bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Anti-HDGF Targets Cancer and Cancer Stromal Stem Cells Resistant to Chemotherapy
Authors: Zhao Jun , Ma Mark Z. , Ren Hening , Liu Zhenqiu , Edelman Martin J. , Pan Hong , Mao Li
Published: April 2023

Abstract
Purpose: Approximately one third of the patients with advanced non–small cell lung carcinoma (NSCLC) will initially respond to platinum-based chemotherapy, but virtually all tumors will progress (acquired resistance). The remainder will progress during initial treatment (primary resistance). In this study, we test whether the treatment can be improved by inhibiting hepatoma-derived growth factor (HDGF).

Experimental Design: Thirteen primary NSCLC heterotransplant models were used to test four treatment regimens, including platinum-based chemotherapy with and without bevacizumab (VEGF-neutralizing antibody) or HDGF-H3 (HDGF-neutralizing antibody) and chemotherapy with bevacizumab and HDGF-H3. Expression of stem cell–related genes was measured using quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry.

Results: Among 13 primary NSCLC heterotransplant models, three (23%) responded to chemotherapy but all relapsed within 20 days. The residual tumors after response to the chemotherapy exhibited an increased expression in 51 (61%) of 84 genes related with stem cell proliferation and maintenance, particularly those in Notch and Wnt pathways, suggesting enrichment for stem cell populations in the residual tumors. Interestingly, tumors from two of three models treated with HDGF-H3, bevacizumab, and chemotherapy combination did not relapse during 6 months of posttreatment observation. Importantly, this treatment combination substantially downregulated expression levels in 57 (68%) of 84 stem cell–related genes, including 34 (67%) of 51 genes upregulated after the chemotherapy.

Conclusion: These data support the hypothesis that cancer stem cells (CSC) are a mechanism for chemotherapy resistance and suggest HDGF may be a target for repressing CSCs to prevent relapse of NSCLC sensitive to chemotherapy. Clin Cancer Res; 19(13); 3567–76. ©2013 AACR.
Data from Dual Targeting of the Type 1 Insulin-like Growth Factor Receptor and Its Ligands as an Effective Antiangiogenic Strategy
Authors: Bid Hemant K. , London Cheryl A. , Gao Jin , Zhong Haihong , Hollingsworth Robert E. , Fernandez Soledad , Mo Xiaokui , Houghton Peter J.
Published: April 2023

Abstract
Background: In pediatric tumor xenograft models, tumor-derived insulin growth factor (IGF-2) results in intrinsic resistance to IGF-IR–targeted antibodies, maintaining continued tumor angiogenesis. We evaluated the antiangiogenic activity of a ligand-binding antibody (MEDI-573) alone or in combination with IGF-I receptor binding antibodies (MAB391, CP01-B02).

Methods: IGF-stimulated signaling was monitored by increased Akt phosphorylation in sarcoma and human umbilical cord vascular endothelial cells (HUVEC). Angiogenesis was determined in vitro using capillary tube formation in HUVECs and in vivo using a VEGF-stimulated Matrigel assay. Tumor growth delay was examined in 4 sarcoma xenograft models.

Results: The IGF ligand-binding antibody MEDI-573 suppressed Akt phosphorylation induced by exogenous IGF-I and IGF-2 in sarcoma cells. Receptor-binding antibodies suppressed IGF-I stimulation of Akt phosphorylation, but IGF-2 circumvented this effect and maintained HUVEC tube formation. MEDI-573 inhibited HUVEC proliferation and tube formation in vitro, but did not inhibit angiogenesis in vivo, probably because MEDI-573 binds murine IGF-I with low affinity. However, in vitro antiangiogenic activity of MEDI-573 was also circumvented by human recombinant IGF-I. The combination of receptor- and ligand-binding antibodies completely suppressed VEGF-stimulated proliferation of HUVECs in the presence of IGF-I and IGF-2, prevented ligand-induced phosphorylation of IGF-IR/IR receptors, and suppressed VEGF/IGF-2–driven angiogenesis in vivo. The combination of CP1-BO2 plus MEDI-573 was significantly superior to therapy with either antibody alone against IGF-I and IGF-2 secreting pediatric sarcoma xenograft models.

