bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Resection of Non–Small Cell Lung Cancers Reverses Tumor-Induced Gene Expression Changes in the Peripheral Immune System
Authors: Kossenkov Andrew V. , Vachani Anil , Chang Celia , Nichols Calen , Billouin Shere , Horng Wenhwai , Rom William N. , Albelda Steven M. , Showe Michael K. , Showe Louise C.
Published: April 2023

Abstract
Purpose: To characterize the interactions of non–small cell lung cancer (NSCLC) tumors with the immune system at the level of mRNA and microRNA (miRNA) expression and to define expression signatures that characterize the presence of a malignant tumor versus a nonmalignant nodule.

Experimental Design: We have examined the changes of both mRNA and miRNA expression levels in peripheral blood mononuclear cells (PBMC) between paired samples collected from NSCLC patients before and after tumor removal using Illumina gene expression arrays.

Results: We found that malignant tumor removal significantly changes expression of more than 3,000 protein-coding genes, especially genes in pathways associated with suppression of the innate immune response, including natural killer cell signaling and apoptosis-associated ceramide signaling. Binding sites for the ETS domain transcription factors ELK1, ELK4, and SPI1 were enriched in promoter regions of genes upregulated in the presence of a tumor. Additional important regulators included five miRNAs expressed at significantly higher levels before tumor removal. Repressed protein-coding targets of those miRNAs included many transcription factors, several involved in immunologically important pathways. Although there was a significant overlap in the effects of malignant tumors and benign lung nodules on PBMC gene expression, we identified one gene panel which indicates a tumor or nodule presence and a second panel that can distinguish malignant from nonmalignant nodules.

Conclusions: A tumor presence in the lung influences mRNA and miRNA expression in PBMC and this influence is reversed by tumor removal. These results suggest that PBMC gene expression signatures could be used for lung cancer diagnosis. Clin Cancer Res; 17(18); 5867–77. ©2011 AACR.
Data from Pretargeted Radioimmunotherapy Using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma
Authors: Park Steven I. , Shenoi Jaideep , Frayo Shani M. , Hamlin Donald K. , Lin Yukang , Wilbur D. Scott , Stayton Patrick S. , Orgun Nural , Hylarides Mark , Buchegger Franz , Kenoyer Aimee L. , Axtman Amanda , Gopal Ajay K. , Green Damian J. , Pagel John M. , Press Oliver W.
Published: April 2023

Abstract
Purpose: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, “endogenous” biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.

Experimental Design: The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified, and compared in studies using athymic mice bearing Ramos lymphoma xenografts.

Results: Biodistribution studies showed delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by 111In-DOTA-bis-biotin [6.2 ± 1.7% of the injected dose per gram (%ID/gm) of tumor 24 hours after Y43A-SAv FP and 5.6 ± 2.2%ID/g with S45A-SAv FP] than in mice on normal diets pretargeted with WT-SAv FP (2.5 ± 1.6%ID/g; P = 0.01). These superior biodistributions translated into superior antitumor efficacy in mice treated with mutant FPs and 90Y-DOTA-bis-biotin [tumor volumes after 11 days: 237 ± 66 mm3 with Y43A-SAv, 543 ± 320 mm3 with S45A-SAv, 1129 ± 322 mm3 with WT-SAv, and 1435 ± 212 mm3 with control FP (P < 0.0001)].

Conclusions: Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high. Clin Cancer Res; 17(23); 7373–82. ©2011 AACR.
Data from Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer
Authors: de Weger Vincent A. , Turksma Annelies W. , Voorham Quirinus J.M. , Euler Zelda , Bril Herman , van den Eertwegh Alfons J. , Bloemena Elisabeth , Pinedo Herbert M. , Vermorken Jan B. , van Tinteren Harm , Meijer Gerrit A. , Hooijberg Erik
Published: April 2023

Abstract
Purpose: Active specific immunotherapy (ASI) consisting of an autologous tumor cell vaccine given as adjuvant treatment has been shown to improve recurrence-free survival of patients with colon cancer. The aim of the current retrospective study was to investigate whether the beneficial effects of ASI given as adjuvant treatment correlated with microsatellite instability (MSI), which is considered an important biologic determinant of colon cancer.

Experimental Design: Microsatellite status was assessed on archival tumor material from patients with stage II and III colon cancer. Microsatellite status was next associated with clinical outcome in control and ASI treatment groups using Kaplan–Meier analysis.

