bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3567: Interaction of pralatrexate with the EGFR/MAPK pathway leads to synergistic activity with EGFR inhibitors
Authors: Serova Maria , Bieche Ivan , Vidaud Michel , Pronk Gijsbertus J. , Cvitkovic Esteban , Faivre Sandrine , Raymond Eric 
Published: June 2012

Abstract
Background: Pralatrexate (FOLOTYN®), an antifolate targeting dihydrofolate reductase, has high affinity for reduced folate carrier-1 and is an efficient substrate for polyglutamation by folypolyglutamyl synthetase. Combinations of cytotoxics and small molecule EGFR inhibitors (EGFRi's) have had little clinical success. Recent demonstration that intracellular folates may modulate survival signaling pathways, including EGFR/MAPK, suggests a potential for rational combinations of antifolates and EGFRi's. This study investigated potential roles of the EGFR/MAPK pathway in pralatrexate sensitivity and explored combinations of pralatrexate with EGFRi's.
Materials and Methods: Anti-proliferative effects of pralatrexate were evaluated in a panel of human cancer cell lines. mRNA expression was analyzed by qRT-PCR and protein was evaluated by Western blot. Effects of drug combinations were evaluated using the Chou & Talalay method.
Results: Pralatrexate displayed potent anti-proliferative effects in 9 of 15 human cancer cell lines, with HEP2 (head & neck [H&N]) and DU145 (prostate) cell lines showing IC50s of 50 nM and 15 nM, respectively. Sensitivity to pralatrexate correlated with higher pre-treatment mRNA expression of EGFR. After 5 hrs of exposure to 10 nM pralatrexate, increased phosphorylation of ERK1/2, MEK1/2, and the downstream target c-JUN was seen in HEP2 and DU145 cells. In addition, early activation of EGFR and EGFR protein degradation was observed. To further explore possible interactions between pralatrexate and the EGFR pathway, combination studies with EGFRi's were performed. Synergistic activity was observed in the MTT assay when pralatrexate was used in combination with erlotinib, gefitinib, and lapatinib in DU145, PC3, and LNCaP prostate and HEP2 H&N cancer cells. Synergistic activity was most pronounced when pralatrexate was given prior to the EGFRi's.
Conclusions: Higher expression of EGFR was associated with pralatrexate sensitivity in a panel of human cancer cell lines. Pralatrexate treatment resulted in activation of the EGFR/MAPK pathway. Sequential administration of pralatrexate followed by EGFRi's resulted in synergistic anti-tumor activity. These findings provide rationale for clinical evaluation of pralatrexate in combination with EGFRi's, in particular in tumors sensitive to antifolates and EGFRi's such as NSCLC and H&N cancer. In addition, evaluation of pralatrexate in combination with inhibitors of downstream EGFR targets is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3567. doi:10.1158/1538-7445.AM2011-3567
Abstract 357: CYP3A4 Activates Stat3 in ER + breast cancer
Authors: Potter David A. , Guo Zhijun , Mitra Ranjana , Milani Monica , Rodriguez Mariangellys , Ding Li , Bliss Robin , Nguyen Julia , Luo Xianghua , Gupta Kalpna , Capdevila Jorge , Blair Ian , Thomas Dafydd , Bae Young K. 
Published: June 2012

Abstract
CYP3A4 expression in breast cancer has been reported to correlate with nodal metastases and decreased overall survival, but its mechanisms in cancer progression are unknown. ERalpha has been reported to promote CYP3A4 expression. We have previously demonstrated that CYP3A4 is an arachidonic acid (AA) epoxygenase that activates breast cancer cell proliferation through biosynthesis of 14,15-epoxyeicosatrienoic acid (EET).
Methods: Effects of 14,15-EET on Stat3 regulation were studied in MCF7 lines expressing CYP3A4 shRNA. Quantitative immunofluorescence (AQUA) interrogation of a tissue microarray was performed to evaluate CYP3A4 in cytoplasm, ERalpha and pY705Stat3 (pYStat3) in nuclei, and HER2 in cytoplasm/membrane. Values were transformed using the natural logarithm. These values were then averaged across the two spot sets. Pearson's correlation was calculated between the markers of interest.
