bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Radiosensitivity Enhancement by Combined Treatment of Celecoxib and Gefitinib on Human Lung Cancer Cells
Authors: Park Ji Sun , Jun Hyun Jung , Cho Moon Jun , Cho Kwan Ho , Lee Jin Soo , Zo Jae Ill , Pyo Hongryull
Published: April 2023

Abstract
Purpose: To characterize the radiation-enhancing effects and underlying mechanisms of combined treatment with celecoxib, a cyclooxygenase-2 selective inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in human lung cancer cells.

Experimental Design: Clonogenic cytotoxicity assays and clonogenic radiation survival assays after treatments with celecoxib and gefitinib with or without radiation were done on three human lung cancer cell lines. Synergisms after combined treatment with celecoxib, gefitinib, and radiation were investigated using isobologram and statistical analyses according to an independent action model. Alterations in apoptosis and cell cycle were measured to identify the mechanisms underlying the cell killing or radiation-enhancing effects of celecoxib and gefitinib combination treatment. Western blots for phosphorylated EGFR, EGFR, cyclooxygenase-2, and G2 checkpoint molecules were conducted after treatment with celecoxib and/or gefitinib with or without radiation.

Results: Combination celecoxib, gefitinib, and radiation treatments were shown to be synergistic in causing clonogenic cell deaths in all cell lines tested, but the nature of synergism was cell type specific. The combined drug treatments induced apoptosis in an additive manner in A549 cells and in a synergistic manner in NCI-H460 and VMRC-LCD cells. Celecoxib or gefitinib attenuated radiation-induced G2-M arrest, and combined drug treatment additively attenuated radiation-induced G2-M arrest in all cell lines. Radiation-induced checkpoint kinase (Chk) 1 and Chk2 phosphorylation were inhibited by celecoxib and gefitinib treatment, respectively.

Conclusions: Combined celecoxib and gefitinib treatments were shown to synergistically enhance the effect of radiation on lung cancer cells. The mechanisms underlying these synergistic effects seem to involve the synergistic enhancement of apoptosis and cooperative attenuation of radiation-induced G2-M arrest, possibly via Chk1 and Chk2 inhibition, by the combined drug treatments.
Data from Does Lapatinib Work against HER2-negative Breast Cancers?
Authors: Mayer Ingrid A. , Arteaga Carlos L.
Published: April 2023

Abstract
Aberrant growth factor receptor signaling can augment or suppress estrogen receptor (ER) function in hormone-dependent breast cancer cells and lead to escape from anti-estrogen therapy. Interruption of HER2/ER cross-talk with lapatinib can restore sensitivity to anti-estrogens and thus, should be investigated in combination with endocrine therapy in patients with ER+/HER2-negative breast cancers. Clin Cancer Res; 16(5); 1355–7
Data from Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer
Authors: Kyula Joan N. , Van Schaeybroeck Sandra , Doherty Joanne , Fenning Catherine S. , Longley Daniel B. , Johnston Patrick G.
Published: April 2023

Abstract
Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.

Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.

Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-α, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.

Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC. Clin Cancer Res; 16(13); 3378–89. ©2010 AACR.
Data from Histopathologic and Immunohistochemical Characterization of Rash to Human Epidermal Growth Factor Receptor 1 (HER1) and HER1/2 Inhibitors in Cancer Patients
Authors: Nardone Beatrice , Nicholson Kimberly , Newman Marissa , Guitart Joan , Gerami Pedram , Talarico Nicholas , Yang Ximing J. , Rademaker Alfred , West Dennis P. , Lacouture Mario E.
Published: April 2023

Abstract
Purpose: Human epidermal growth factor receptor (HER) 1 and HER 1/2 inhibitors have shown benefit against a wide range of solid tumors. However, their use is associated with rash in 40% to 90% of patients, which impacts quality of life and interrupts antineoplastic therapy. The pathologic characteristics of affected skin remain unclear, precluding development of rational therapies. The aim of this study was to evaluate differences in histologic and immunohistochemical alterations in rash caused by lapatinib, a dual HER1/2 inhibitor (HER1/2i), and the single HER1 inhibitors (HER1i) cetuximab, erlotinib, and panitumumab.