Results: We identified 162 (83%) microsatellite-stable tumors (MSS) and 34 (17%) MSI tumors. Patients with MSI tumors did well in recurrence-free interval (RFI) as well as disease-specific survival (DSS) irrespective of treatment arm and tumor stage. Patients with MSI tumors had significantly fewer recurrences and prolonged DSS than those with MSS tumors. Patients with MSS Dukes B tumors who received ASI treatment showed a significantly improved recurrence-free survival compared with controls. ASI treatment did not improve recurrence-free interval or DSS for patients with MSS Dukes C tumors.

Conclusion: This retrospective study indicated that patients with MSI tumors did well, irrespective of treatment arm and tumor stage. The data also indicate that the clinical benefit, measured as recurrence-free survival, from adjuvant ASI treatment of patients with colon cancer was restricted to patients with MSS Dukes B tumors. Clin Cancer Res; 18(3); 882–9. ©2011 AACR.
Data from Modulation of Genetic and Epigenetic Biomarkers of Colorectal Cancer in Humans by Black Raspberries: A Phase I Pilot Study
Authors: Wang Li-Shu , Arnold Mark , Huang Yi-Wen , Sardo Christine , Seguin Claire , Martin Edward , Huang Tim H.-M. , Riedl Ken , Schwartz Steven , Frankel Wendy , Pearl Dennis , Xu Yiqing , Winston John , Yang Guang-Yu , Stoner Gary
Published: April 2023

Abstract
Purpose: This study evaluated the effects of black raspberries (BRBs) on biomarkers of tumor development in the human colon and rectum including methylation of relevant tumor suppressor genes, cell proliferation, apoptosis, angiogenesis, and expression of Wnt pathway genes.

Experimental Design: Biopsies of adjacent normal tissues and colorectal adenocarcinomas were taken from 20 patients before and after oral consumption of BRB powder (60 g/d) for 1–9 weeks. Methylation status of promoter regions of five tumor suppressor genes was quantified. Protein expression of DNA methyltransferase 1 (DNMT1) and genes associated with cell proliferation, apoptosis, angiogenesis, and Wnt signaling were measured.

Results: The methylation of three Wnt inhibitors, SFRP2, SFRP5, and WIF1, upstream genes in Wnt pathway, and PAX6a, a developmental regulator, was modulated in a protective direction by BRBs in normal tissues and in colorectal tumors only in patients who received BRB treatment for an average of 4 weeks, but not in all 20 patients with 1–9 weeks of BRB treatment. This was associated with decreased expression of DNMT1. BRBs modulated expression of genes associated with Wnt pathway, proliferation, apoptosis, and angiogenesis in a protective direction.

Conclusions: These data provide evidence of the ability of BRBs to demethylate tumor suppressor genes and to modulate other biomarkers of tumor development in the human colon and rectum. While demethylation of genes did not occur in colorectal tissues from all treated patients, the positive results with the secondary endpoints suggest that additional studies of BRBs for the prevention of colorectal cancer in humans now appear warranted. Clin Cancer Res; 17(3); 598–610. ©2010 AACR.
Data from Oncogene Mutation Profiling of Pediatric Solid Tumors Reveals Significant Subsets of Embryonal Rhabdomyosarcoma and Neuroblastoma with Mutated Genes in Growth Signaling Pathways
Authors: Shukla Neerav , Ameur Nabahet , Yilmaz Ismail , Nafa Khedoudja , Lau Chyau-Yueh , Marchetti Angela , Borsu Laetitia , Barr Frederic G. , Ladanyi Marc
Published: April 2023

Abstract
Purpose: In contrast to the numerous broad screens for oncogene mutations in adult cancers, few such screens have been conducted in pediatric solid tumors. To identify novel mutations and potential therapeutic targets in pediatric cancers, we conducted a high-throughput Sequenom-based analysis in large sets of several major pediatric solid cancers, including neuroblastoma, Ewing sarcoma, rhabdomyosarcoma (RMS), and desmoplastic small round cell tumor (DSRCT).

Experimental Design: We designed a highly multiplexed Sequenom-based assay to interrogate 275 recurrent mutations across 29 genes. Genomic DNA was extracted from 192 neuroblastoma, 75 Ewing sarcoma, 89 RMS, and 24 DSRCT samples. All mutations were verified by Sanger sequencing.

