bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies
Authors: Gerber Hans-Peter , Ferrara Napoleone 
Published: June 2022

AbstractPreclinical models have examined the pharmacologic and pharmacodynamic activities of an anti–vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab/A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or tumor location. Several of these studies also observed significant inhibition of tumor metastases. Various studies have examined the feasibility of combining anti-VEGF therapy with cytotoxic or biological agents. Combining bevacizumab/A4.6.1 with doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy resulted in additive or synergistic tumor growth inhibition. Changes in vascular functions were frequently reported, including decreased vessel diameter, density, and permeability in response to treatment. A reduction in interstitial fluid pressure was also observed. In some studies, these improvements resulted in an increase in intratumoral uptake of chemotherapy, implying that the most effective use of anti-VEGF therapy is in combination with chemotherapy. Alternatively, combination treatment with radiation increased tumor oxygenation and tumor growth inhibition. Interestingly, anti-VEGF therapy has also been reported to reduce the development of ascites in ovarian mouse models. Finally, safety pharmacology studies with bevacizumab in cynomolgus monkeys showed that this agent is generally well tolerated with no unexpected adverse events.
Novel Role of Prostate-Specific Membrane Antigen in Suppressing Prostate Cancer Invasiveness
Authors: Ghosh Arundhati , Wang Xinning , Klein Eric , Heston Warren D.W. 
Published: June 2022

Abstract
Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is overexpressed in prostate cancer. PSMA is a unique cell surface marker, negatively regulated by androgen and extensively used for imaging of hormone refractory carcinomas and metastatic foci. PSMA is a carboxypeptidase with two important enzymatic functions, namely, folate hydrolase and NAALADase. PSMA also exhibits an endocytic function, in which it spontaneously recycles through endocytic vesicles. PSMA is overexpressed at various stages of prostate cancer, including androgen-sensitive and -independent disease, increased in expression with early relapse after therapy. We have used in vitro invasion assays to explore the possible role of PSMA in the metastasis of prostate cancer cells. Androgen-dependent prostate cancer lines, which express PSMA endogenously (e.g., LNCaP, MDA PCa2b, and CWR22Rv1) are less invasive compared with androgen-independent PC3 or DU145 cells, neither of which expresses PSMA. Ectopic expression of PSMA in PC3 cells reduced the invasiveness of these cells, suggesting that this reduction in the invasion capability of PSMA-expressing cells is due to PSMA expression and not to intrinsic properties of different prostate cancer cell lines. Furthermore, knockdown of PSMA expression increased invasiveness of LNCaP cells by 5-fold. Finally, expression of PSMA mutants lacking carboxypeptidase activity reduced the impact of PSMA expression on invasiveness. Thus, it seems that the enzymatic activity is associated with the effect of PSMA on invasiveness.
A Novel Localization of the G-Protein-Coupled CysLT1 Receptor in the Nucleus of Colorectal Adenocarcinoma Cells
Authors: Nielsen Christian Kamp , Campbell Joan I.A. , Öhd John F. , Mörgelin Matthias , Riesbeck Kristian , Landberg Göran , Sjölander Anita 
Published: June 2022