Experimental Design: For each of the four drugs, skin biopsies were collected and analyzed from 8 patients with rash (n = 32). Blinded independent histologic analysis and automated measurement of 17 skin biomarkers involved in proliferation, differentiation, and inflammation were conducted.

Results: Increased expression of pAKT and decreased dermal K16 and p27 for HER1/2i when compared with each of the HER1i were observed. In addition, decreased epidermal atrophy and follicular neutrophilic infiltrate were evidenced in the skin of patients on HER1/2i when compared with HER1i.

Conclusions: We found a lower inhibition of epidermal kinetics and decreased inflammation in HER1/2i-induced rash. These findings underscore differences in skin toxicity as related to specificity of HER blockade, concordant with clinical tolerability and decreased severity of skin toxicity seen with the HER1/2i lapatinib compared with the HER1 inhibitors cetuximab, erlotinib, and panitumumab. Clin Cancer Res; 16(17); 4452–60. ©2010 AACR.
Data from Evidence for Microtubule Target Engagement in Tumors of Patients Receiving Ixabepilone
Authors: Zhuang Sen H. , Hung Y. Elizabeth , Hung Laura , Robey Robert W. , Sackett Dan L. , Linehan W. Marston , Bates Susan E. , Fojo Tito , Poruchynsky Marianne S.
Published: April 2023

Abstract
Purpose: Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. α-Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with ixabepilone(BMS-247550; Ixempra).

Experimental Design: Levels of posttranslationally modified α-tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis.

Results: In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated α-tubulin increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated α-tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated α-tubulin in 11 of 12 serial biopsies obtained from patients receiving ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined.

Conclusion: Assessing the levels of detyrosinated and/or acetylated α-tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.
Data from Expression of Terminally Glycosylated Calcitonin Receptor–Like Receptor in Uterine Leiomyoma: Endothelial Phenotype and Association with Microvascular Density
Authors: Nikitenko Leonid L. , Cross Tanya , Campo Leticia , Turley Helen , Leek Russell , Manek Sanjiv , Bicknell Roy , Rees Margaret C.P.
Published: April 2023

Abstract
Purpose: The role for the hypoxia-inducible angiogenic factor adrenomedullin (AM) in tumor growth and progression has been suggested. Calcitonin receptor–like receptor (CL) is a G protein–coupled receptor (GPCR) that mediates effects of AM, but little information is available on its expression and functional state in human tumors. The present study attempted to determine CL potential for antiangiogenic therapy of uterine leiomyoma.

Experimental Design and Results: GPCR CL is transported to the cell surface and recognized by AM only when terminally/mature glycosylated. The presence and localization of this form of the receptor in tumor and surrounding myometrial tissues obtained from leiomyoma-bearing uteri were examined using deglycosylation, immunoblotting, and immunofluorescence analysis. The mature CL glycoprotein was expressed in both tissues and localized exclusively in normal and tumor endothelium within leiomyoma-bearing uteri. The functionality of the receptor expressed in myometrial microvascular endothelial cells (MMVEC) was examined in vitro using receptor internalization and angiogenic assays. The mature CL glycoprotein expressed by primary MMVECs was functional because AM interacted with this GPCR and induced its internalization as well as angiogenic effects (proliferation and migration) in MMVECs in vitro. Finally, the levels of tissue-expressed mature CL glycoprotein as a functional form of this GPCR were analyzed by immunoblotting. The expression of this functional form of the receptor in vivo was significantly decreased (P = 0.01) in leiomyoma tissue, and this was concurrent with the decrease in microvascular density (measured by Chalkley counting) in tumor compared with surrounding myometrium (P = 0.031).

Conclusions: Our findings suggest that GPCR CL mediates angiogenic effects of AM in myometrium and that further evaluation of the properties of the CL expressed in both normal and tumor endothelium in vivo may be essential before targeting this endothelial GPCR for antiangiogenic therapies.
Data from Tumor-Targeting Properties of Novel Antibodies Specific to the Large Isoform of Tenascin-C
Authors: Brack Simon S. , Silacci Michela , Birchler Manfred , Neri Dario
Published: April 2023

Abstract
Background: The targeted delivery of bioactive molecules with antibodies specific to tumor-associated antigens represents a promising strategy for improving the efficacy of tumor therapy. The large isoform of tenascin-C, an abundant glycoprotein of the tumor extracellular matrix, is strongly overexpressed in adult tissue undergoing tissue remodeling, including wound healing and neoplasia, and has been implicated in a variety of different cancers while being virtually undetectable in most normal adult tissues.