Conclusions: These results suggest that combination of antibodies targeting IGF receptor and ligands may be an effective therapeutic strategy to block angiogenesis for IGF-driven tumors. Clin Cancer Res; 19(11); 2984–94. ©2013 AACR.
Data from A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with Genotypically Defined Advanced Non–Small Cell Lung Cancer
Authors: Socinski Mark A. , Goldman Jonathan , El-Hariry Iman , Koczywas Marianna , Vukovic Vojo , Horn Leora , Paschold Eugene , Salgia Ravi , West Howard , Sequist Lecia V. , Bonomi Philip , Brahmer Julie , Chen Lin-Chi , Sandler Alan , Belani Chandra P. , Webb Timothy , Harper Harry , Huberman Mark , Ramalingam Suresh , Wong Kwok-Kin , Teofilovici Florentina , Guo Wei , Shapiro Geoffrey I.
Published: April 2023

Abstract
Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC).

Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.

Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.

Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement. Clin Cancer Res; 19(11); 3068–77. ©2013 AACR.
Data from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
Authors: Di Cosimo Serena , Sathyanarayanan Sriram , Bendell Johanna C. , Cervantes Andrés , Stein Mark N. , Braña Irene , Roda Desamparados , Haines Brian B. , Zhang Theresa , Winter Christopher G. , Jha Sharda , Xu Youyuan , Frazier Jason , Klinghoffer Richard A. , Leighton-Swayze Ann , Song Yang , Ebbinghaus Scot , Baselga José
Published: April 2023

Abstract
Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.

Experimental Design:In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.

Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity.

Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.
Data from miR-409-3p/-5p Promotes Tumorigenesis, Epithelial-to-Mesenchymal Transition, and Bone Metastasis of Human Prostate Cancer
Authors: Josson Sajni , Gururajan Murali , Hu Peizhen , Shao Chen , Chu Gina Chia-Yi , Zhau Haiyen E. , Liu Chunyan , Lao Kaiqin , Lu Chia-Lun , Lu Yi-Tsung , Lichterman Jake , Nandana Srinivas , Li Quanlin , Rogatko Andre , Berel Dror , Posadas Edwin M. , Fazli Ladan , Sareen Dhruv , Chung Leland W.K.
Published: April 2023

Abstract
Purpose: miR-409-3p/-5p is a miRNA expressed by embryonic stem cells, and its role in cancer biology and metastasis is unknown. Our pilot studies demonstrated elevated miR-409-3p/-5p expression in human prostate cancer bone metastatic cell lines; therefore, we defined the biologic impact of manipulation of miR-409-3p/-5p on prostate cancer progression and correlated the levels of its expression with clinical human prostate cancer bone metastatic specimens.

Experimental Design: miRNA profiling of a prostate cancer bone metastatic epithelial-to-mesenchymal transition (EMT) cell line model was performed. A Gleason score human tissue array was probed for validation of specific miRNAs. In addition, genetic manipulation of miR-409-3p/-5p was performed to determine its role in tumor growth, EMT, and bone metastasis in mouse models.

Results: Elevated expression of miR-409-3p/-5p was observed in bone metastatic prostate cancer cell lines and human prostate cancer tissues with higher Gleason scores. Elevated miR-409-3p expression levels correlated with progression-free survival of patients with prostate cancer. Orthotopic delivery of miR-409-3p/-5p in the murine prostate gland induced tumors where the tumors expressed EMT and stemness markers. Intracardiac inoculation (to mimic systemic dissemination) of miR-409-5p inhibitor–treated bone metastatic ARCaPM prostate cancer cells in mice led to decreased bone metastasis and increased survival compared with control vehicle–treated cells.