AbstractSearching for a link between inflammation and colon cancer, we have found that the inflammatory mediator leukotriene D4 (LTD4), via its receptor CysLT1, induces cyclooxygenase-2 expression, survival, and proliferation in intestinal epithelial cells. In conjunction with our previous observation that CysLT1 receptor expression is increased in colorectal adenocarcinomas, we here found an increased nuclear localization of the CysLT1 receptor in colorectal adenocarcinomas. This novel discovery of CysLT1 receptors in the nucleus was further analyzed. It was found to be located in the outer nuclear membrane in colon cancer cells and in the nontransformed epithelial cell line Int 407 cells by Western blot and electron microscopy. Cancer cells displayed higher amounts of the nuclear CysLT1 receptor, but prolonged LTD4 exposure induced its nuclear translocation in nontransformed cells. Truncation of a nuclear localization sequence abrogated this translocation as well as the LTD4-induced proliferative response. In accordance, nuclear CysLT1 receptors exhibited proliferative extracellular signal-regulated kinase 1/2 signaling. The significance of these experimental findings is supported by the observed correlation between the proliferative marker Ki-67 and nuclear CysLT1 receptor localization in colorectal adenocarcinomas. The present findings indicate that LTD4 cannot only be synthesized but also signal proliferation through nuclear CysLT1 receptors, stressing the importance of leukotrienes in inflammation-induced colon carcinogenesis.
Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups
Authors: Wong Kwong-Kwok , Chang Yi-Mieng , Tsang Yvonne T.M. , Perlaky Laszlo , Su Jack , Adesina Adekunle , Armstrong Dawna L. , Bhattacharjee Meenakshi , Dauser Robert , Blaney Susan M. , Chintagumpala Murali , Lau Ching C. 
Published: June 2022

Abstract
Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expression profiles of 21 JPAs, determined using Affymetrix GeneChip U133A, were compared with subjects with normal cerebella. The genes involved in neurogenesis, cell adhesion, synaptic transmission, central nervous system development, potassium ion transport, protein dephosphorylation, and cell differentiation were found to be significantly deregulated in JPA. These 21 JPAs were further clustered into two major groups by unsupervised hierarchical clustering using a set of 848 genes with high covariance (0.5-10). Supervised analysis with Significance Analysis of Microarrays software between these two potential subgroups identified a list of significant differentially expressed genes involved in cell adhesion, regulation of cell growth, cell motility, nerve ensheathment, and angiogenesis. Immunostaining of myelin basic protein on paraffin sections derived from 18 incompletely resected JPAs suggests that JPA without myelin basic protein–positively stained tumor cells may have a higher tendency to progress.
Protein Expression Profiling Identifies Subclasses of Breast Cancer and Predicts Prognosis
Authors: Jacquemier Jocelyne , Ginestier Christophe , Rougemont Jacques , Bardou Valérie-Jeanne , Charafe-Jauffret Emmanuelle , Geneix Jeannine , Adélaïde José , Koki Alane , Houvenaeghel Gilles , Hassoun Jacques , Maraninchi Dominique , Viens Patrice , Birnbaum Daniel , Bertucci François 
Published: June 2022

Abstract
Breast cancer is a heterogeneous disease whose evolution is difficult to predict by using classic histoclinical prognostic factors. Prognostic classification can benefit from molecular analyses such as large-scale expression profiling. Using immunohistochemistry on tissue microarrays, we have monitored the expression of 26 selected proteins in more than 1,600 cancer samples from 552 consecutive patients with early breast cancer. Both an unsupervised approach and a new supervised method were used to analyze these profiles. Hierarchical clustering identified relevant clusters of coexpressed proteins and clusters of tumors. We delineated protein clusters associated with the estrogen receptor and with proliferation. Tumor clusters correlated with several histoclinical features of samples, including 5-year metastasis-free survival (MFS), and with the recently proposed pathophysiologic taxonomy of disease. The supervised method identified a set of 21 proteins whose combined expression significantly correlated to MFS in a learning set of 368 patients (P &lt; 0.0001) and in a validation set of 184 patients (P &lt; 0.0001). Among the 552 patients, the 5-year MFS was 90% for patients classified in the “good-prognosis class” and 61% for those classified in the “poor-prognosis class” (P &lt; 0.0001). This difference remained significant when the molecular grouping was applied according to lymph node or estrogen receptor status, as well as the type of adjuvant systemic therapy. In multivariate analysis, the 21-protein set was the strongest independent predictor of clinical outcome. These results show that protein expression profiling may be a clinically useful approach to assess breast cancer heterogeneity and prognosis in stage I, II, or III disease.
Comparative Genomic Hybridization Profiles in Human BRCA1 and BRCA2 Breast Tumors Highlight Differential Sets of Genomic Aberrations
Authors: van Beers Erik H. , van Welsem Tibor , Wessels Lodewyk F.A. , Li Yunlei , Oldenburg Rogier A. , Devilee Peter , Cornelisse Cees J. , Verhoef Senno , Hogervorst Frans B.L. , van't Veer Laura J. , Nederlof Petra M. 
Published: June 2022