Experimental Design: We have used antibody phage technology to generate good-quality human recombinant antibodies (F16 and P12) specific to the alternatively spliced domains A1 and D of the large isoform of tenascin-C. The tumor-targeting properties of F16 and P12 were assessed by biodistribution studies in tumor xenografts using the antibodies in small immunoprotein (SIP) format.

Results: SIP(F16) selectively accumulated at the tumor site with 4.5%ID/g at 24 hours in the U87 glioblastoma model but was rapidly cleared from other organs (tumor-to-organ ratios, ∼10:1). The accumulation of SIP(P12) in the tumor was lower compared with SIP(F16) and persistent levels of radioactivity were observed in the intestine.

Conclusions: These data suggest that the F16 antibody, specific to domain A1 of tenascin-C, is a promising building block for the development of antibody-based pharmaceuticals in view of its excellent tumor-targeting performance and the strong expression of the antigen in a variety of primary and metastatic tumors.
Data from An Adenoviral Vaccine Encoding Full-Length Inactivated Human Her2 Exhibits Potent Immunogenicty and Enhanced Therapeutic Efficacy without Oncogenicity
Authors: Hartman Zachary C. , Wei Junping , Osada Takuya , Glass Oliver , Lei Gangjun , Yang Xiao-Yi , Peplinski Sharon , Kim Dong-Wan , Xia Wenle , Spector Neil , Marks Jeffrey , Barry William , Hobeika Amy , Devi Gayathri , Amalfitano Andrea , Morse Michael A. , Lyerly H. Kim , Clay Timothy M.
Published: April 2023

Abstract
Purpose: Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in imunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use.

Experimental Design: We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo.

Results: Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo.

Conclusions: Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials. Clin Cancer Res; 16(5); 1466–77
Data from Pharmacometabonomic Profiling as a Predictor of Toxicity in Patients with Inoperable Colorectal Cancer Treated with Capecitabine
Authors: Backshall Alexandra , Sharma Rohini , Clarke Stephen J. , Keun Hector C.
Published: April 2023

Abstract
Purpose: Endogenous metabolic profiles have been shown to predict the fate and toxicity of drugs such as acetaminophen in healthy individuals. However, the clinical utility of metabonomics in oncology remains to be defined. We aimed to evaluate the effect of pretreatment serum metabolic profiles generated by 1H NMR spectroscopy on toxicity in patients with inoperable colorectal cancer receiving single agent capecitabine.

Experimental Design: Serum was collected from 54 patients with a diagnosis of locally advanced or metastatic colorectal cancer prior to treatment with single agent capecitabine. 1H NMR spectroscopy was used to generate metabolic profile data for each patient. Toxicities were graded according to National Cancer Institute Common Toxicity Criteria version 2.0.

Results: Higher levels of low-density lipoprotein–derived lipids, including polyunsaturated fatty acids and choline phospholipids predicted for higher grade toxicity over the treatment period. Statistical analyses revealed a “pharmacometabonomic” lipid profile that correlated with severity of toxicity.

Conclusions: This study suggests that metabolic profiles can delineate subpopulations susceptible to adverse events and have a potential role in the assessment of treatment viability for cancer patients prior to commencing chemotherapy. Clin Cancer Res; 17(9); 3019–28. ©2011 AACR.
Data from Hypoxia-Inducible Factor-1α and Hypoxia-Inducible Factor-2α Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I
Authors: Catrina Sergiu-Bogdan , Botusan Ileana Ruxandra , Rantanen Anja , Catrina Anca Irinel , Pyakurel Pawan , Savu Octavian , Axelson Magnus , Biberfeld Peter , Poellinger Lorenz , Brismar Kerstin
Published: April 2023

Abstract
Purpose: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (α and β), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF α subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF α subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line.