Conclusion: miR-409-3p/-5p plays an important role in prostate cancer biology by facilitating tumor growth, EMT, and bone metastasis. This finding bears particular translational importance as miR-409-3p/-5p appears to be an attractive biomarker and/or possibly a therapeutic target to treat bone metastatic prostate cancer. Clin Cancer Res; 20(17); 4636–46. ©2014 AACR.
Data from CSPG4 as a Target of Antibody-Based Immunotherapy for Malignant Mesothelioma
Authors: Rivera Zeyana , Ferrone Soldano , Wang Xinhui , Jube Sandro , Yang Haining , Pass Harvey I. , Kanodia Shreya , Gaudino Giovanni , Carbone Michele
Published: April 2023

Abstract
Purpose: Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)–based immunotherapy for MM.

Experimental design: We assayed adhesion, motility, invasiveness, wound-healing, apoptosis, and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM severe combined immunodeficient (SCID) mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments.

Results: CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of ECM. Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of focal adhesion kinase (FAK) and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, mAb TP41.2 significantly reduced MM cell motility, migration, and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival.

Conclusion: These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM. Clin Cancer Res; 18(19); 5352–63. ©2012 AACR.
Data from The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells In Vitro and In Vivo
Authors: Zhou Ning , Singh Kamini , Mir Maria C. , Parker Yvonne , Lindner Daniel , Dreicer Robert , Ecsedy Jeffrey A. , Zhang Zhongfa , Teh Bin T. , Almasan Alexandru , Hansel Donna E.
Published: April 2023

Abstract
Purpose: Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target.

Experimental Design: Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model.

Results: A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells.

Conclusions: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer. Clin Cancer Res; 19(7); 1717–28. ©2013 AACR.
Data from Systemic Immune-Inflammation Index Predicts Prognosis of Patients after Curative Resection for Hepatocellular Carcinoma
Authors: Hu Bo , Yang Xin-Rong , Xu Yang , Sun Yun-Fan , Sun Chao , Guo Wei , Zhang Xin , Wang Wei-Min , Qiu Shuang-Jian , Zhou Jian , Fan Jia
Published: April 2023

Abstract
Purpose: We developed a novel systemic immune-inflammation index (SII) based on lymphocyte, neutrophil, and platelet counts and explored its prognostic value in hepatocellular carcinoma (HCC).

Experimental Design: The SII was developed based on a retrospective study of 133 patients with HCC undergoing resection between 2005 and 2006, and validated in a prospective study of 123 patients enrolled from 2010 to 2011. The circulating tumor cell (CTC) level in the validation cohort was measured using the CellSearch system. Prediction accuracy was evaluated with area under the receiver operating characteristic curve (AUC).

Results: An optimal cutoff point for the SII of 330 × 109 stratified the patients with HCC into high (≥330) and low SII (<330) groups in the training cohort. Univariate and multivariate analyses revealed the SII was an independent predictor for overall survival and relapse-free survival, and prognostic for patients with negative α-fetoprotein and Barcelona Clinic Liver Cancer stage 0+A. The AUCs of the SII for survival and recurrence were higher than other conventional clinical indices. An SII ≥ 330 was significantly associated with vascular invasion, large tumors, and early recurrence. CTC levels were significantly higher in the SII ≥ 330 group (1.71 ± 0.34 vs. 4.37 ± 1.04, P = 0.029). In patients with detectable CTCs, those with SII ≥ 330 had higher recurrence rates and shorter survival time than patients with SII < 330.