Results: Mutations were identified in 13% of neuroblastoma samples, 4% of Ewing sarcoma samples, 21.1% of RMS samples, and no DSRCT samples. ALK mutations were present in 10.4% of neuroblastoma samples. The remainder of neuroblastoma mutations involved the BRAF, RAS, and MAP2K1 genes and were absent in samples harboring ALK mutations. Mutations were more common in embryonal RMS (ERMS) samples (28.3%) than alveolar RMS (3.5%). In addition to previously identified RAS and FGFR4 mutations, we report for the first time PIK3CA and CTNNB1 (β-catenin) mutations in 5% and 3.3% of ERMS, respectively.

Conclusions: In ERMS, Ewing sarcoma, and neuroblastoma, we identified novel occurrences of several oncogene mutations recognized as drivers in other cancers. Overall, neuroblastoma and ERMS contain significant subsets of cases with nonoverlapping mutated genes in growth signaling pathways. Tumor profiling can identify a subset of pediatric solid tumor patients as candidates for kinase inhibitors or RAS-targeted therapies. Clin Cancer Res; 18(3); 748–57. ©2011 AACR.
Data from Effective Targeting of Triple-Negative Breast Cancer Cells by PF-4942847, a Novel Oral Inhibitor of Hsp 90
Authors: Mehta Pramod P. , Whalen Pamela , Baxi Sangita M. , Kung Pei-Pei , Yamazaki Shinji , Yin Min-Jean
Published: April 2023

Abstract
Purpose: Triple-negative breast cancer (TNBC) patients have poor prognoses and survival outcomes such that the development of new targeted therapies is in strong demand. Mechanisms associated with high proliferation and aggressive tumor progression, such as PI3K/PTEN aberration, epidermal growth factor receptor (EGFR) overexpression, and cell-cycle upregulation, play important roles in TNBC. The molecular chaperone Hsp90 is required for the conformational maturation and stability of a variety of proteins in multiple pathways, such as EGFR, AKT, Raf, cdk4, etc. Therefore, an Hsp90 inhibitor may show therapeutic benefit in TNBC by targeting multiple pathways.

Experimental Design: The novel oral Hsp90 inhibitor PF-4942847 was characterized in multiple in vitro and in vivo assays to determine its antitumor activity in TNBC cell lines. In addition, the correlation of AKT degradation and Hsp70 induction in host peripheral blood lymphocytes (PBL) and xenograft tumors was determined.

Results: PF-4942847 induces degradation of multiple client proteins, cell-cycle block, apoptosis, and inhibits cell proliferation in TNBC lines, subsequently leading to tumor growth inhibition in mouse xenograft models. The correlation of AKT degradation and Hsp70 induction between PBLs and xenograft tumors reveals a differential modulation of Hsp90 activity between host and tumor tissues, and suggests that AKT degradation in PBLs may serve as a pharmacodynamic biomarker in future clinical development.

Conclusions: The novel oral Hsp90 inhibitor, PF-4942847, is a candidate for clinical development in TNBC by collaboratively targeting multiple signaling pathways. In addition, AKT degradation in PBLs may serve as a biomarker in clinical development. Clin Cancer Res; 17(16); 5432–42. ©2011 AACR.
Data from CPTH6, a Thiazole Derivative, Induces Histone Hypoacetylation and Apoptosis in Human Leukemia Cells
Authors: Trisciuoglio Daniela , Ragazzoni Ylenia , Pelosi Andrea , Desideri Marianna , Carradori Simone , Gabellini Chiara , Maresca Giovanna , Nescatelli Riccardo , Secci Daniela , Bolasco Adriana , Bizzarri Bruna , Cavaliere Chiara , D'Agnano Igea , Filetici Patrizia , Ricci-Vitiani Lucia , Rizzo Maria Giulia , Del Bufalo Donatella
Published: April 2023

Abstract
Purpose: We previously identified novel thiazole derivatives able to reduce histone acetylation and histone acetyltransferase (HAT) activity in yeast. Among these compounds, 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) has been selected and used throughout this study.

Experimental Design: The effect of CPTH6 on histone acetylation, cell viability and differentiation, cell-cycle distribution, and apoptosis in a panel of acute myeloid leukemia and solid tumor cell lines has been evaluated.

