bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Benefit of Lapatinib-Based Therapy in Patients with Human Epidermal Growth Factor Receptor 2–Positive Breast Tumors Coexpressing the Truncated p95HER2 Receptor
Authors: Scaltriti Maurizio , Chandarlapaty Sarat , Prudkin Ludmila , Aura Claudia , Jimenez José , Angelini Pier Davide , Sánchez Gertrudis , Guzman Marta , Parra Josep Lluis , Ellis Catherine , Gagnon Robert , Koehler Maria , Gomez Henry , Geyer Charles , Cameron David , Arribas Joaquin , Rosen Neal , Baselga José 
Published: April 2010

AbstractPurpose: A subgroup of human epidermal growth factor receptor 2 (HER2)–overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting.Experimental Design: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a first-line lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease ≥24 wk), and progression-free survival using logistic regression and Cox proportional hazard models.Results: Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors.Conclusions: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors. Clin Cancer Res; 16(9); 2688–95. ©2010 AACR.
Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients
Authors: Besser Michal J. , Shapira-Frommer Ronnie , Treves Avraham J. , Zippel Dov , Itzhaki Orit , Hershkovitz Liat , Levy Daphna , Kubi Adva , Hovav Einat , Chermoshniuk Natalia , Shalmon Bruria , Hardan Izhar , Catane Raphael , Markel Gal , Apter Sara , Ben-Nun Alon , Kuchuk Iryna , Shimoni Avichai , Nagler Arnon , Schachter Jacob 
Published: April 2010

Abstract
Purpose: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability.
Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients.
The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.
Experimental Design: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.
Results: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.
Conclusion: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer. Clin Cancer Res; 16(9); 2646–55. ©2010 AACR.
Phase I and Pharmacokinetic Study of Sequential Paclitaxel and Trabectedin Every 2 Weeks in Patients with Advanced Solid Tumors
Authors: Chu Quincy , Mita Alain , Forouzesh Bahram , Tolcher Anthony W. , Schwartz Gary , Nieto Antonio , Soto-Matos Arturo , Alfaro Vicente , Lebedinsky Claudia , Rowinsky Eric K. 
Published: April 2010

Abstract
Purpose: This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for disease-directed studies.
Experimental Design: Twenty-seven patients were treated with paclitaxel (80-120 mg/m2; 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m2; 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done.
Results: Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal dose-limiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin. At the MTD (120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response.
Conclusions: The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m2, respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings. Clin Cancer Res; 16(9); 2656–65. ©2010 AACR.
Assessment of the In vivo Antitumor Effects of ENMD-2076, a Novel Multitargeted Kinase Inhibitor, against Primary and Cell Line–Derived Human Colorectal Cancer Xenograft Models
Authors: Tentler John J. , Bradshaw-Pierce Erica L. , Serkova Natalie J. , Hasebroock Kendra M. , Pitts Todd M. , Diamond Jennifer R. , Fletcher Graham C. , Bray Mark R. , Eckhardt S. Gail 
Published: April 2010

Abstract
Purpose: This in vivo study was designed to investigate the efficacy of ENMD-2076, a small-molecule kinase inhibitor with activity against the Aurora kinases A and B, and several other tyrosine kinases linked to cancer, including vascular endothelial growth factor receptor 2, cKit, and fibroblast growth factor receptor 1, against murine xenograft models of human colorectal cancer (CRC).
Experimental Design: HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 (100 or 200 mg/kg) orally daily for 28 days. Tumor growth inhibition, dynamic contrast-enhanced magnetic resonance imaging, and 18FDG-positron emission tomography were conducted to assess the antiproliferative, antiangiogenic, and antimetabolic responses, respectively. Effects on proliferation were also analyzed by immunohistochemical methods. Additionally, three patient-derived xenografts from primary and metastatic sites were treated with ENMD-2076 (100 mg/kg) and assessed for tumor growth inhibition.
Results: In the HT-29 xenograft model, ENMD-2076 induced initial tumor growth inhibition followed by regression. Treatment was associated with significant tumor blanching, indicating a loss of vascularity and substantial reductions in tumor vascular permeability and perfusion as measured by dynamic contrast-enhanced magnetic resonance imaging. Positron emission tomography scanning showed significant decreases in 18FDG uptake at days 3 and 21 of treatment, which was associated with a marked reduction in proliferation as assessed by Ki-67. All three of the patient-derived xenografts tested were sensitive to treatment with ENMD 2076 as measured by tumor growth inhibition.
Conclusions: ENMD-2076 showed robust antitumor activity against cell line and patient-derived xenograft models of CRC that is detectable by functional imaging, supporting clinical investigation of this agent in CRC. Clin Cancer Res; 16(11); 2989–98. ©2010 AACR.
Imaging Breast Cancer Chemotherapy Response with Light
Authors: Tromberg Bruce J. , Cerussi Albert E. 
Published: April 2010