Conclusion: The SII was a powerful prognostic indicator of poor outcome in patients with HCC and is a promising tool for HCC treatment strategy decisions. The dismal outcome in patients with high SII scores might be related to higher CTC levels. Clin Cancer Res; 20(23); 6212–22. ©2014 AACR.
Data from Concurrent Alterations in TERT, KDM6A, and the BRCA Pathway in Bladder Cancer
Authors: Nickerson Michael L. , Dancik Garrett M. , Im Kate M. , Edwards Michael G. , Turan Sevilay , Brown Joseph , Ruiz-Rodriguez Christina , Owens Charles , Costello James C. , Guo Guangwu , Tsang Shirley X. , Li Yingrui , Zhou Quan , Cai Zhiming , Moore Lee E. , Lucia M. Scott , Dean Michael , Theodorescu Dan
Published: April 2023

Abstract
Purpose: Genetic analysis of bladder cancer has revealed a number of frequently altered genes, including frequent alterations of the telomerase (TERT) gene promoter, although few altered genes have been functionally evaluated. Our objective is to characterize alterations observed by exome sequencing and sequencing of the TERT promoter, and to examine the functional relevance of histone lysine (K)–specific demethylase 6A (KDM6A/UTX), a frequently mutated histone demethylase, in bladder cancer.

Experimental Design: We analyzed bladder cancer samples from 54 U.S. patients by exome and targeted sequencing and confirmed somatic variants using normal tissue from the same patient. We examined the biologic function of KDM6A using in vivo and in vitro assays.

Results: We observed frequent somatic alterations in BRCA1 associated protein-1 (BAP1) in 15% of tumors, including deleterious alterations to the deubiquitinase active site and the nuclear localization signal. BAP1 mutations contribute to a high frequency of tumors with breast cancer (BRCA) DNA repair pathway alterations and were significantly associated with papillary histologic features in tumors. BAP1 and KDM6A mutations significantly co-occurred in tumors. Somatic variants altering the TERT promoter were found in 69% of tumors but were not correlated with alterations in other bladder cancer genes. We examined the function of KDM6A, altered in 24% of tumors, and show depletion in human bladder cancer cells, enhanced in vitro proliferation, in vivo tumor growth, and cell migration.

Conclusions: This study is the first to identify frequent BAP1 and BRCA pathway alterations in bladder cancer, show TERT promoter alterations are independent of other bladder cancer gene alterations, and show KDM6A loss is a driver of the bladder cancer phenotype. Clin Cancer Res; 20(18); 4935–48. ©2014 AACR.
Data from Squamous Cell Carcinoma of the Oral Tongue in Young Non-Smokers Is Genomically Similar to Tumors in Older Smokers
Authors: Pickering Curtis R. , Zhang Jiexin , Neskey David M. , Zhao Mei , Jasser Samar A. , Wang Jiping , Ward Alexandra , Tsai C. Jillian , Ortega Alves Marcus V. , Zhou Jane H. , Drummond Jennifer , El-Naggar Adel K. , Gibbs Richard , Weinstein John N. , Wheeler David A. , Wang Jing , Frederick Mitchell J. , Myers Jeffrey N.
Published: April 2023

Abstract
Purpose: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.

Experimental Design: DNA isolated from tongue tumors of young (<45 years, non-smokers) and old (>45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.

Results: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site–specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.

Conclusions: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood. Clin Cancer Res; 20(14); 3842–8. ©2014 AACR.
Data from Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel
Authors: Abraham Jean E. , Guo Qi , Dorling Leila , Tyrer Jonathan , Ingle Susan , Hardy Richard , Vallier Anne-Laure , Hiller Louise , Burns Russell , Jones Linda , Bowden Sarah J. , Dunn Janet A. , Poole Christopher J. , Caldas Carlos , Pharoah Paul P.D. , Earl Helena M.
Published: April 2023

Abstract
Purpose: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer.

Experimental Design: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated.

Results: The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28–0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20–2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05.

