bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B128: A phase IB study of the MEK inhibitor GSK1120212 combined with everolimus in patients with solid tumors: Interim results.
Authors: Infante Jeffrey R. , Patnaik Amita , Jones Suzanne F. , Papadopoulos Kiriakos P. , Bendell Johanna C. , Rasco Drew W. , Bellew Kevin M. , Cox Donna S. , Durante Michael G. , Park Joohyun J. , Burris Howard A. , Le Ngocdiep T. , Tolcher Anthony W. 
Published: June 2012

Abstract
Background: GSK1120212 (MEK) is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. MEK was combined with everolimus (EVE), an mTOR inhibitor, to provide simultaneous inhibition of the MAPK and PI3K/mTOR pathways. This Phase I escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MEK+EVE and assessed the recommended Phase II regimen (RP2R).
Materials and Methods: Advanced solid tumor patients (pts) with adequate end-organ function received MEK (0.5–2mg) orally once daily (QD). EVE (5–7.5mg) was given orally with various schedules (QD, QOD, 5/7D, or 7/14D).
Results: Sixty-seven pts (21 pancreatic, 14 colorectal, 6 melanoma, 4 breast, 3 neuroendocrine and 19 other cancers) received ≥ 1 dose of MEK + EVE. Cohorts 4A and 5 exceeded the maximum tolerated dose. Dose-limiting toxicities (DLTs) were G3 mucositisa (n=5), G4 thrombocytopenia (n=1), G3 acneiform rash/fatigue/dehydration (n=1) and G3 hypokalemia secondary to diarrhea. All DLTs were reversible. 2 pts had fatal serious adverse events (pneumonia, GI hemorrhage); both considered unrelated to study drugs. The most common adverse events (AEs) (≥ 25%) were mucositisa (67%), skin-related toxicities (66%), fatigue (60%), diarrhea (45%), nausea (40%), vomiting (37%), pyrexia (30%) and decreased appetite (28%). G3/G4 AEs included mucositisa (12% G3), AST elevation (10% G3) and hyperglycemia (7% G3). Mucositisa led to dose interruptions, reductions, and discontinuations in 27%, 9%, and 1% of pts, respectively.
There was no PK interaction when MEK was coadministered with EVE, and PK results were consistent with previous reports when either agent was administered alone. There did not appear to be a relationship between EVE or MEK exposure and mucositisa incidence or severity. 62 pts had measurable disease at baseline and 5 achieved a partial response: 3 confirmed (1 adenoid cystic carcinoma, on-going &gt;13 months; 1 squamous cell lung, 6 months, withdrawn due to co-morbidity; 1 melanoma, 6 months), and 2 unconfirmed (1 laryngeal, 1 pancreatic cancer). 18 pts had stable disease with median duration on study treatment of 18.5 (range: 5.9–52.9) weeks.

Conclusion: Despite evidence of clinical activity in this heavily pretreated patient population, the toxicity profiles limit the ability to give MEK+EVE. Although multiple dosing schedules were explored, an RP2R was not identified.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B128.
Abstract B147: P-Rex1 is required for efficient melanoma metastasis.
Authors: Lindsay Colin R. , Lawn Samuel , Campbell Andrew , Faller William , Rambow Florian , Mort Richard , Timpson Paul , Li Ang , Cammareri Patrizia , Rafferty Mairin , Murphy Ian , McDermott Enda , Sheahan Kieran , Gallacher William , Van Kempen Leon , Beermann Friedrich , Der Channing , Larue Lionel , Welch Heidi , Ozanne Brad , Sansom Owen 
Published: June 2012