Abstract
Diffuse optical spectroscopy (DOS), which is used to image tumor metabolic response to neoadjuvant chemotherapy (NAC), shows large changes in tumor functional parameters with significant reductions in oxy- and deoxyhemoglobin for responders versus nonresponders. Although investigational, DOS may provide a cost-effective, risk-free method for optimizing NAC drug and dosing strategies for individual patients. Clin Cancer Res; 16(9); 2486–8. ©2010 AACR.
Driven to Death: Inhibition of Farnesylation Increases Ras Activity and Promotes Growth Arrest and Cell Death
Authors: Geryk-Hall Mandy , Yang Yanwen , Hughes Dennis P.M. 
Published: April 2010

Abstract
To improve cancer outcomes, investigators are turning increasingly to small molecule medicines that disrupt vital signaling cascades, inhibit malignant growth, or induce apoptosis. One vital signaling molecule is Ras, and a key step in Ras activation is membrane anchoring of Ras through prenylation, the C-terminal addition of a lipid anchor. Small molecule inhibitors of farnesyltransferase (FTI), the enzyme most often responsible for prenylating Ras, showed clinical promise, but development of FTIs such as tipifarnib has been stalled by uncertainty about their mechanism of action, because Ras seemed unimpeded in tipifarnib-treated samples. Interpretation was further complicated by the numerous proteins that may be farnesylated, as well as availability of an alternate prenylation pathway, geranylgeranylation. Our initial observations of varied response by cancer cell lines to tipifarnib led us to evaluate the role of FTI in Ras signal alteration using various tumor models. We describe our novel counterintuitive finding that endogenous Ras activity increases in cancer cell lines with low endogenous Ras activity when farnesyltransferase is inhibited by either tipifarnib or short hairpin RNA. In response to tipifarnib, variable growth arrest and/or cell death correlated with levels of activated extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Sensitivity to tipifarnib treatment was shown by growth inhibition and by an increase in subdiploid cell numbers; cells with such sensitivity had increased activation of ERK and p38 MAPK. Because Ras must be prenylated to be active, our findings suggest that geranylgeranylated N-Ras or K-Ras B interacts differently with downstream effector proteins in sensitive cancer cells responding to tipifarnib, switching the balance from cell proliferation to growth inhibition. Mol Cancer Ther; 9(5); 1111–9. ©2010 AACR.
1,25-Dihydroxyvitamin D3 Enhances the Apoptotic Activity of MDM2 Antagonist Nutlin-3a in Acute Myeloid Leukemia Cells Expressing Wild-type p53
Authors: Thompson Thelma , Andreeff Michael , Studzinski George P. , Vassilev Lyubomir T. 
Published: April 2010