Conclusion: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility. Clin Cancer Res; 20(9); 2466–75. ©2014 AACR.
Data from Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy
Authors: Hu Lingmin , Wu Chen , Zhao Xueying , Heist Rebecca , Su Li , Zhao Yang , Han Baohui , Cao Songyu , Chu Minjie , Dai Juncheng , Dong Jing , Shu Yongqian , Xu Lin , Chen Yijiang , Wang Yi , Lu Feng , Jiang Yue , Yu Dianke , Chen Hongyan , Tan Wen , Ma Hongxia , Chen Jiaping , Jin Guangfu , Wu Tangchun , Lu Daru , Christiani David C. , Lin Dongxin , Hu Zhibin , Shen Hongbing
Published: April 2023

Abstract
Purpose: Genetic variation may influence chemotherapy response and overall survival in cancer patients.

Experimental design: We conducted a genome-wide scan in 535 advanced-stage non–small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA).

Results: Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10−5 to 4.19 × 10−7 in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population.

Conclusion: In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients. Clin Cancer Res; 18(19); 5507–14. ©2012 AACR.
Data from Functional Genetic Approach Identifies MET, HER3, IGF1R, INSR Pathways as Determinants of Lapatinib Unresponsiveness in HER2-Positive Gastric Cancer
Authors: Zhang Zhe , Wang Jiping , Ji Dongmei , Wang Chenchen , Liu Rujiao , Wu Zheng , Liu Lian , Zhu Dan , Chang Jinjia , Geng Ruixuan , Xiong Lei , Fang Qiangyi , Li Jin
Published: April 2023

Abstract
Purpose: Targeting human epidermal growth factor receptor 2 (HER2) therapy is currently considered as the standard treatment for HER2-positive (HER2+) advanced gastric cancer. However, as seen in recent clinical trials, most of HER2+ gastric cancer are actually unresponsive to HER2-targeted agents, including lapatinib. The aim of this study is to identify the responsible receptor tyrosine kinases (RTK) potentially conferring lapatinib unresponsiveness in HER2+ gastric cancer and elucidate the molecular mechanism underlying this RTKs-induced resistance.

Experimental Design: A functional RNAi screen targeting human RTKs and related growth factors was used to identify candidate RTKs conferring lapatinib unresponsiveness in HER2+ gastric cancer cells. Independent siRNAs transfection and corresponding ligands supplement were performed to validate the effects of candidate RTKs on lapatinib sensitivity. Cross-talks of pathways involved were analyzed via Western blot analysis. Cell apoptosis and cell motility were detected using FACS system and Transwell assay. Immunohistochemistry was used to analyze protein expression in clinical samples.

Results: MET, HER3, insulin-like growth factor (IGF)-1R, and INSR were identified to mediate lapatinib unresponsiveness in HER2+ gastric cancer cells. Activation of these bypass RTKs attenuated lapatinib-induced apoptosis and suppression of cell motility, mechanistically because of restimulating the shared downstream AKT or ERK signaling, as well as restimulating WNT signaling and epithelial-to-mesenchymal transition (EMT)–like process. Patients' specimens revealed that these unresponsiveness-conferring RTKs were particularly enriched in the majority of patients with HER2+ gastric cancer.

Conclusions: MET, HER3, IGF1R, and INSR pathways activation represent novel mechanism underlying lapatinib unresponsiveness in HER2+ gastric cancer. Combination strategy may be recommended in treating patients with HER2+ gastric cancer with these pathways activation. Clin Cancer Res; 20(17); 4559–73. ©2014 AACR.
Data from Secreted Protein Acidic and Rich in Cysteines-like 1 Suppresses Aggressiveness and Predicts Better Survival in Colorectal Cancers
Authors: Hu Hanguang , Zhang Hang , Ge Weiting , Liu Xiyong , Loera Sofia , Chu Peiguo , Chen Huarong , Peng Jiaping , Zhou Lun , Yu Shujing , Yuan Ying , Zhang Suzhan , Lai Lily , Yen Yun , Zheng Shu
Published: April 2023

Abstract
Purpose:Secreted protein acidic and rich in cysteines-like 1 (SPARCL1) is an extracellular matrix glycoprotein with malignancy-suppressing potential. The hypothesis that SPARCL1 reduces cancer invasiveness and predicts better survival in colorectal cancers (CRC) was investigated.