Results: Both HIF-1α and HIF-2α were expressed in KS biopsies in all tumoral stages. HIF-1α immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF α subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I–induced HIF α accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with αIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I–dependent induction of both HIF α congeners.

Conclusion: These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.
Data from The Green Tea Polyphenol EGCG Potentiates the Antiproliferative Activity of c-Met and Epidermal Growth Factor Receptor Inhibitors in Non–small Cell Lung Cancer Cells
Authors: Milligan Shawn A. , Burke Patrick , Coleman David T. , Bigelow Rebecca L. , Steffan Joshua J. , Carroll Jennifer L. , Williams Briana Jill , Cardelli James A.
Published: April 2023

Abstract
Purpose: Activation of the c-Met and epidermal growth factor receptors (EGFR) promotes the growth and survival of non–small cell lung cancer (NSCLC). Specific receptor antagonists have shown efficacy in the clinic, but tumors often become resistant to these therapies. We investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to inhibit cell proliferation, and c-Met receptor and EGFR kinase activation in several NSCLC cell lines.

Experimental Design: NSCLC cell lines with variable sensitivity to the EGFR antagonist erlotinib were studied. Cell growth was evaluated using proliferation and colony formation assays. Kinase activation was assessed via Western blot analysis. Experiments were conducted with EGCG, the EGFR antagonist erlotinib, and the c-Met inhibitor SU11274. The antagonists were also tested in a xenograft model using SCID mice.

Results: EGCG inhibited cell proliferation in erlotinib-sensitive and -resistant cell lines, including those with c-Met overexpression, and acquired resistance to erlotinib. The combination of erlotinib and EGCG resulted in greater inhibition of cell proliferation and colony formation than either agent alone. EGCG also completely inhibited ligand-induced c-Met phosphorylation and partially inhibited EGFR phosphorylation. The triple combination of EGCG/erlotinib/SU11274 resulted in a greater inhibition of proliferation than EGCG with erlotinib. Finally, the combination of EGCG and erlotinib significantly slowed the growth rate of H460 xenografts.

Conclusion: EGCG is a potent inhibitor of cell proliferation, independent of EGFR inhibition, in several NSCLC cell lines, including those resistant to both EGFR kinase inhibitors and those overexpressing c-Met. Therefore, EGCG might be a useful agent to study as an adjunct to other anticancer agents.
Data from Arsenic Trioxide and the Phosphoinositide 3-Kinase/Akt Pathway in Chronic Lymphocytic Leukemia
Authors: Goussetis Dennis J. , Platanias Leonidas C.
Published: April 2023

Abstract
Simultaneous targeting of the phosphoinositide 3-kinase (PI3K)/Akt pathway increases arsenic trioxide (ATO)–dependent cytotoxicity of chronic lymphocytic leukemia (CLL) cells, whereas it has no significant effects on normal lymphocytes. Combinations of ATO with small molecules that target PI3K and/or Akt may provide a novel approach for the treatment of CLL. Clin Cancer Res; 16(17); 4311–2. ©2010 AACR.
Data from Molecular Classification of Gastric Cancer: A New Paradigm
Authors: Shah Manish A. , Khanin Raya , Tang Laura , Janjigian Yelena Y. , Klimstra David S. , Gerdes Hans , Kelsen David P.
Published: April 2023

Abstract
Purpose: Gastric cancer may be subdivided into 3 distinct subtypes—proximal, diffuse, and distal gastric cancer—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology. Our aim is to test the hypothesis that these distinct gastric cancer subtypes may also be distinguished by gene expression analysis.

Experimental Design: Patients with localized gastric adenocarcinoma being screened for a phase II preoperative clinical trial (National Cancer Institute, NCI #5917) underwent endoscopic biopsy for fresh tumor procurement. Four to 6 targeted biopsies of the primary tumor were obtained. Macrodissection was carried out to ensure more than 80% carcinoma in the sample. HG-U133A GeneChip (Affymetrix) was used for cDNA expression analysis, and all arrays were processed and analyzed using the Bioconductor R-package.