Abstract
The tumor suppressor p53 is often referred to as “the guardian of the genome” because of its central role in the cellular response to oncogenic stress and prevention of tumor development. Mutations of p53 in acute myeloid leukemia (AML) are rare but resistance to chemotherapy has been reported because of the deregulation of the p53 signaling and differentiation pathways. It is known that the interaction of the vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25D) with its functional vitamin D receptor leads to differentiation, G1 arrest, and increased cell survival in p53-null AML cells. However, there are no reports on the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we examine vitamin D signaling in AML cells MOLM-13 and OCI-AML3 expressing wild-type p53 in the presence and absence of the MDM2 antagonist nutlin-3. We find that 1,25D alone induces monocytic differentiation in these cell lines similar to that seen in p53-null AML cells, suggesting that the presence of wild-type p53 is compatible with activation of vitamin D signaling. Combination of nutlin-3a with 1,25D accelerated programmed cell death, likely because of enhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and downregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, and phosphorylated extracellular signal-regulated kinase 2. Mol Cancer Ther; 9(5); 1158–68. ©2010 AACR.
Identification of c-Src as a Potential Therapeutic Target for Gastric Cancer and of MET Activation as a Cause of Resistance to c-Src Inhibition
Authors: Okamoto Wataru , Okamoto Isamu , Yoshida Takeshi , Okamoto Kunio , Takezawa Ken , Hatashita Erina , Yamada Yuki , Kuwata Kiyoko , Arao Tokuzo , Yanagihara Kazuyoshi , Fukuoka Masahiro , Nishio Kazuto , Nakagawa Kazuhiko 
Published: April 2010

Abstract
Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G1 arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G1 arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188–97. ©2010 AACR.
Activation by Tyrosine Phosphorylation as a Prerequisite for Protein Kinase Cζ to Mediate Epidermal Growth Factor Receptor Signaling to ERK
Authors: Valkova Christina , Mertens Carmen , Weisheit Simona , Imhof Diana , Liebmann Claus 
Published: April 2010

Abstract
The atypical protein kinase Cζ (PKCζ) was recently shown to mediate epidermal growth factor (EGF)–induced activation of extracellular signal–regulated kinase (ERK) in head and neck squamous carcinoma (HNSCC) cells. Here, it is shown that EGF may induce tyrosine phosphorylation of PKCζ in several HNSCC cells, breast carcinoma cells, as well as mouse embryonic fibroblasts. In COS-7 cells overexpressing EGF receptor (EGFR) and PKCζ as a tumor cell model, we show that PKCζ tyrosine phosphorylation by EGF is induced by catalytic activation. Using a loss-of-function mutant of PKCζ, we can show that the tyrosine residue 417 in PKCζ plays an important role in both PKCζ activation and the ability of PKCζ to mediate activation of ERK. The importance of PKCζ in EGF-induced ERK activation can also be shown in several HNSCC and breast carcinoma cell lines as well as in PKCζ-deficient mouse embryonic fibroblasts. In addition, we present several lines of evidence suggesting the physical association of PKCζ with EGFR and the importance of the EGFR tyrosine kinase c-Src and the Src-specific phosphorylation site pY845-EGFR in the tyrosine phosphorylation as well as catalytic activation of PKCζ. This study characterizes PKCζ as a novel mitogenic downstream mediator of EGFR and indicates PKCζ as a therapeutic target in some carcinomas. Mol Cancer Res; 8(5); 783–97. ©2010 AACR.
The β1-Integrin–Dependent Function of RECK in Physiologic and Tumor Angiogenesis
Authors: Miki Takao , Shamma Awad , Kitajima Shunsuke , Takegami Yujiro , Noda Makoto , Nakashima Yasuaki , Watanabe Ken-ichiro , Takahashi Chiaki 
Published: April 2010

