg/i.p./daily) with UCN-01 for 5 consecutive days. Total sustained abolition of tumor growth (P < 0.00001) was obtained with only one cycle of UCN-01 treatment. Terminal deoxynucleotidyl transferase-mediated nick end labeling staining of xenograft samples revealed a higher incidence of apoptosis in treated tissues when compared with control. Additional tissue analysis demonstrated that elevated p27KIP1 with minimal increase in p21WAF1 and reduced cyclin D3 levels were readily detected in those animals treated with UCN-01, similar to those observed in HNSCC cells. Thus, UCN-01 exhibits both in vitro and in vivo antitumor properties in HNSCC models, and these effects are associated with a decrease in cyclin D3 and an increase in p27KIP1 protein levels, thus providing appropriate surrogate markers to follow treatment efficacy in vivo and, therefore, a suitable drug candidate for treating HNSCC patients.
AU  - Patel, V.*
AU  - Lahusen, T.*
AU  - Leethanakul, C.*
AU  - Igishi, T.*
AU  - Kremer, M.
AU  - Quintanilla-Martinez, L.
AU  - Ensley, J.F.*
AU  - Sausville, E.A.*
AU  - Gutkind, J.S.*
AU  - Senderowicz, A.M.*
C1  - 21983
C2  - 20511
SP  - 3549-3560
TI  - Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27KIP1.
JO  - Clin. Cancer Res.
VL  - 8
IS  - 11
PY  - 2002
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Purpose: Overexpression of cyclin D1 mRNA and protein as a result of the chromosomal translocation t(11;14)(q13;q32) is a highly specific molecular marker of mantle cell lymphoma, but cyclin D1 dysregulation can also be found in other B-cell neoplasias. The aim of the study was to develop a precise and reliable tool for quantitation of cyclin D1 mRNA suitable for archival clinical specimens. Experimental Design: A real-time reverse transcription-PCR (RT-PCR) assay was used to quantitate cyclin D1 mRNA copy numbers. Using 2000 microdissected cells as template, 104 formalin-fixed, paraffin-embedded lymph node, spleen, and decalcified bone marrow biopsies from a panel of 95 cases of B-cell non-Hodgkin’s lymphomas (B-NHLs) were analyzed. In addition, cyclin D1 protein expression was assessed by immunohistochemistry. Results: Strong cyclin D1 mRNA overexpression was detected in mantle cell lymphomas (23 of 23), hairy cell leukemias (5 of 19), and multiple myelomas (7 of 23) with particularly high levels in 2 of the latter cases. Intermediate transcript levels were found in 5 of 23 multiple myelomas and 7 of 19 hairy cell leukemias. B-cell chronic lymphocytic leukemias (10 of 10), follicular lymphomas (9 of 9), mucosa-associated lymphoid tissue lymphomas (5 of 5) and reactive lymphoid tissues with the exception of normal spleen had no or very low cyclin D1 expression. In comparison with real-time RT-PCR, immunohistochemistry showed a lower level of sensitivity, more variability, and did not allow accurate quantitation. Conclusions: Real-time RT-PCR for cyclin D1 mRNA is an excellent tool for the differential diagnosis of B-NHLs and, in combination with microdissection, a powerful approach for retrospective trials using archival clinical specimens as tissue source. Furthermore, real-time RT-PCR may help to identify subgroups of B-NHLs according to cyclin D1 mRNA copy numbers and to investigate the possible influence of different chromosomal breakpoints on cyclin D1 expression.
AU  - Specht, K.
AU  - Kremer, M.*
AU  - Müller, U.
AU  - Dirnhofer, S.*
AU  - Rosemann, M.
AU  - Höfler, H.
AU  - Quintanilla-Martinez, L.
AU  - Fend, F.*
C1  - 21951
C2  - 20469
SP  - 2902-2911
TI  - Identification of Cyclin D1 mRNA Overexpression in B-Cell Neoplasias by Real-Time Reverse Transcription-PCR of Microdissected Paraffin Sections.
JO  - Clin. Cancer Res.
VL  - 8
IS  - 9
PY  - 2002
SN  - 1078-0432
ER  - 

TY  - JOUR
AB  - Some human tumor cells exhibit deficient expression of the peptide transporters TAP1 and TAP2 and of the proteasome subunits low molecular weight protein (LMP)-2 and LMP-7, which could be partially restored by cytokine treatment. Here, we show that IFN-gamma stimulation of human renal cell carcinoma lines increased the MHC class I, transporter associated with antigen processing (TAP), and LMP transcript and protein levels, but TAP and LMP expression are more rapidly induced by IFN-gamma than MHC class I molecules. No correlation between the level of induction of the MHC class I antigen presentation genes and IFN sensitivity/resistance was detected. The IFN-gamma-mediated increase of MHC class I, TAP-1, and LMP-2 expression was independent of de novo protein synthesis. Analysis of the dual TAP-1/LMP-2 promoter activity revealed that TAP-1 and LMP-2 expression are controlled by IFN-gamma at the transcriptional level. Site-specific mutations in the IFN-gamma-responsive element of the TAP-1/LMP-2 promoter blocked induction by IFN-gamma. Thus, the IFN-gamma-mediated coordinated transcriptional up-regulation of TAP-1 and LMP-2 expression occurs through the use of a common regulatory element, which might result in enhanced recognition of renal cell carcinoma cells by the immune system.
AU  - Seliger, B.*
AU  - Hammers, S.*
AU  - Höhne, A.*
AU  - Zeidler, R.
AU  - Knuth, A.*
AU  - Gerharz, C.D.*
AU  - Huber, C.*
C1  - 27622
C2  - 32771
SP  - 573-578
TI  - IFN-gamma-mediated coordinated transcriptional regulation of the human TAP-1 and LMP-2 genes in human renal cell carcinoma.
JO  - Clin. Cancer Res.
VL  - 3
IS  - 4
PY  - 1997
SN  - 1078-0432
ER  -