Results: Between November 2003 and January 2006, 57 patients were screened to identify 36 patients with localized gastric cancer who had adequate RNA for expression analysis. Using supervised analysis, we built a classifier to distinguish the 3 gastric cancer subtypes, successfully classifying each into tightly grouped clusters. Leave-one-out cross-validation error was 0.14, suggesting that more than 85% of samples were classified correctly. Gene set analysis with the false discovery rate set at 0.25 identified several pathways that were differentially regulated when comparing each gastric cancer subtype to adjacent normal stomach.

Conclusions: Subtypes of gastric cancer that have epidemiologic and histologic distinctions are also distinguished by gene expression data. These preliminary data suggest a new classification of gastric cancer with implications for improving our understanding of disease biology and identification of unique molecular drivers for each gastric cancer subtype. Clin Cancer Res; 17(9); 2693–701. ©2011 AACR.
Data from MAGE-A Inhibits Apoptosis in Proliferating Myeloma Cells through Repression of Bax and Maintenance of Survivin
Authors: Nardiello Tricia , Jungbluth Achim A. , Mei Anna , DiLiberto Maurizio , Huang Xiangao , Dabrowski Ania , Andrade Valéria C.C. , Wasserstrum Rebecca , Ely Scott , Niesvizky Ruben , Pearse Roger , Coleman Morton , Jayabalan David S. , Bhardwaj Nina , Old Lloyd J. , Chen-Kiang Selina , Cho Hearn Jay
Published: April 2023

Abstract
Purpose: The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67+ malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells.

Experimental Design: The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis.

Results: MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms.

Conclusions: These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms. Clin Cancer Res; 17(13); 4309–19. ©2011 AACR.
Data from Phase I Studies of CBP501, a G2 Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors
Authors: Shapiro Geoffrey I. , Tibes Raoul , Gordon Michael S. , Wong Bryan Y. , Eder Joseph Paul , Borad Mitesh J. , Mendelson David S. , Vogelzang Nicholas J. , Bastos Bruno R. , Weiss Glen J. , Fernandez Cristian , Sutherland William , Sato Hitoshi , Pierceall William E. , Weaver David , Slough Scott , Wasserman Ernesto , Kufe Donald W. , Von Hoff Daniel , Kawabe Takumi , Sharma Sunil
Published: April 2023

Abstract
Purpose: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G2 checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.

Experimental Design: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m2), or with cisplatin (both on D1, q3w, from 3.6 mg/m2 CBP501, 50 mg/m2 cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles.

Results: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m2 CBP501 and 75 mg/m2 cisplatin, with two patients at the highest dose (36.4 mg/m2 CBP501, 75 mg/m2 cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G3 rise of troponin in one patient. Grade 3 to 4 treatment–related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease.

Conclusions: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients. Clin Cancer Res; 17(10); 3431–42. ©2011 AACR.
Data from Gene Expression Profiling–Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome
Authors: Jönsson Göran , Busch Christian , Knappskog Stian , Geisler Jürgen , Miletic Hrvoje , Ringnér Markus , Lillehaug Johan R. , Borg Åke , Lønning Per Eystein
Published: April 2023

Abstract
Purpose: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.

Experimental Design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus, and NRAS/BRAF mutation screening.

Results: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P < 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).

Conclusions: Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome. Clin Cancer Res; 16(13); 3356–67. ©2010 AACR.
Data from Homozygous Deletion Mapping in Myeloma Samples Identifies Genes and an Expression Signature Relevant to Pathogenesis and Outcome
Authors: Dickens Nicholas J. , Walker Brian A. , Leone Paola E. , Johnson David C. , Brito José L. , Zeisig Athanasia , Jenner Matthew W. , Boyd Kevin D. , Gonzalez David , Gregory Walter M. , Ross Fiona M. , Davies Faith E. , Morgan Gareth J.
Published: April 2023

Abstract
Purpose: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes.

Experimental Design: Using single nucleotide polymorphism–based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome.

Results: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the “cell death” network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets.

Conclusions: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma. Clin Cancer Res; 16(6); 1856–64
Data from Genomic and Clinical Analysis of Amplification of the 13q31 Chromosomal Region in Alveolar Rhabdomyosarcoma: A Report from the Children's Oncology Group
Authors: Reichek Jennifer L. , Duan Fenghai , Smith Lynette M. , Gustafson Donna M. , O'Connor Roddy S. , Zhang Chune , Dunlevy Mandy J. , Gastier-Foster Julie M. , Barr Frederic G.
Published: April 2023

Abstract
Purpose: This study determined the molecular characteristics and clinical significance of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma (ARMS), an aggressive pediatric cancer with frequent PAX3-FOXO1 and PAX7-FOXO1 gene fusions.