Abstract
Background: P-Rex1 is a Rac-specific Rho GTPase guanine nucleotide exchange factor that has recently been implicated in cancer for the first time. As Rac has a central role in control of cell motility, we assessed the role of P-Rex1 in melanoma, a cancer where metastasis is the major cause of death. This was the first evaluation of P-Rex1 in a genetically modified animal model of cancer. We also investigated the function of P-Rex1 in melanoblasts, as the molecular pathways that drive their developmental migration are believed to underpin the movement of metastatic melanoma cells.
Methods: P-Rex1−/− mice were crossed to mice carrying the DCT-lacZ transgene, a melanoblast reporter line, and a Tyr::NrasQ61K/°; INK4a−/− metastatic melanoma mouse model. Allograft tail vein (TV) injections were performed to further assess the endogenous function of P-Rex1 in metastasis. Panels of human melanoma cell lines and tissue were investigated with microarray, tissue culture, and immunohistochemical techniques.
Results: P-Rex1−/− mice have a melanoblast migration defect during development (p=0.01), evidenced by a white belly. They were resistant to metastasis when crossed to the Tyr::NrasQ61K/°; INK4a−/− murine model of melanoma (1/30 mice with metastases vs 13/30 in control cohort; p=0.001). When melanocytes derived from this model were TV-injected into immune-competent allografts, endogenous P-Rex1 was found to facilitate metastatic incidence, growth, and organ spread following the intravasation stage of the metastatic cascade (p=0.02). Mechanistically, this was associated with P-Rex1 driving invasion in a Rac-dependent manner. In humans, P-Rex1 was elevated in the great majority of melanoma cell lines, with mRNA levels above the median statistically associated with metastasic propensity (p=0.005). Tissue immunohistochemistry revealed an association between tumor progression and P-Rex1 expression.
Conclusions: P-Rex1 is a key component of melanoma progression, invasion and metastatic signaling, supporting the value of pharmacological inhibition of P-Rex1 activation of Rac for treatment of metastatic or high risk primary melanomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B147.
Abstract B165: Structural and biological studies on analogues of the natural product histone methyltransferase inhibitor chaetocin.
Authors: Cherblanc Fanny L. , Lo Ya-Pei , Bignell Elaine M. , Alcazar-Fuoli Laura , Brown Robert , Chapman-Rothe Nadine , Rzepa Henry S. , Fuchter Matthew J. 
Published: June 2012

Abstract
Epigenetic mechanisms play a critical role in the regulation of gene expression, and how such regulation becomes aberrant in cancer. Along with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), histone methyltransferases (HKMTs) have recently appeared as new promising drug targets for epigenetic cancer therapies. While several HDAC and DNMT inhibitors have been clinically validated, to date only few HKMT inhibitors have been reported. Chaetocin, a fungal metabolite belonging to the 3,6-epidithio-diketopiperazine (ETP) class was first described as a specific inhibitor of the histone methyltransferase SU(VAR)3–9.(1) Like other fungal metabolites of the ETP class however, it exhibits a broad range of antibacterial and cytostatic activity, including a remarkable cytotoxicity against HeLa cells. Since the broad cytotoxicity of the ETPs is due to the presence of the disulfide bridge of the 3,6-epidithio-diketopiperazine (causing protein crosslinking, reactive oxygen species generation, or zinc chelation), we reasoned that access to semi-synthetic derivatives devoid of such functionality, would provide valuable insight into the chemical biology of this natural product, particularly its reported HKMT activity. We developed conditions to extract and purify the natural product culture (Chaetomium virescens var. thielavioideum), followed several semi-synthetic approaches to obtain chaetocin analogues. Comparison of experimental and computationally simulated chiroptical spectroscopy allowed unambiguous structural characterization of our products. Evaluation of our compounds in a number of in vitro HKMT assays revealed a total loss in inhibitory potency upon modification of the disulfide bridge. These studies thus demonstrate the ETP functionality of chaetocin to be responsible for its reported HKMT activity. In conclusion, we have synthetically prepared distinct and novel chaetocin analogues from the natural product and explored their HKMT activity, implicating the ETP functionality as the active pharmacophore.
Reference:
1. Greiner, D.; Bonaldi, T.; Eskeland, R.; Roemer, E.; Imhof, A. Nat. Chem. Biol. 2005, 1, 143.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B165.
Abstract B17: Establishment, characterization and evaluation of a panel of patient-derived colorectal tumor models.
Authors: Wick Michael J. , Nieves Francis E. , Thangasamy Amalraj , Tolcher Anthony W. , Patnaik Amita , Drengler Ronald L. , Smith Lon S. , Garner Allison M. , Mangold Gina L. , Papadopoulos Kyriakos P. 
Published: June 2012