Experimental Design: Stable SPARCL1 transfectants, RKO-SPARCL1, and corresponding vector control were constructed and implanted into nude mice to generate a mouse xenograft model of liver metastasis. Also, a retrospective outcome study was conducted on the COH set (222 CRCs) and ZJU set (412 CRCs). The protein expression level of SPARCL1 was determined by immunohistochemistry. The Kaplan–Meier and Cox analyses were used for survival analysis. The association of SPARCL1 with mesenchymal–epithelial transition (MET) was examined by reverse transcription PCR (RT-PCR) and Western blot analysis.

Results: The ectopic expression of SPARCL1 significantly reduced the potential for anchorage-independent growth, migration, invasion and induced cell differentiation in RKO and SW620 cells. In mouse xenograft model, the expression of SPARCL1 significantly reduced the liver metastasis (P < 0.01). The patient-based studies revealed that the expression of SPARCL1 was related to better differentiation (P < 0.01), less lymph node involvement [OR, 0.67; 95% confidence interval (CI), 0.45–1.00], and less distant metastasis (OR, 0.38; 95% CI, 0.18–0.79). The Kaplan–Meier and Cox analysis showed that the expression of SPARCL1 was associated with better overall survival (log-rank: P < 0.01; HR, 0.57; 95% CI, 0.39–0.84). Transfection of SPARCL1 induced MET of colon cancer cells.

Conclusion:SPARCL1 functions as a tumor suppressor promoting differentiation possibly via MET, which inhibits the aggressiveness of CRCs. Clin Cancer Res; 18(19); 5438–48. ©2012 AACR.
Data from Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity
Authors: Kennedy-Nasser Alana A. , Ku Stephanie , Castillo-Caro Paul , Hazrat Yasmin , Wu Meng-Fen , Liu Hao , Melenhorst Jos , Barrett A. John , Ito Sawa , Foster Aaron , Savoldo Barbara , Yvon Eric , Carrum George , Ramos Carlos A. , Krance Robert A. , Leung Kathryn , Heslop Helen E. , Brenner Malcolm K. , Bollard Catherine M.
Published: April 2023

Abstract
Purpose: GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4+CD25+FoxP3+ regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD.

Experimental Design: We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000–200,000 IU/m2 ×3 per week), starting

Results: No grade 3/4 toxicities were associated with ULD IL-2. CD4+CD25+FoxP3+ Tregs increased from a mean of 4.8% (range, 0%–11.0%) pre IL-2 to 11.1% (range, 1.2%–31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants. No IL-2 patients developed grade 2–4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022).

Conclusions: Hence, ULD IL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD. Clin Cancer Res; 20(8); 2215–25. ©2014 AACR.
Data from Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor
Authors: Osgood Christy L. , Maloney Nichole , Kidd Christopher G. , Kitchen-Goosen Susan , Segars Laura , Gebregiorgis Meti , Woldemichael Girma M. , He Min , Sankar Savita , Lessnick Stephen L. , Kang Min , Smith Malcolm , Turner Lisa , Madaj Zachary B. , Winn Mary E. , Núñez Luz-Elena , González-Sabín Javier , Helman Lee J. , Morís Francisco , Grohar Patrick J.
Published: April 2023

Abstract
Purpose: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients.

Experimental Design: We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time-lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma.

Results: EC-8105 was found to be the most potent analogue and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo.

Conclusions: These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic. Clin Cancer Res; 22(16); 4105–18. ©2016 AACR.
Data from MYD88 L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome
Authors: Rovira Jordina , Karube Kennosuke , Valera Alexandra , Colomer Dolors , Enjuanes Anna , Colomo Lluís , Martínez-Trillos Alejandra , Giné Eva , Dlouhy Ivan , Magnano Laura , Delgado Julio , Martínez Antonio , Villamor Neus , Campo Elías , López-Guillermo Armando
Published: April 2023

Abstract
Purpose: Mutations in MYD88 are found in different lymphoproliferative disorders associated with particular biologic characteristics and clinical impact. The aim of this study was to analyze the incidence of MYD88 mutations and its clinical impact in diffuse large B-cell lymphoma (DLBCL).