Abstract
BRCA1 or BRCA2 germline mutations cause ∼30% of breast cancers within high-risk families. This represents 5% of total breast cancer incidence. Although BRCA1 and BRCA2 are both implicated in DNA repair and genome stability, it is unknown whether BRCA1 and BRCA2 are associated with similar or distinct diseases. In a previous study we reported that BRCA1-related breast carcinomas show a distinct genomic profile as determined by comparative genomic hybridization (CGH). We now hypothesize that, if functionally equivalent, mutations in BRCA1 and BRCA2 would result in similar genomic profiles in tumors. Here we report the chromosomal gains and losses as measured by CGH in 25 BRCA2-associated breast tumors and compared them with our existing 36 BRCA1 and 30 control profiles. We compared all chromosomal regions and determined the regions of differential gain or loss between tumor classes and controls. BRCA2 and control tumors have very similar genomic profiles. As a consequence, and in contrast to BRCA1-associated tumors, CGH profiles from BRCA2-associated tumors could not be distinguished from control tumors using the classification methodology as we have developed before. The largest number of significant differences existed between BRCA1 and controls, followed by BRCA1 compared with BRCA2, suggesting different tumor development pathways for BRCA1 and BRCA2.
Receptor for Hyaluronan-Mediated Motility Correlates with Centrosome Abnormalities in Multiple Myeloma and Maintains Mitotic Integrity
Authors: Maxwell Christopher A. , Keats Jonathan J. , Belch Andrew R. , Pilarski Linda M. , Reiman Tony 
Published: June 2022

Abstract
Elevated expression of receptor for hyaluronan-mediated motility (RHAMM) within ex vivo diagnostic multiple myeloma plasma cells predicts for aggressive disease and patient survival. Here, we investigate the relationship between RHAMM and centrosomal abnormalities within multiple myeloma patient samples. We report that myeloma patient samples contain pervasive structural and numerical centrosomal abnormalities. Structural, but not numerical, centrosomal abnormalities strongly correlate with elevated RHAMM expression. As others have shown that excess pericentriolar material strongly associates with abnormal mitoses, we modeled centrosomal abnormalities with exogenous RHAMM overexpression. RHAMM overexpression in vitro resulted in centrosomal and mitotic defects. To elucidate a mechanism for RHAMM-mediated spindle defects, we further investigated RHAMM mitotic function. RHAMM mitotic localization mirrors that of targeting protein for Xklp2 (TPX2), and RHAMM interacts with the spindle assembly factors dynein and TPX2. Like TPX2, RHAMM expression is up-regulated during mitosis. Moreover, inhibition of function experiments reveals that RHAMM and TPX2 functions converge to maintain spindle integrity after spindle assembly. We postulate that augmentation of RHAMM expression within human cancers, including myeloma, can directly affect centrosomal structure and spindle integrity and potentially modulate apoptotic and cell cycle progression pathways.
Folate Transport Gene Inactivation in Mice Increases Sensitivity to Colon Carcinogenesis
Authors: Ma David W.L. , Finnell Richard H. , Davidson Laurie A. , Callaway Evelyn S. , Spiegelstein Ofer , Piedrahita Jorge A. , Salbaum J. Michael , Kappen Claudia , Weeks Brad R. , James Jill , Bozinov Daniel , Lupton Joanne R. , Chapkin Robert S. 
Published: June 2022