Results: Stat3 (Tyr 705) phosphorylation is inhibited by CYP3A4 silencing. CYP3A4 synthesizes 14,15-EET in breast cancer cells and silencing of Stat3 blocks breast cancer cell growth and abrogates 14,15-EET-induced proliferation, indicating that CYP3A4 requires 14,15-EET biosynthesis and Stat3 to induce cell growth. Silencing of CYP3A4 reduces nuclear pY705-Stat3, while 14,15-EET restores this signaling process. By preliminary immunofluorescence study of consecutive breast cancers (n=48) nuclear ERalpha was associated with cytoplasmic CYP3A4 with a correlation of r=0.7575 (p-value &lt; 0.0001). Cytoplasmic CYP3A4 correlated with nuclear pYStat3, with a correlation of r=0.2708, approaching statistical significance (p = 0.0656). Cytoplasmic/membrane HER2, known to be induced by Stat3, was associated with nuclear pYStat3, exhibiting a correlation of r=0.4460 (p-value = 0.0015).
Conclusions: ER+ breast cancer cell growth is therefore mediated, in part, by CYP3A4 biosynthesis of 14,15-EET that induces nuclear pY705-Stat3. These studies indicate that CYP3A4 is an AA epoxygenase that is expressed in ER+ breast cancer and promotes Stat3-mediated breast cancer cell growth, in part, through 14,15-EET biosynthesis. Activated Stat3 may mediate cytoplasmic/membrane HER2 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 357. doi:10.1158/1538-7445.AM2011-357
Abstract 3575: Dovitinib (TKI258), a dual inhibitor of FGFR and VEGFR, induces tumor growth suppression in xenograft models of human bladder cancer
Authors: Shi Michael M. , Linnartz Ronald , Versace Richard , Brueggen Joseph , Chatenay-Rivauday Christian , Stamm Christelle , Dugan Margaret , Porta Diana Graus 
Published: June 2012

Abstract
Introduction: The aim of this study was to evaluate the efficacy of dovitinib (TKI258), a small molecule dual inhibitor of fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) in mouse models of human bladder cancer. Molecular epidemiological studies have implicated FGFR and VEGFR pathways in the pathogenesis of high grade, muscle invasive bladder cancer. Somatic activating mutations in FGFR3 have been identified in 16%-20% of muscle-invasive bladder cancer and FGFR3 overexpression has also been documented in a high fraction of bladder cancers. High microvessel density, serum VEGF levels and urine FGF2 levels have also been associated with high grade bladder cancer and poor disease-free survival. Dual FGFR/VEGFR inhibitory activities of dovitinib make it an attractive molecule targeting advanced bladder cancer. Experimental Design: Dovitinib was evaluated in the RT112 human bladder carcinoma xenograft model. Dovitinib was administered orally at three dose levels (n = 10/group), once daily for 28 consecutive days (qd × 28). A rat RT112 xenograft study was also carried out to evaluate the PK/PD effect of single dose dovitinib administration. Results: Dovitinib at 15, 30, and 60 mg/kg resulted in tumor growth suppression, with mean changes of 60% T/C, 6% T/C (P &lt; 0.01), and -71% T/T0 (P &lt; 0.001), respectively. The 60 mg/kg regimen yielded 6 partial regressions out of 10 animals by day 28. In the rat RT112 model, dovitinib caused dose- and time-dependent inhibition of pFRS2 at 25 and 50 mg/kg after 3, 7 and 24 h of a single oral dose administration. Conclusion: Dovitinib demonstrated significant antitumor effect in a mouse model of human bladder cancer xenograft. This study provides a strong rationale for clinical investigation of dovitinib in patients with advanced bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3575. doi:10.1158/1538-7445.AM2011-3575
Abstract 3578: A novel and selective 3-phosphoinositide-dependent kinase-1 inhibitor, PF-5177624, blocks insulin-like growth factor-1 induced tumorigenesis in breast cancer cells
Authors: Baxi Sangita M. , Walls Marlena , Murphy Sean , Ermolieff Jacques , Smeal Tod , Yin Min-Jean 
Published: June 2012

Abstract
Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (PIP3); PIP3 serves as an important secondary messenger recruiting and activating proteins that contain a pleckstrin homology (PH) domain including AKT and 3’-phosphoinositide-dependent kinase-1 (PDK1). PDK1 is a 63-kDa Ser/Thr kinase with a catalytic domain near its N-terminus and a pleckstrin homology domain at its C-terminus. The PH domain is necessary for targeting PDK1 to the plasma membrane to phosphroylate the T-loop sites of numerous substrates such as AKT at the residue threonine-308 (T308). The phosphorylation at both T308 and the serine-473 residue by mTORC2, fully activates AKT to induce the downstream signaling pathways that are important for tumor progression. PDK1 also has been shown to phosphorylate p70S6K, isoforms of PKCs, and many other kinase substrates. The oncogenic activity of aberrant PI3K pathway signaling through PDK1 has been extensively validated. PDK1 is highly expressed in a majority of human breast cancers and cell lines, and elevated phosphorylation of PDK1 was associated with PIK3CA mutations in human breast tumors and cell lines. Therefore, targeting PDK1 in the PI3K/AKT pathway may provide an opportunity for breast cancer treatment.
In this study, we demonstrate that insulin-like growth factor-1 (IGF-1) stimulates PDK1 activity and a specific and potent PDK1 inhibitor, PF-5177624, inhibits IGF-1 stimulated downstream signaling in breast cancer cells, including a reduction in phosphorylation of both AKT (T308) and p70S6K. The inhibition of PDK1 activity through the IGF-1 axis is sufficient to induce in vitro anti-tumor activity in breast cancer cells such that PF-5177624 inhibits cell proliferation and cell transformation in breast cancer cells. Our data suggest that a specific and potent PDK1 inhibitor (PF-5177624) is likely to have antitumor activity in breast cancer cells and can be developed as a cancer drug for breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3578. doi:10.1158/1538-7445.AM2011-3578
Abstract 3584: Effects of the investigational selective MEK inhibitor TAK-733 against cutaneous and uveal melanoma cell lines
Authors: von Euw Erika , Atefi Mohammad , Attar Narsis , Zachariah Sybil , Burgess Barry L. , McCannel Tara , Lichter David I. , Izmailova Elena , Ribas Antoni 
Published: June 2012

Abstract
Background. There are several MEK inhibitors currently under clinical investigation, including, TAK-733, a novel non-ATP-competitive allosteric selective inhibitor of MEK. We have analyzed the sensitivity of human melanoma cell lines of different origins to TAK-733.
Methods. The half maximal inhibitory concentration (IC50) of TAK-733 was assessed in a panel of 27 skin melanoma cell lines and 5 ocular melanoma cell lines genotyped for driver and secondary oncogenic mutations. Flow cytometry was used to analyze effects on cell cycle progression, and Western blots to analyze the downstream signaling changes upon exposure to TAK-733.
Results. Among 12 BRAFV600E mutated cell lines tested, 6 were sensitive to TAK-733 with IC50s less than 10 nM, including 4 highly sensitive cell lines with IC50s below 1 nM. In 5 cell lines with BRAFV600E mutation the IC50 was higher than 100 nM and were considered highly resistant. Among 10 NRASQ61L mutant melanoma cell lines, 6 were sensitive with IC50s below 10 nM. Among 5 melanoma cell lines with wild type sequences for NRAS, BRAF, GNAQ and GNA11 genes only 1 was sensitive to TAK-733. All 5 of the uveal melanoma cell lines were highly sensitive to TAK-733 IC50 regardless of having a GNAQ or GNA11 mutations. MEK inhibition resulted in increase of pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. In all cases TAK-733 induced marked dose-dependent inhibition of pERK, regardless of the driver oncogenic mutation or the sensitivity or resistance to this agent in cell viability assays. Cell lines resistant to TAK-733 showed no inhibition of pAKT or pS6K, while there was a general trend towards inhibition of these two phosphorylated molecules in sensitive cell lines.