Results: Here, we showed that CPTH6 leads to an inhibition of Gcn5 and pCAF HAT activity. Moreover, it inhibits H3/H4 histones and α-tubulin acetylation of a panel of leukemia cell lines. Concentration- and time-dependent inhibition of cell viability, paralleled by accumulation of cells in the G0/G1 phase and depletion from the S/G2M phases, was observed. The role of mitochondrial pathway on CPTH6-induced apoptosis was shown, being a decrease of mitochondrial membrane potential and the release of cytochrome c, from mitochondria to cytosol, induced by CPTH6. Also the involvement of Bcl-2 and Bcl-xL on CPTH6-induced apoptosis was found after overexpression of the two proteins in leukemia cells. Solid tumor cell lines from several origins were shown to be differently sensitive to CPTH6 treatment in terms of cell viability, and a correlation between the inhibitory efficacy on H3/H4 histones acetylation and cytotoxicity was found. Differentiating effect on leukemia and neuroblastoma cell lines was also induced by CPTH6.

Conclusions: These results make CPTH6 a suitable tool for discovery of molecular targets of HAT and, potentially, for the development of new anticancer therapies, which warrants further investigations. Clin Cancer Res; 18(2); 475–86. ©2011 AACR.
Data from Predictive and Prognostic Roles of BRAF Mutation in Stage III Colon Cancer: Results from Intergroup Trial CALGB 89803
Authors: Ogino Shuji , Shima Kaori , Meyerhardt Jeffrey A. , McCleary Nadine J. , Ng Kimmie , Hollis Donna , Saltz Leonard B. , Mayer Robert J. , Schaefer Paul , Whittom Renaud , Hantel Alexander , Benson Al B. , Spiegelman Donna , Goldberg Richard M. , Bertagnolli Monica M. , Fuchs Charles S.
Published: April 2023

Abstract
Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer.

Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status.

Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05–2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25–1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72–1.46).

Conclusions:BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy. Clin Cancer Res; 18(3); 890–900. ©2011 AACR.
Data from Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants
Authors: Mostaghel Elahe A. , Marck Brett T. , Plymate Stephen R. , Vessella Robert L. , Balk Stephen , Matsumoto Alvin M. , Nelson Peter S. , Montgomery R. Bruce
Published: April 2023

Abstract
Purpose: Abiraterone is a potent inhibitor of the steroidogenic enzyme CYP17A1 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The effectiveness of abiraterone in reducing tumor androgens is not known, nor have mechanisms contributing to abiraterone resistance been established.

Experimental Design: We treated human CRPC xenografts with abiraterone and measured tumor growth, tissue androgens, androgen receptor (AR) levels, and steroidogenic gene expression versus controls.

Results: Abiraterone suppressed serum PSA levels and improved survival in two distinct CRPC xenografts: median survival of LuCaP35CR improved from 17 to 39 days (HR = 3.6, P = 0.0014) and LuCaP23CR from 14 to 24 days (HR = 2.5, P = 0.0048). Abiraterone strongly suppressed tumor androgens, with testosterone (T) decreasing from 0.49 ± 0.22 to 0.03 ± 0.01 pg/mg (P < 0.0001), and from 0.69 ± 0.36 to 0.03 ± 0.01 pg/mg (P = 0.002) in abiraterone-treated 23CR and 35CR, respectively, with comparable decreases in tissue DHT. Treatment was associated with increased expression of full-length AR (ARFL) and truncated AR variants (ARFL 2.3-fold, P = 0.008 and ARdel567es 2.7-fold, P = 0.036 in 23 CR; ARFL 3.4-fold, P = 0.001 and ARV7 3.1-fold, P = 0.0003 in 35CR), and increased expression of the abiraterone target CYP17A1 (∼2.1-fold, P = 0.0001 and P = 0.028 in 23CR and 35CR, respectively) and transcript changes in other enzymes modulating steroid metabolism.

Conclusions: These studies indicate that abiraterone reduces CRPC growth via suppression of intratumoral androgens and that resistance to abiraterone may occur through mechanisms that include upregulation of CYP17A1, and/or induction of AR and AR splice variants that confer ligand-independent AR transactivation. Clin Cancer Res; 17(18); 5913–25. ©2011 AACR.
Data from Combination of a Novel Gene Expression Signature with a Clinical Nomogram Improves the Prediction of Survival in High-Risk Bladder Cancer
Authors: Riester Markus , Taylor Jennifer M. , Feifer Andrew , Koppie Theresa , Rosenberg Jonathan E. , Downey Robert J. , Bochner Bernard H. , Michor Franziska
Published: April 2023

Abstract
Purpose: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder.

Experimental Design: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence.

Results: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean ΔC-statistic: 0.14; 95% confidence interval (CI), 0.01–0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI, −0.04–0.20; P < 0.005).