Experimental Design: The 13q31 amplicon was localized in an initial panel of ARMS cases using oligonucleotide arrays. A fluorescence in situ hybridization assay for this localized region was designed, and applied to more ARMS cases to determine the frequency and distribution of amplification. Quantitative reverse transcription-PCR assays were applied to measure gene expression. The clinical significance of copy number and expression was determined with Kaplan–Meier and Cox proportional hazard models.

Results: We localized the 13q31 amplicon to a 0.15 Mb region containing the MIR17HG gene encoding the polycistronic microRNA cluster, miR-17–92. This amplicon is present in 23% of ARMS cases with a marked preference for PAX7-FOXO1-positive cases. In tumors with 13q31 amplification, there is significantly increased expression of 5 of 6 microRNA's within the miR-17–92 cluster (miR-17, miR-19a, miR-19b, miR-20a, and miR-92a). In addition, a subset of nonamplified tumors with copy number-independent overexpression of all 6 microRNA's was identified. In clinical analyses, there was a significantly worse outcome associated with increased expression of the 5 microRNA's described above in 13q31-amplified cases when compared to nonamplified cases. There was also an improved outcome in 13q31-amplified cases with lower expression of these microRNA's.

Conclusions: 13q31 amplification and expression of the miR-17–92 cluster provide novel markers for identifying good and poor prognostic subsets of PAX7-FOXO1-positive ARMS. Clin Cancer Res; 17(6); 1463–73. ©2011 AACR.
Data from The Tissue Is the Issue: Personalized Medicine for Non-Small Cell Lung Cancer
Authors: Hirsch Fred R. , Wynes Murry W. , Gandara David R. , Bunn Paul A.
Published: April 2023

Abstract
The development of molecular markers is crucial for improving therapy in advanced non-small cell lung cancer (NSCLC). Here, we review perspectives of biomarker-driven personalized therapy in NSCLC, with particular reference to the detection of EML4-ALK gene rearrangements. Different molecular assays, validation, and clinical application to different types of tissue specimens are discussed. Clin Cancer Res; 16(20); 4909–11. ©2010 AACR.
Data from The Progression from MGUS to Smoldering Myeloma and Eventually to Multiple Myeloma Involves a Clonal Expansion of Genetically Abnormal Plasma Cells
Authors: López-Corral Lucía , Gutiérrez Norma C. , Vidriales Maria Belén , Mateos Maria Victoria , Rasillo Ana , García-Sanz Ramón , Paiva Bruno , San Miguel Jesús F.
Published: April 2023

Abstract
Purpose: Genetic aberrations detected in multiple myeloma (MM) have also been reported in the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Our aim was to investigate in depth the level of clonal heterogeneity of recurrent genetic abnormalities in these conditions.

Experimental Design: Immunoglobulin heavy chain (IGH) translocations, 13q14 and 17p13 deletions, and 1q21 gains using FISH were evaluated in 90 MGUS, 102 high-risk SMM, and 373 MM. To this end, we not only purified plasma cells (PC) for the FISH analysis (purity > 90%), but subsequently, we examined the correlation between the proportion of PC with cytogenetic changes and the number of clonal PC present in the same sample, as measured by multiparametric flow cytometry.

Results: We observed a significant difference between the proportion of clonal PC with specific genetic abnormalities in MGUS compared with SMM and in SMM compared with MM. Thus, the median proportion of PC with IGH translocations globally considered, t(11;14) and 13q deletions was significantly lower in MGUS than in SMM, and in SMM than in MM [IGH translocations: 34% vs. 57% vs. 76%; t(11;14): 38% vs. 61% vs. 81%; and 13q deletion: 37% vs. 61% vs. 74% in MGUS, SMM, and MM, respectively]. For t(4;14), the difference was significant in the comparison between MGUS/SMM and MM and for 1q between MGUS and SMM/MM.