Conclusions. TAK-733 is a potent MEK inhibitor with high antitumor activity against human melanoma cell lines with BRAF, NRAS, GNAQ and GNA11 driver mutations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3584. doi:10.1158/1538-7445.AM2011-3584
Abstract 3631: NMDA receptors as possible therapeutic targets for cancer
Authors: Akerman Bonnie L. , Allen Chenoa D. , Sylvain Nathan P. , North William G. 
Published: June 2012

Abstract
NMDA receptors constitute important calcium channels that are chiefly found within the central nervous system. Our laboratory has shown that these receptors are also expressed by human tumors such as neuroblastoma, small-cell lung carcinoma, breast cancer, and now ovarian and prostate cancer. The hypothesis being tested in our studies is that selective tumor expression of NMDA receptors is essential for cancer cell growth and proliferation. Human breast and ovarian cancer cells were treated with NMDA antagonists and agonists and changes measured in cell proliferation/growth and apoptosis. It was shown NMDA receptors are critically involved in cell growth of these cancer cells, and if blocked, cell growth is inhibited. Interestingly, the non-cancerous cell line, HEK 293, also expresses NMDA receptors, but NMDA antagonists were found to not influence growth of these cells. Receptor knock-down in MCF-7 breast cancer cells is being accomplished with lentavirus-coupled shRNAs, and selection performed for puromyocin resistance. We have thus far been able to selectively stably reduce NMDA receptor expression by 70-80% for a period of two weeks. The rate of cell growth was significantly decreased when the expression level of NMDAR1 is knocked down. The response of NMDA receptor knock-down cells to antagonists such as MK-801 and Mementine will be examined. Confirmation that the actions of antagonists such as MK-801 on cancer growth are specifically due to blockade of NMDA receptors will further their potential future use in cancer treatment. By confocal microscopy we were able to demonstrate that breast, ovarian, and prostate cancer cells express NMDA receptors within the membrane of tumor cells. Treating breast cancer cells with NMDA receptor antagonists and an antibody against an extracellular region of the subunit 1 changes the sub-cellular localization of these NMDA receptors. This change in sub-cellular localization could be an indicator of the mechanism of action of these compounds on cancer cell growth through the expression levels of the receptors. Additional studies are now being performed using sub-cellular fractionation and fluorescent microscopy to determine the nature of NMDAR1 cellular translocalization. The goal of this project is to further evaluate NMDA receptors as possible targets for treatment of breast cancer and perhaps several other cancer types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3631. doi:10.1158/1538-7445.AM2011-3631
Abstract 3637: MM-302, a HER2-targeted liposomal doxorubicin, shows binding/uptake and efficacy in HER2 2+ cells and xenograft models
Authors: Klinz Stephan , Eckelhofer Isabelle , Gaddy Daniel , Geretti Elena , Hendriks Bart , Lee Helen , Leonard Shannon , Reynolds Joe , Wickham Tom 
Published: June 2012

Abstract
Introduction: MM-302 is an ErbB2/HER2-targeted liposomal doxorubicin formulation designed to target doxorubicin to HER2-overexpressing cancer cells while limiting uptake into non-target cells. The characterization of the binding and uptake of MM-302 as a function of HER2 surface levels on various cell lines and in tumor models will help determine the minimum HER2 receptor levels required for MM-302 patient selection.