Conclusions: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting. Clin Cancer Res; 18(5); 1323–33. ©2012 AACR.
Data from Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma
Authors: Finn Richard S. , Kang Yoon-Koo , Mulcahy Mary , Polite Blase N. , Lim Ho Yeong , Walters Ian , Baudelet Christine , Manekas Demetrios , Park Joong-Won
Published: April 2023

Abstract
Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment.

Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression-free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability.

Results: Forty-six patients were treated. Best responses to treatment with brivanib (N = 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension.

Conclusion: Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib. Clin Cancer Res; 18(7); 2090–8. ©2012 AACR.
Data from To DNA or not to DNA? That Is the Question, When It Comes to Molecular Subtyping for the Clinic!
Authors: Smeets Serge J. , Harjes Ulrike , van Wieringen Wessel N. , Sie Daoud , Brakenhoff Ruud H. , Meijer Gerrit A. , Ylstra Bauke
Published: April 2023

Abstract
Genome-wide RNA expression profiling has yielded tumor subtypes with strong predictive or prognostic value for a wide variety of cancers. Recently, for breast cancer two RNA expression classifiers have been adopted by the World Health Organization (WHO) and approved by the Food and Drug Administration (FDA). Also on the basis of DNA copy number profiles, tumor subtypes with different prognosis have been described, but have not yet led to clinical implementation. The genomic revolution caused by next generation sequencing of DNA samples presents additional mutation, balanced translocations, single-nucleotide polymorphisms (SNP), and copy neutral loss of heterozygosity data simultaneously. We foresee a further boost of the potential of DNA profiling in the clinic when these multidimensional DNA factors will be implemented. Here we evaluate the current stratification power with DNA copy numbers. In a training and validation approach using data of 400 published breast cancer samples, we show that a DNA copy number classifier accurately classifies RNA expression subtypes. We consider this an important step forward for clinical implementation of genomic subtyping using DNA and discuss the extra dimensions upcoming techniques will bring to the DNA palette. Clin Cancer Res; 17(15); 4959–64. ©2011 AACR.
Data from Akt Inhibitors MK-2206 and Nelfinavir Overcome mTOR Inhibitor Resistance in Diffuse Large B-cell Lymphoma
Authors: Petrich Adam M. , Leshchenko Violetta , Kuo Pei-Yu , Xia Bing , Thirukonda Venu K. , Ulahannan Netha , Gordon Shanisha , Fazzari Melissa J. , Ye B. Hilda , Sparano Joseph A. , Parekh Samir
Published: April 2023

Abstract
Purpose: The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor.

Experimental Design: We sought to identify a GEP of mTOR inhibitor resistance by stratification of eight DLBCL cell lines with respect to response to rapamycin. Then, using pathway analysis and connectivity mapping, we sought targets likely accounting for this resistance and compounds likely to overcome it. We then evaluated two compounds thus identified for their potential to synergize with rapamycin in DLBCL and confirmed mechanisms of activity with standard immunoassays.

Results: We identified a GEP capable of reliably distinguishing rapamycin-resistant from rapamycin-sensitive DLBCL cell lines. Pathway analysis identified Akt as central to the differentially expressed gene network. Connectivity mapping identified compounds targeting Akt as having a high likelihood of reversing the GEP associated with mTOR inhibitor resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR.

Conclusions: GEP identifies DLBCL subsets resistant to mTOR inhibitor therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials. Clin Cancer Res; 18(9); 2534–44. ©2012 AACR.
Data from Telomerase Peptide Vaccination in NSCLC: A Phase II Trial in Stage III Patients Vaccinated after Chemoradiotherapy and an 8-Year Update on a Phase I/II Trial
Authors: Brunsvig Paal Fr. , Kyte Jon Amund , Kersten Christian , Sundstrøm Stein , Møller Mona , Nyakas Marta , Hansen Gaute L. , Gaudernack Gustav , Aamdal Steinar
Published: April 2023

Abstract
Purpose: We report two clinical trials in non–small cell lung cancer (NSCLC) patients evaluating immune response, toxicity, and clinical outcome after vaccination with the telomerase peptide GV1001: a phase II trial (CTN-2006) in patients vaccinated after chemoradiotherapy and an 8-year update on a previously reported phase I/II trial (CTN-2000).

Experimental Design: CTN-2006: 23 inoperable stage III patients received radiotherapy (2 Gy × 30) and weekly docetaxel (20 mg/m2), followed by GV1001 vaccination. CTN-2000: 26 patients were vaccinated with two telomerase peptides (GV1001 and I540). The immune responses were evaluated by T-cell proliferation and cytokine assays.