Experimental Design: The incidence, clinicobiological features, and outcome of 213 patients (115 M/98 F; median age, 65 years) with DLBCL treated with immunochemotherapy in a single institution according to MYD88 mutational status as assessed by an allele-specific PCR assay were analyzed. The cell of origin (COO) was determined in 129 cases by gene expression.

Results: MYD88 mutations were found in 47 cases (22%), including L265P in 39 and S219C and M232F in 4 cases, respectively. Patients with MYD88 L265P were older, presenting frequent extranodal involvement, and mostly corresponded to activated B-cell like (ABC) subtype, whereas no preference in COO was observed in patients with other MYD88 mutations. Five-year overall survival (OS) for MYD88 wild-type, MYD88 L265P, and other variants was 62%, 52%, and 75%, respectively (P = 0.05). International Prognostic Index (IPI) (HR, 2.71; P < 0.001) and MYD88 L265P (HR, 1.786; P = 0.023) were independent variables predicting OS in the multivariate analysis. However, MYD88 L265P lost its independent value when COO was included in the model.

Conclusions: Our findings indicate that MYD88 L265P mutations, but no other variants, identify a subgroup of DLBCL mainly of ABC origin, with extranodal involvement and poor outcome. Clin Cancer Res; 22(11); 2755–64. ©2016 AACR.
Data from Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma
Authors: Fabre Claire , Mimura Naoya , Bobb Kathryn , Kong Sun-Young , Gorgun Güllü , Cirstea Diana , Hu Yiguo , Minami Jiro , Ohguchi Hiroto , Zhang Jie , Meshulam Jeffrey , Carrasco Ruben D. , Tai Yu-Tzu , Richardson Paul G. , Hideshima Teru , Anderson Kenneth C.
Published: April 2023

Abstract
Purpose: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity.

Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways.

Results: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)–induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti–multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells.

Conclusions: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions. Clin Cancer Res; 18(17); 4669–81. ©2012 AACR.
Data from Persistence of CTL Clones Targeting Melanocyte Differentiation Antigens Was Insufficient to Mediate Significant Melanoma Regression in Humans
Authors: Chandran Smita S. , Paria Biman C. , Srivastava Abhishek K. , Rothermel Luke D. , Stephens Daniel J. , Dudley Mark E. , Somerville Robert , Wunderlich John R. , Sherry Richard M. , Yang James C. , Rosenberg Steven A. , Kammula Udai S.
Published: April 2023

Abstract
Purpose: Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable cancer regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8+ T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively.

Experimental Design: We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8+ T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2+ treatment-refractory metastatic melanoma received highly avid MDA-specific CD8+ T-cell clones specific for either gp100 (n = 10) or MART-1 (n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen.

Results: Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria.

Conclusions: Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens. Clin Cancer Res; 21(3); 534–43. ©2014 AACR.
Data from Inhibition of Bromodomain Proteins for the Treatment of Human Diffuse Large B-cell Lymphoma
Authors: Trabucco Sally E. , Gerstein Rachel M. , Evens Andrew M. , Bradner James E. , Shultz Leonard D. , Greiner Dale L. , Zhang Hong
Published: April 2023

Abstract
Purpose: Approximately 50% of patients with diffuse large B-cell lymphoma (DLBCL) enter long-term remission after standard chemotherapy. Patients with DLBCL who do not respond to chemotherapy have few treatment options. There remains a critical need to identify effective and targeted therapeutics for DLBCL.