Abstract
Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1+/− and Folbp1−/−) significantly reduced (P &lt; 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1+/−). These animals had reduced (P &lt; 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1+/− and Folbp1−/− mice had larger crypts expressed as greater (P &lt; 0.05) numbers of cells per crypt column relative to Folbp1+/+ mice. Colonic cell proliferation was increased in RFC1+/− mice relative to RFC1+/+ mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1+/+ mice, RFC1+/− mice developed increased (P &lt; 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1+/− mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1+/+ mice. In contrast, Folbp1+/− mice developed 4-fold (P &lt; 0.05) more lesions relative to Folbp1+/+ mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.
Antiangiogenic and Antitumor Activity of a Selective PDGFR Tyrosine Kinase Inhibitor, CP-673,451
Authors: Roberts W. Gregory , Whalen Pamela M. , Soderstrom Erik , Moraski Garrett , Lyssikatos Joseph P. , Wang Huifen-F. , Cooper Beth , Baker Deborah A. , Savage Douglas , Dalvie Deepak , Atherton James A. , Ralston Sherry , Szewc Ruby , Kath John C. , Lin Jing , Soderstrom Cathy , Tkalcevic George , Cohen Bruce D. , Pollack Vince , Barth Wayne , Hungerford Will , Ung Ethan 
Published: June 2022

Abstract
CP-673,451 is a potent inhibitor of platelet-derived growth factor β-receptor (PDGFR-β) kinase- and PDGF-BB-stimulated autophosphorylation of PDGFR-β in cells (IC50 = 1 nmol/L) being more than 450-fold selective for PDGFR-β versus other angiogenic receptors (e.g., vascular endothelial growth factor receptor 2, TIE-2, and fibroblast growth factor receptor 2). Multiple models have been used to evaluate in vivo activity of CP-673,451 and to understand the pharmacology of PDGFR-β inhibition and the effect on tumor growth. These models include an ex vivo measure of PDGFR-β phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition. Inhibition of PDGFR-β phosphorylation in tumors correlates with plasma and tumor levels of CP-673,451. A dose of 33 mg/kg was adequate to provide &gt;50% inhibition of receptor for 4 hours corresponding to an EC50 of 120 ng/mL in plasma at Cmax. In a sponge angiogenesis model, CP-673,451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. × 5, p.o., corresponding to 5.5 ng/mL at Cmax). The compound did not inhibit vascular endothelial growth factor- or basic fibroblast growth factor-induced angiogenesis at concentrations which inhibited tumor growth. The antitumor efficacy of CP-673,451 was evaluated in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. Once-daily p.o. × 10 days dosing routinely inhibited tumor growth (ED50 ≤ 33 mg/kg). These data show that CP-673,451 is a pharmacologically selective PDGFR inhibitor, inhibits tumor PDGFR-β phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.
RLIP76 Transports Vinorelbine and Mediates Drug Resistance in Non–Small Cell Lung Cancer
Authors: Stuckler David , Singhal Jyotsana , Singhal Sharad S. , Yadav Sushma , Awasthi Yogesh C. , Awasthi Sanjay 
Published: June 2022

AbstractVinorelbine (Navelbine), an amphiphilic semisynthetic Vinca alkaloid, has displayed superior activity and decreased resistance in the treatment of advanced non–small cell lung cancer (NSCLC) compared with other members of its class. Recently, vinorelbine and cisplatin combination chemotherapy has been shown for the first time to confer a significant survival advantage in early-stage lung cancer after surgical therapy. The biological mechanisms underlying the differential response of NSCLC to cytocidal activity of vinorelbine have yet to be elucidated. Our recent findings indicate a role of RLIP76, a non–ATP binding cassette transport protein, in catalyzing the ATP-dependent efflux of structurally and functionally unrelated chemotherapeutic agents such as doxorubicin and vinblastine in NSCLC. Present studies were conducted to assess whether RLIP76 mediates vinorelbine transport and resistance. Here we show that RLIP76 catalyzes the transport of vinorelbine in a saturable manner with respect to vinorelbine (Km 75 nmol/L) and ATP (Km = 3.4 mmol/L). Three-fold overexpression of RLIP76 in NSCLC and SCLC confers increased resistance to cytotoxicity. RLIP76 overexpression causes a sustained intracellular decrease in vinorelbine concentration because of increased efflux, and anti-RLIP76 antibodies sensitize lung cancer cells to vinorelbine by inhibiting its efflux. These studies for the first time show that RLIP76 mediates vinorelbine transport and is capable of conferring drug accumulation defect and resistance to lung cancer cells.
Abstract 6285: MicroRNA-217 affects tumor microenvironment and enhances the chemosensitivity of pancreatic cancer
Authors: Kaneko Yuki , Ohzawa HIdeyuki , Kimura Yuki , Tamura Kohei , Futoh Yurie , Takahashi Kazuya , Saito Akira , Tojo Mineyuki , Miyato Hideyo , Sata Naohiro , Kitayama Joji 
Published: June 2022