Results: CTN-2006 trial: a GV1001-specific immune response developed in 16/20 evaluable patients. Long-term immunomonitoring showed persisting responses in 13 subjects. Serious adverse events were not observed. Immune responders recorded a median PFS of 371 days, compared with 182 days for nonresponders (P = 0.20). CTN-2000 trial update: 13/24 evaluable subjects developed a GV1001 response. The immune responders achieved increased survival compared with nonresponders (median 19 months vs. 3.5 months; P < 0.001). Follow-up of four long-time survivors showed that they all harbored durable GV1001-specific T-cell memory responses and IFNγhigh/IL-10low/IL-4low cytokine profiles. Two patients are free of disease after 108 and 93 months, respectively.

Conclusions: Vaccination with GV1001 is well tolerated, immunizes the majority of NSCLC patients and establishes durable T-cell memory. The considerable immune response rate and low toxicity in the phase II trial support the concept of combining chemoradiotherapy with vaccination. The survival advantage observed for immune responders warrants a randomized trial. Clin Cancer Res; 17(21); 6847–57. ©2011 AACR.
Data from Therapeutic Oligonucleotides: The Road Not Taken
Authors: Stein Cy A. , Goel Sanjay
Published: April 2023

Abstract
Antisense oligonucleotide therapeutics have been in development for almost 25 years without a single U.S. Food and Drug Administration–approved product in cancer. The reasons for this absence stem, in part, from a deep lack of understanding about how to deliver these molecules to cancer cells in vivo. Clin Cancer Res; 17(20); 6369–72. ©2011 AACR.
Data from A Three-Gene Expression Signature Model for Risk Stratification of Patients with Neuroblastoma
Authors: Garcia Idoia , Mayol Gemma , Ríos José , Domenech Gema , Cheung Nai-Kong V. , Oberthuer André , Fischer Matthias , Maris John M. , Brodeur Garrett M. , Hero Barbara , Rodríguez Eva , Suñol Mariona , Galvan Patricia , de Torres Carmen , Mora Jaume , Lavarino Cinzia
Published: April 2023

Abstract
Purpose: Neuroblastoma is an embryonal tumor with contrasting clinical courses. Despite elaborate stratification strategies, precise clinical risk assessment still remains a challenge. The purpose of this study was to develop a PCR-based predictor model to improve clinical risk assessment of patients with neuroblastoma.

Experimental Design: The model was developed using real-time PCR gene expression data from 96 samples and tested on separate expression data sets obtained from real-time PCR and microarray studies comprising 362 patients.

Results: On the basis of our prior study of differentially expressed genes in favorable and unfavorable neuroblastoma subgroups, we identified three genes, CHD5, PAFAH1B1, and NME1, strongly associated with patient outcome. The expression pattern of these genes was used to develop a PCR-based single-score predictor model. The model discriminated patients into two groups with significantly different clinical outcome [set 1: 5-year overall survival (OS): 0.93 ± 0.03 vs. 0.53 ± 0.06, 5-year event-free survival (EFS): 0.85 ± 0.04 vs. 0.042 ± 0.06, both P < 0.001; set 2 OS: 0.97 ± 0.02 vs. 0.61 ± 0.1, P = 0.005, EFS: 0.91 ± 0.8 vs. 0.56 ± 0.1, P = 0.005; and set 3 OS: 0.99 ± 0.01 vs. 0.56 ± 0.06, EFS: 0.96 ± 0.02 vs. 0.43 ± 0.05, both P < 0.001]. Multivariate analysis showed that the model was an independent marker for survival (P < 0.001, for all). In comparison with accepted risk stratification systems, the model robustly classified patients in the total cohort and in different clinically relevant risk subgroups.

Conclusion: We propose for the first time in neuroblastoma, a technically simple PCR-based predictor model that could help refine current risk stratification systems. Clin Cancer Res; 18(7); 2012–23. ©2012 AACR.
Data from Ang-2-VEGF-A CrossMab, a Novel Bispecific Human IgG1 Antibody Blocking VEGF-A and Ang-2 Functions Simultaneously, Mediates Potent Antitumor, Antiangiogenic, and Antimetastatic Efficacy
Authors: Kienast Yvonne , Klein Christian , Scheuer Werner , Raemsch Romi , Lorenzon Erica , Bernicke Dirk , Herting Frank , Yu Sidney , The Huynh Hung , Martarello Laurent , Gassner Christian , Stubenrauch Kay-Gunnar , Munro Kate , Augustin Hellmut G. , Thomas Markus
Published: April 2023

Abstract
Purpose: VEGF-A blockade has been clinically validated as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis.