Experimental Design: Recent studies have highlighted the incidence of increased c-MYC protein in DLBCL and the correlation between high levels of c-MYC protein and poor survival prognosis of patients with DLBCL, suggesting that c-MYC is a compelling target for DLBCL therapy. The small molecule JQ1 suppresses c-MYC expression through inhibition of the bromodomain and extra-terminal (BET) family of bromodomain proteins. We investigated whether JQ1 can inhibit proliferation of DLBCL cells in culture and xenograft models in vivo.

Results: We show that JQ1 at nanomolar concentrations efficiently inhibited proliferation of human DLBCL cells in a dose-dependent manner regardless of their molecular subtypes, suggesting a broad effect of JQ1 in DLBCL. The initial G1 arrest induced by JQ1 treatment in DLBCL cells was followed by either apoptosis or senescence. The expression of c-MYC was suppressed as a result of JQ1 treatment from the natural, chromosomally translocated, or amplified loci. Furthermore, JQ1 treatment significantly suppressed growth of DLBCL cells engrafted in mice and improved survival of engrafted mice.

Conclusion: Our results demonstrate that inhibition of the BET family of bromodomain proteins by JQ1 has potential clinical use in the treatment of DLBCL. Clin Cancer Res; 21(1); 113–22. ©2014 AACR.

See related commentary by Mottok and Gascoyne, p. 4
Data from Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)
Authors: Sharkey Robert M. , McBride William J. , Cardillo Thomas M. , Govindan Serengulam V. , Wang Yang , Rossi Edmund A. , Chang Chien-Hsing , Goldenberg David M.
Published: April 2023

Abstract
Purpose: This study examined the delivery of SN-38 to Trop-2–expressing tumors and assessed the constitutive products in the serum, liver, and small intestine in nude mice bearing human tumor xenografts (Capan-1 or NCI-N87) given a single injection of irinotecan (40 mg/kg; ∼0.8 mg/mouse, containing ∼460 μg SN-38 equivalents) or sacituzumab govitecan (IMMU-132), an antibody–drug conjugate composed of a humanized anti-Trop-2 IgG coupled site specifically with an average of 7.6 molecules of SN-38.

Experimental Design: At select times, tissues were extracted and concentrations of the products measured by reversed-phase high-performance liquid chromatography (HPLC).

Results: In serum, >98% irinotecan cleared within 5 minutes; peak levels of SN-38 and SN-38G (glucuronidated SN-38) were detected in equal amounts at this time, and no longer detected after 6 to 8 hours. IMMU-132 was detected in the serum over 3 days, and at each interval, ≥95% of total SN-38 was bound to the antibody. Intact IMMU-132 cleared with a half-life of 14 hours, which closely reflected the in vitro rate of SN-38 released from the conjugate in mouse serum (i.e., 17.5 hours), whereas the IgG portion of the conjugate cleared with a half-life of 67.1 hours. In vitro and in vivo studies disclosed IgG-bound SN-38 was protected from glucuronidation. Area under the curve (AUC) analysis indicated that IMMU-132 delivers 20-fold to as much as 136-fold more SN-38 to tumors than irinotecan, with tumor:blood ratios favoring IMMU-132 by 20- to 40-fold. Intestinal concentrations of SN-38/SN-38G also were 9-fold lower with IMMU-132.

Conclusions: These studies confirm a superior SN-38 tumor delivery by IMMU-132 compared with irinotecan. Clin Cancer Res; 21(22); 5131–8. ©2015 AACR.
Data from LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth
Authors: Liu Ling , Zeng Wei , Wortinger Mark A. , Yan S. Betty , Cornwell Paul , Peek Victoria L. , Stephens Jennifer R. , Tetreault Jonathan W. , Xia Jinqi , Manro Jason R. , Credille Kelly M. , Ballard Darryl W. , Brown-Augsburger Patricia , Wacheck Volker , Chow Chi-Kin , Huang Lihua , Wang Yong , Denning Irene , Davies Julian , Tang Ying , Vaillancourt Peter , Lu Jirong
Published: April 2023

Abstract
Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.

Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.

Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059–70. ©2014 AACR.