Abstract
Vascular endothelial cells produce considerable amounts of matrix metalloproteinases (MMP), including MMP-2, MMP-9, and membrane type 1 (MT1)–MMP. However, little is known about the regulatory mechanisms of these protease activities exhibited during vascular development. A glycosylphosphatidylinositol-anchored glycoprotein, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), has been shown to attenuate MMP-2 maturation by directly interacting with MT1-MMP. Here, we show that an angiogenic factor angiopoietin-1 induces RECK expression in human umbilical vein endothelial cells (HUVEC), and RECK depletion in these cells results in defective vascular tube formation and cellular senescence. We further observed that RECK depletion downregulates β1-integrin activation, which was associated with decreased autophosphorylation of focal adhesion kinase and increased expression of a cyclin-dependent kinase inhibitor p21CIP1. In agreement, significant downregulation of β1-integrin activity was observed in vascular endothelial cells in Reck−/− mouse embryos. In HUVECs, specific inhibition of MMP-2 significantly antagonized the effect of RECK depletion on β1-integrin signaling, cell proliferation, and tube elongation. Furthermore, we observed that hypervascular tumor-derived cell lines can induce high RECK expression in convoluted vascular endothelial cells, and this in turn supports tumor growth. Targeting RECK specifically in tumor-associated vascular endothelial cells resulted in tumor regression. Therefore, we propose that RECK in tumor vascular endothelial cells can be an interesting target of cancer treatment via abortion of tumor angiogenesis. Mol Cancer Res; 8(5); 665–76. ©2010 AACR.
Altered-Function p53 Missense Mutations Identified in Breast Cancers Can Have Subtle Effects on Transactivation
Authors: Jordan Jennifer J. , Inga Alberto , Conway Kathleen , Edmiston Sharon , Carey Lisa A. , Wu Lin , Resnick Michael A. 
Published: April 2010

Abstract
Mutations of the sequence-specific master regulator p53 that alter transactivation function from promoter response elements (RE) could result in changes in the strength of gene activation or spectra of genes regulated. Such mutations in this tumor suppressor might lead to dramatic phenotypic changes and diversification of cell responses to stress. We have determined “functional fingerprints” of sporadic breast cancer–related p53 mutants, many of which are also associated with familial cancer proneness such as the Li-Fraumeni syndrome and germline BRCA1/2 mutant-associated cancers. The ability of p53, wild-type and mutants, to transactivate from 11 human target REs has been assessed at variable expression levels using a cellular, isogenomic yeast model system that allows for the rapid analysis of p53 function using a qualitative and a quantitative reporter. Among 50 missense mutants, 29 were classified as loss of function. The remaining 21 retained transactivation toward at least one RE. At high levels of galactose-induced p53 expression, 12 of 21 mutants that retain transactivation seemed similar to wild-type. When the level of galactose was reduced, transactivation defects could be revealed, suggesting that some breast cancer–related mutants can have subtle changes in transcription. These findings have been compared with clinical data from an ongoing neoadjuvant chemotherapy treatment trial for locally advanced breast tumors. The functional and nonfunctional missense mutations may distinguish tumors in terms of demographics, appearance, and relapse, implying that heterogeneity in the functionality of specific p53 mutations could affect clinical behavior and outcome. Mol Cancer Res; 8(5); 701–16. ©2010 AACR.
Drugs that Target Specificity Proteins Downregulate Epidermal Growth Factor Receptor in Bladder Cancer Cells
Authors: Chadalapaka Gayathri , Jutooru Indira , Burghardt Robert , Safe Stephen 
Published: April 2010

Abstract
The epidermal growth factor receptor (EGFR) is an important chemotherapeutic target for tyrosine kinase inhibitors and antibodies that block the extracellular domain of EGFR. Betulinic acid (BA) and curcumin inhibited bladder cancer cell growth and downregulated specificity protein (Sp) transcription factors, and this was accompanied by decreased expression of EGFR mRNA and protein levels. EGFR, a putative Sp-regulated gene, was also decreased in cells transfected with a cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3, and Sp4, and RNA interference with individual Sp knockdown indicated that EGFR expression was primarily regulated by Sp1 and Sp3. BA, curcumin, and iSp also decreased phosphorylation of Akt in these cells, and downregulation of EGFR by BA, curcumin, and iSp was accompanied by induction of LC3 and autophagy, which is consistent with recent studies showing that EGFR suppresses autophagic cell death. The results show that EGFR is an Sp-regulated gene in bladder cancer, and drugs such as BA and curcumin that repress Sp proteins also ablate EGFR expression. Thus, compounds such as curcumin and BA that downregulate Sp transcription factors represent a novel class of anticancer drugs that target EGFR in bladder cancer cells and tumors by inhibiting receptor expression. Mol Cancer Res; 8(5); 739–50. ©2010 AACR.