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and an inherently chemoresistant tumor. Dense fibrotic stroma is a major obstacle for drug delivery to the tumor cells in PDAC. Pancreatic stellate cells (PSCs) are the major stromal cells responsible for fibrotic microenvironment. MicroRNA-217 (miR-217) is known mainly as a tumor suppressor. However, the detailed roles of miR-217 on pathophysiology of PDAC remain unclarified.
Methods: Expressions levels of miR-217 were measured in surgically resected human PDAC samples. Using Lipofectamine RNAiMAX, miR-217 or negative control miR (NC) were transfected in human pancreatic cancer cells, Panc-1, MIApaca-2, BxPC-3 and murine PAN02 cells, and chemosensitivities to gemcitabine and paclitaxel were investigated by MTS assay. Human hPSC-1 (obtained from Riken cell bank, Japan) was cultured in 20%FBS+DMEM and the changes of phenotypes and expression levels of miR-217 after the stimulation with TGF-β1 was measured by fluorescein microscope and digital PCR, respectively.
Results: The expression level of miR-217 was markedly downregulated in PDAC tissues than in noncancerous pancreatic tissues (P&lt;0.001, n=9). Overexpression of miR-217 significantly inhibited the proliferation of Panc-1, MIApaca-2 and BxPC-3 (P&lt;0.001) and migration of Panc-1, MIApaca-2 and PAN02 (P&lt;0.05). Lipofection of miR-217 further reduced the number of PAN02 exposed to 1-5nM gemcitabine (P&lt;0.0001) and 0.01-0.1uM paclitaxel (P=0.0085) which resulted in the reduced the IC-50 as compared with NC. Human PSC-1 stimulated with TGF-β1 (10ng/ml) significantly reduced miR-217 expression compared to nascent cells. The stimulation with TGF-β1 upregulated the expression of cancer associated fibroblast (CAF) markers, α-smooth muscle actin (SMA) and vimentin. However, the expression levels of these markers were significantly reduced by the kipofection of miR-217.
Conclusion: MiR-217 affects both cancer and stromal cells in PDAC which may regulate chemosensitivity in PDAC. Restoring miR-217 levels in tumor cells and/or PSCs could be a future therapeutic strategy.
Citation Format: Yuki Kaneko, HIdeyuki Ohzawa, Yuki Kimura, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Naohiro Sata, Joji Kitayama. MicroRNA-217 affects tumor microenvironment and enhances the chemosensitivity of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6285.
Abstract ND11: Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers
Authors: Purkey Hans 
Published: June 2022

Abstract
Mutations in KRAS are the most common oncogenic driver mutations in human cancers. The KRAS G12C mutation is one of the most prevalent KRAS mutations, present in approximately 12% of non-small cell lung cancer, 4% of colorectal cancer, and up to 4% of other cancer types. The recent discovery and development of covalent KRAS G12C inhibitors provides an opportunity to inhibit what has historically been considered to be an “undruggable” target. GDC-6036 is an orally bioavailable, highly potent and selective KRAS G12C inhibitor, with a median IC50 in the sub-nanomolar range and greater than 18,000-fold selectivity for G12C versus non-G12C cell lines. GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will highlight the research program that led to the discovery and optimization of GDC-6036, which is currently in clinical development.
Citation Format: Hans Purkey. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND11.