Methods: Cellular models included 16+ established human tumor cell lines as well as 4T1 murine breast cancer and HeLa human cervical cancer cells engineered to overexpress HER2 from 1E05-1E06 receptors/cell. Cells were incubated with MM-302, untargeted liposomes or free doxorubicin and binding/uptake was measured by HPLC or flow cytometry. In vivo efficacy was determined in select mouse xenograft models. Tumors were mechanically and enzymatically dissociated, followed by flow cytometry to quantify the uptake of targeted and untargeted liposomes into HER2-expressing tumor cells, macrophages and other cell types.
Results: Binding and uptake of MM-302 increased with rising HER2 surface levels in cells of common parental origin (4T1, HeLa), with significant uptake into cells with &gt;2E05 HER2/cell. Further, total cell binding/uptake of MM-302 also increased with rising HER2 expression across a panel of 16+ cell lines. There was negligible uptake of untargeted liposomes under all conditions that showed no dependence on HER2 expression. Improved anti-tumor efficacy of MM-302 was observed in BT474-M3 and NCI-N87 mouse xenograft models relative to untargeted liposomal doxorubicin and free doxorubicin. Further, using disaggregated tumors, the relationship between HER2 expression and MM-302 uptake was confirmed in vivo in both models.
Conclusions: Our studies identified a HER2 threshold for uptake of MM-302 of approximately 2E05 receptors/cell, and suggest a role for MM-302 not only in HER2 3+ cancers, but also in HER2 2+ cancers as well. The ability to treat HER2 2+ tumors offers an exciting opportunity to serve a major unmet clinical need.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2011-3637
Abstract 3677: Prediction of oral cancer recurrence at post-surgery follow-up using fluorescence visualization
Authors: Poh Catherine F.Y , Wu Lang , Ko Kevin , Williams P. Michele , Rosin Miriam P. 
Published: June 2012

Abstract
Background: Recurrence is observed in up to 30% of surgically treated high-risk oral lesions (HRLs, severe dysplasia, carcinoma in situ and cancer) and is associated with poor prognosis. Reactive tissue change observed post-treatment often masks recurrence and makes early detection difficult. New advances using fluorescence visualization (FV) represent a promising approach to this problem that may facilitate early detection of disease recurrence.
Objectives: 1) To identify FV alterations post-treatment of HRLs and 2) To determine whether a relationship exists between FV alterations and local recurrence.
Methods: In the BC Oral Cancer Longitudinal Study, we have recruited ∼400 HRLs with surgical treatment as the primary modality. Patients eligible for this analysis included those that had an initial follow-up appointment within 6 months of surgery with at least 2 follow-up appointments within the first year of treatment, with each visit involving FV examination of the treatment site. Recurrence was defined as the presence of biopsy-proven HRLs. The ‘plateau’ of the FV during the follow-ups is defined as the change of FV measurement in width within ± 1 mm (superior-inferiorly) in various time intervals of 3, 6, 9, or 12 months.
Results: A total of 198 patients were identified of which 24 (12%) had lesion recurrence at the previously treated site. There was no difference in gender, age, ethnicity, smoking habit, anatomical site, primary diagnoses, and follow-up time between the recurrence and non-recurrence groups. The duration of plateau was longer in non-recurrence group compared to those in recurrence group (P = 0.03). When we examined the duration ‘plateau’ at various intervals of follow-ups, among 166 patients/lesions with at least 9 months follow-ups, we found out that the presence of plateau was more frequent in the non-recurrence group than those recurrent case (P = 0.03). Using linear mixed effects and logistic regression analyses, there was a significant difference of the individual slopes between recurrence and non-recurrence group (P = 0.001), adjusted for the individual intercepts (i.e., the original FV width).
Conclusion: The stability, i.e., timing and duration of the plateau, of the FV alteration during post-surgical follow-ups can be potentially used to predict local recurrence of HRLs.
(Supported by Supported by grant R01 DE17013 from the National Institute of Dental and Craniofacial Research and grant CCSRI-20336 from Canadian Cancer Society Research Institute; Canadian Institute for Health Research and Michael Smith Foundation from Health Research)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3677. doi:10.1158/1538-7445.AM2011-3677