Experimental Design: We have applied the recently developed CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on bevacizumab (Avastin), and the other arm recognizing Ang-2 based on LC06, an Ang-2 selective human IgG1 antibody. The potency of Ang-2-VEGF CrossMab was evaluated alone and in combination with chemotherapy using orthotopic and subcutaneous xenotransplantations, along with metastasis analysis by quantitative real-time Alu-PCR and ex vivo evaluation of vessels, hypoxia, proliferation, and apoptosis. The mechanism of action was further elucidated using Western blotting and ELISA assays.

Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and patient or cell line-derived human tumor xenografts, especially at later stages of tumor development. Ang-2-VEGF-A CrossMab treatment led to a strong inhibition of angiogenesis and an enhanced vessel maturation phenotype. Neoadjuvant combination with chemotherapy resulted in complete tumor regression in primary tumor-bearing Ang-2-VEGF-A CrossMab-treated mice. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiologic vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting.

Conclusion: These data establish Ang-2-VEGF-A CrossMab as a promising antitumor, antiangiogenic, and antimetastatic agent for the treatment of cancer. Clin Cancer Res; 19(24); 6730–40. ©2013 AACR.
Data from Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates
Authors: Perkins Janelle B. , Goldstein Steven C. , Dawson Jana L. , Kim Jongphil , Field Teresa L. , Partyka James S. , Fields Karen K. , Maddox Beth L. , Simonelli Christine E. , Neuger Anthony M. , Lush Richard M. , Sullivan Daniel M.
Published: April 2023

Abstract
Purpose: To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies.

Experimental Design: Patients were treated with (in mg/m2/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days −8 through −6 and etoposide 500 (days −5 through −3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured.

Results: The topotecan MTD in this regimen was 64 mg/m2 (21.3 mg/m2/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose.

Conclusion: Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy. Clin Cancer Res; 17(24); 7743–53. ©2011 AACR.
Data from Clinicopathologic Features and Long-term Outcomes of NUT Midline Carcinoma
Authors: Bauer Daniel E. , Mitchell Chelsey M. , Strait Kelly M. , Lathan Christopher S. , Stelow Edward B. , Lüer Sonja C. , Muhammed Somala , Evans Andrew G. , Sholl Lynette M. , Rosai Juan , Giraldi Eugenia , Oakley Richard P. , Rodriguez-Galindo Carlos , London Wendy B. , Sallan Stephen E. , Bradner James E. , French Christopher A.
Published: April 2023

Abstract
Purpose: NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the NUT gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations.

Experimental Design: A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of patients with NMC studied to date. Outcome data from 54 patients were available for survival analyses.

Results: The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (P < 0.05). Geographic distribution of patients with NMC has been concentrated in the United States (n = 41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% confidence interval (CI) of 1% to 17% [1-year PFS 15% (5–24%) and 2-year overall survival (OS) was 19% with a 95% CI of 7%–31% (1-year OS: 30% (27–34%)]. Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome.

Conclusions: NMC portends a poor prognosis among all squamous cell neoplasms and seems to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival. Clin Cancer Res; 18(20); 5773–9. ©2012 AACR.
Data from microRNA Expression Profiles Identify Subtypes of Mantle Cell Lymphoma with Different Clinicobiological Characteristics
Authors: Navarro Alba , Clot Guillem , Prieto Miriam , Royo Cristina , Vegliante Maria Carmela , Amador Virginia , Hartmann Elena , Salaverria Itziar , Beà Sílvia , Martín-Subero Jose Ignacio , Rosenwald Andreas , Ott German , Wiestner Adrian , Wilson Wyndham H. , Campo Elías , Hernández Luis
Published: April 2023

Abstract
Purpose: microRNAs (miRNA) are posttranscriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRNAs and their relationship with clinicopathologic and biologic relevant features in leukemic mantle cell lymphomas (MCL).

Experimental Design: Expression profiling of 664 miRNAs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCLs. Statistical and bioinformatic analyses were conducted to define miRNAs associated with different clinicopathologic parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRNAs. The prognostic value of miR-34a was investigated in 2 independent series of 29 leukemic and 50 nodal MCLs.