Conclusions: This study demonstrates that the progression from MGUS to SMM, and eventually to MM, involves a clonal expansion of genetically abnormal PC. Clin Cancer Res; 17(7); 1692–700. ©2011 AACR.
Data from Clinical Implications of Gene Dosage and Gene Expression Patterns in Diploid Breast Carcinoma
Authors: Parris Toshima Z. , Danielsson Anna , Nemes Szilárd , Kovács Anikó , Delle Ulla , Fallenius Ghita , Möllerström Elin , Karlsson Per , Helou Khalil
Published: April 2023

Abstract
Purpose: Deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells. In cancer, regulation of gene transcription can be mediated in a variety of ways. The purpose of this study was to assess the impact of gene dosage on gene expression patterns and the effect of other mechanisms on transcriptional levels, and to associate these genomic changes with clinicopathologic parameters.

Experimental Design: We screened 97 invasive diploid breast tumors for DNA copy number alterations and changes in transcriptional levels using array comparative genomic hybridization and expression microarrays, respectively.

Results: The integrative analysis identified an increase in the overall number of genetic alterations during tumor progression and 15 specific genomic regions with aberrant DNA copy numbers in at least 25% of the patient population, i.e., 1q22, 1q22-q23.1, 1q25.3, 1q32.1, 1q32.1-q32.2, 8q21.2-q21.3, 8q22.3, 8q24.3, and 16p11.2 were recurrently gained, whereas 11q25, 16q21, 16q23.3, and 17p12 were frequently lost (P < 0.01). An examination of the expression patterns of genes mapping within the detected genetic aberrations identified 47 unique genes and 1 Unigene cluster significantly correlated between the DNA and relative mRNA levels. In addition, more malignant tumors with normal gene dosage levels displayed a recurrent overexpression of UBE2C, S100A8, and CBX2, and downregulation of LOC389033, STC2, DNALI1, SCUBE2, NME5, SUSD3, SERPINA11, AZGP1, and PIP.

Conclusions: Taken together, our findings suggest that the dysregulated genes identified here are critical for breast cancer initiation and progression, and could be used as novel therapeutic targets for drug development to complement classical clinicopathologic features. Clin Cancer Res; 16(15); 3860–74. ©2010 AACR.
Data from X-Linked Ectodermal Dysplasia Receptor Is Downregulated in Breast Cancer via Promoter Methylation
Authors: Punj Vasu , Matta Hittu , Chaudhary Preet M.
Published: April 2023

Abstract
Purpose: The X-linked ectodermal dysplasia receptor (XEDAR) is a novel receptor of the tumor necrosis factor receptor family that binds to ectodysplasin-A2 (EDA-A2) and induces cell death. The purpose of this study was to determine the tumor-suppressive potential of XEDAR in the development of breast cancer.

Experimental Design: We analyzed the expression of XEDAR in breast cancer cell lines and tumor samples using quantitative real-time PCR analysis and immunoblotting. We analyzed the human XEDAR gene promoter for the presence of any CpG island and examined its methylation status using methylation-specific real-time PCR. We examined the effect of 5-aza-2′-deoxycytidine on the expression of XEDAR and sensitivity to EDA-A2–induced apoptosis in breast cancer cell lines.

Results: Expression of XEDAR, but not EDA-A2, was downregulated in most tumorigenic breast cancer cell lines and tumor samples. Loss of XEDAR expression correlated with the hypermethylation of its promoter. Ectopic expression of XEDAR in MDA-MB-231 cells resulted in significant induction of apoptosis and reduction in colony formation. Treatment with 5-aza-2′-deoxycytidine restored XEDAR expression in breast cancer cell lines with methylated XEDAR promoter and sensitized them to EDA-A2–induced cell death.