Results: Robust consensus clustering defined 2 main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity, and nodal clinical presentation. Supervised analyses of IGHV and SOX11 categories identified 17 and 22 miRNAs differentially expressed, respectively. Enriched targets of these miRNAs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling, and chromatin modification. In addition, we found 7 miRNAs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in 2 independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene.

Conclusion: We have identified miRNAs and target pathways related to clinical and biologic variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL. Clin Cancer Res; 19(12); 3121–9. ©2013 AACR.
Data from BEAMing Sheds Light on Drug Resistance
Authors: Lauring Josh , Park Ben Ho
Published: April 2023

Abstract
Targeted therapies against somatically altered genes are currently used for the treatment of many human cancers. The nascent technology known as BEAMing has the potential to increase the clinical utility of these agents because it allows for the detection of cancer mutations in peripheral blood, providing a rapid assessment of tumor mutation status. Clin Cancer Res; 17(24); 7508–10. ©2011 AACR.
Data from The Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth
Authors: Marian Calin O. , Cho Steve K. , Mcellin Brian M. , Maher Elizabeth A. , Hatanpaa Kimmo J. , Madden Christopher J. , Mickey Bruce E. , Wright Woodring E. , Shay Jerry W. , Bachoo Robert M.
Published: April 2023

Abstract
Purpose: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo.

Experimental Design: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat.

Results: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45 μmol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed ∼70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth.

Conclusion: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies. Clin Cancer Res; 16(1); 154–63
Data from Temporal and Spatial Evolution of Therapy-Induced Tumor Apoptosis Detected by Caspase-3–Selective Molecular Imaging
Authors: Nguyen Quang-Dé , Lavdas Ioannis , Gubbins James , Smith Graham , Fortt Robin , Carroll Laurence S. , Graham Martin A. , Aboagye Eric O.
Published: April 2023

Abstract
Purpose: Induction of apoptosis in tumors is considered a desired goal of anticancer therapy. We investigated whether the dynamic temporal and spatial evolution of apoptosis in response to cytotoxic and mechanism-based therapeutics could be detected noninvasively by the caspase-3 radiotracer [18F]ICMT-11 and positron emission tomography (PET).

Experimental Design: The effects of a single dose of the alkylating agent cyclophosphamide (CPA or 4-hydroperoxycyclophosphamide), or the mechanism-based small molecule SMAC mimetic birinapant on caspase-3 activation was assessed in vitro and by [18F]ICMT-11–PET in mice bearing 38C13 B-cell lymphoma, HCT116 colon carcinoma, or MDA-MB-231 breast adenocarcinoma tumors. Ex vivo analysis of caspase-3 was compared to the in vivo PET imaging data.

Results: Drug treatment increased the mean [18F]ICMT-11 tumor uptake with a peak at 24 hours for CPA (40 mg/kg; AUC40–60: 8.04 ± 1.33 and 16.05 ± 3.35 %ID/mL × min at baseline and 24 hours, respectively) and 6 hours for birinapant (15 mg/kg; AUC40–60: 20.29 ± 0.82 and 31.07 ± 5.66 %ID/mL × min, at baseline and 6 hours, respectively). Voxel-based spatiotemporal analysis of tumor-intrinsic heterogeneity suggested that discrete pockets of caspase-3 activation could be detected by [18F]ICMT-11. Increased tumor [18F]ICMT-11 uptake was associated with caspase-3 activation measured ex vivo, and early radiotracer uptake predicted apoptosis, distinct from the glucose metabolism with [18F]fluorodeoxyglucose-PET, which depicted continuous loss of cell viability.

Conclusion: The proapoptotic effects of CPA and birinapant resulted in a time-dependent increase in [18F]ICMT-11 uptake detected by PET. [18F]ICMT-11–PET holds promise as a noninvasive pharmacodynamic biomarker of caspase-3–associated apoptosis in tumors. Clin Cancer Res; 19(14); 3914–24. ©2013 AACR.
Data from Rehabilitation for Oncogene Addiction: Role of Immunity in Cellular Sobriety
Authors: Bajor David L. , Vonderheide Robert H.
Published: April 2023

Abstract
Clinical responses to oncogene inhibitors result from direct effects on cell-intrinsic growth signals and disruption of downstream messages that produce a protumor immunosuppressive microenvironment. Combining oncogene-targeted and immunomodulatory therapies may result in synergistic effects, producing increased response rates and longer periods of tumor control than can be achieved with either class alone. Clin Cancer Res; 18(5); 1192–4. ©2012 AACR.