Conclusions: Our results suggest that XEDAR expression is downregulated in most breast cancers via promoter methylation, which may contribute to accelerated tumor development by blocking EDA-A2–induced cell death. XEDAR may represent a novel breast tumor suppressor gene, and restoration of its expression by treatment with DNA demethylating agents may represent an attractive approach for the treatment of breast cancer. Clin Cancer Res; 16(4); 1140–8
Data from Overcoming Antiangiogenic Resistance
Authors: Yao James C. , Phan Alexandria
Published: April 2023

Abstract
The success of drugs targeting angiogenesis is tempered by the transient duration of disease control and modest survival improvement. The very hypoxic stress produced by successful therapy may lead to upregulation of multiple pathways that promote angiogenesis and invasive behavior. Overcoming this evasive resistance may further improve outcome. Clin Cancer Res; 17(16); 5217–9. ©2011 AACR.
Data from Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer
Authors: Kondo Shunsuke , Iwata Satoshi , Yamada Taketo , Inoue Yusuke , Ichihara Hiromi , Kichikawa Yoshiko , Katayose Tomoki , Souta-Kuribara Akiko , Yamazaki Hiroto , Hosono Osamu , Kawasaki Hiroshi , Tanaka Hirotoshi , Hayashi Yuichiro , Sakamoto Michiie , Kamiya Kazunori , Dang Nam H. , Morimoto Chikao
Published: April 2023

Abstract
Purpose: In a substantial population of non–small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.

Experimental Design: Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs.

Results: We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγnull mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival.

Conclusion: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis. Clin Cancer Res; 18(22); 6326–38. ©2012 AACR.
Data from Cyclophosphamide Induces a Type I Interferon–Associated Sterile Inflammatory Response Signature in Cancer Patients' Blood Cells: Implications for Cancer Chemoimmunotherapy
Authors: Moschella Federica , Torelli Giovanni Fernando , Valentini Mara , Urbani Francesca , Buccione Carla , Petrucci Maria Teresa , Natalino Fiammetta , Belardelli Filippo , Foà Robin , Proietti Enrico
Published: April 2023

Abstract
Purpose: Certain chemotherapeutics, particularly cyclophosphamide, can enhance the antitumor efficacy of immunotherapy. A better understanding of the cellular and molecular basis of cyclophosphamide-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy.

Experimental Design: Transcript profiling and flow cytometry were used to explore cyclophosphamide-induced immunoadjuvanticity in patients with hematologic malignancies.

Results: A single high-dose treatment rapidly (1–2 days) induced peripheral blood mononuclear cell (PBMC) transcriptional modulation, leading to reduction of cell-cycle and biosynthetic/metabolic processes and augmentation of DNA damage and cell death pathways (p53 signaling pathway), death-related scavenger receptors, antigen processing/presentation mediators, T-cell activation markers and, noticeably, a type I IFN (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, IFN-I–induced proinflammatory mediators (CXCL10, CCL2, IL-8, and BAFF) were increased in patients' plasma. Accordingly, cyclophosphamide induced the expansion/activation of CD14+CD16+ monocytes, of HLA-DR+, IL-8RA+, and MARCO+ monocytes/dendritic cells, and of CD69+, OX40+, and IL-8RA+ lymphocytes.

Conclusions: Altogether, these data identify the cyclophosphamide-induced immunomodulatory factors in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated with blood cell death, through p53 and IFN-I–related mechanisms. Clin Cancer Res; 19(15); 4249–61. ©2013 AACR.
Predicting postoperative gastric cancer prognosis based on inflammatory factors and machine learning technology
Authors: Zhou Cheng-Mao , Wang Ying , Yang Jian-Jun , Zhu Yu
Published: April 2023

Objective

There is a strong association between gastric cancer and inflammatory factors. Many studies have shown that machine learning can predict cancer patients’ prognosis. However, there has been no study on predicting gastric cancer death based on machine learning using related inflammatory factor variables.

Methods

Six machine learning algorithms are applied to predict total gastric cancer death after surgery.

Results

The Gradient Boosting Machine (GBM) algorithm factors accounting for the prognosis weight outcome show that the three most important factors are neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and age. The total postoperative death model showed that among patients with gastric cancer from the predictive test group: The highest accuracy was LR (0.759), followed by the GBM algorithm (0.733). For the six algorithms, the AUC values, from high to low, were LR, GBM, GBDT, forest, Tr and Xgbc. Among the six algorithms, Logistic had the highest precision (precision = 0.736), followed by the GBM algorithm (precision = 0.660). Among the six algorithms, GBM had the highest recall rate (recall = 0.667).

Conclusion

Postoperative mortality from gastric cancer can be predicted based on machine learning.