Abstract
Background: Patient-derived tumor models passaged only a few times in vivo retain physical and molecular characteristics of human cancer and may prove essential in identifying disease biomarkers and drug targets in later stage development. Currently we have collected tumor tissue from chemo-naïve and pretreated patients and established and characterized a panel of low passage colorectal tumor models.
Methods: For each model, tissue was implanted into immune-deficient mice and once established, each model was confirmed by histologic analysis and linked with donor patient treatment and outcome data. Model characterization including mutation profiling and drug sensitivity studies were performed and results compared with clinical patient information; each model was evaluated with the EGFR inhibitor cetuximab and two standard clinical therapies FOLFOX and irinotecan and compared with patient's drug sensitivity before and after tissue sample collection. Single agent tumor growth inhibition was evaluated and study endpoints included mean control tumor volumes of approximately 1 cm3 or up to sixty days following treatment initiation.
Results: Eighteen low passage colorectal models have been established and characterized. KRAS mutations were identified in 44% of models and activating mutations identified in some models include: PI3KCA (6%), TP53 (33%) and BRAF (6%). In vivo response to FOLFOX and irinotecan correlated to ≥65% of donor patient outcome to these treatments. Cetuximab sensitivity did not fully correlate with Ras mutation status as 4/6 wildtype and 4/8 Ras demonstrated cetuximab sensitivity in these studies.
Conclusion: We have generated a panel of low passage colorectal tumor models with differential mutation status and drug sensitivity profiles. Expansion of this panel of patient-derived tumors is planned and should further enhance its utility in identifying agents potentially useful for treatment of colorectal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B17.
Abstract B192: Pharmacokinetic characterization of anti-ETBR antibody drug conjugate in preclinical species.
Authors: Zhang Crystal , Roth Leslie , Cook Ryan , Tsai Siao Ping , Qiu Julia , Nazzal Denise , Asundi Jyoti , Lin Kedan 
Published: June 2012

Abstract
Purpose. Anti-ETBR-MC-vc-PAB-MMAE (anti-ETBR-vc-E) is an antibody-drug conjugate (ADC) targeting the Endothelin B receptor. It comprises the humanized IgG1 anti-ETBR monoclonal antibody and a potent anti-mitotic agent, monomethyl auristatin E (MMAE), linked through MC-VC-PAB linker. Anti-ETBR antibody and its conjugate cross-react with mouse, rat, cynomolgus monkey and human, which provides an opportunity to compare and evaluate the impact of normal tissue expression on ADC disposition in preclinical species.
Methods. Anti-ETBR-vc-E was administered intravenously in mice (0.5 and 5 mg/kg), rats (0.5 and 5 mg/kg), and cynomolgus monkeys (0.3 and 1 mg/kg). The samples were assayed for total antibody and conjugated antibody concentrations in mice and rats while total antibody and antibody-conjugated MMAE concentrations were determined in monkeys. Concentration-time data were used to estimate the pharmacokinetic parameters.
Results. The pharmacokinetic behavior of the ADC was characterized by monitoring and comparing total antibody, conjugated antibody, and antibody-conjugated MMAE disposition. The clearances for all three analytes were dose-independent after intravenous administration in mice, rats, or cynomolgus monkeys over the dose range studied. Conjugated antibody and antibody-conjugated MMAE clearances were approximately 2-fold higher than total antibody clearance. Clearance of total antibody in rat was approximately 2-fold higher than in mouse and monkey, with values of 19.4, 7.91, and 8.99 mL/day/kg, respectively. Half-life ranged from 8 to 10 days and volume of distribution ranged from 37 to 40 mL/kg.
Conclusions. The pharmacokinetics of anti-ETBR-vc-E total antibody was dose proportional in rodents and monkey suggesting that the presence of cross-reactive antigen in the preclinical species had no impact on clearance. All three species showed a relatively higher deconjugation clearance compared to total antibody clearance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B192.
Abstract B200: Selective induction of CXCL8 signaling maintains viability in PTEN-depleted prostate cancer cells.
Authors: Maxwell Pamela J. , Coulter Jonathan , McKechnie Melanie , Kennedy Richard , Salto-Tellez Manuel , Albanese Chris , Waugh David J. 
Published: June 2012

Abstract
Background: PTEN loss is associated with early prostate cancer progression. We sought to characterize whether PTEN loss regulates pro-inflammatory chemokine signaling and its functional significance to PTEN-depleted prostate cancer cells.
Methods: Chemokine/chemokine receptor expression was assessed in vitro in established cell lines, exhibiting different levels of endogenous PTEN expression. Down-regulation of endogenous PTEN expression in DU145 and 22Rv1 cells was effected using transient siRNA or stable shRNA interventions. Chemokine expression was further evaluated by immunohistochemistry in prostate tissue from wild-type and PTEN+/− mice.
Results: Loss of PTEN induced transcription-mediated increases in expression of CXCL8 and its receptors, CXCR1 and CXCR1 in DU145 and 22Rv1 cells. Stress-induced expression of CXCL8, CXCR1 and CXCR2 was greater in magnitude and duration in PTEN-null PC3 and LNCaP cells, in contrast to the dampened response observed in PTEN-expressing cells. PTEN loss had no effect on basal or stress-induced expression of CCL2, CXCL12 or their receptors CCR2 or CXCR4 in prostate cancer cells. The efficacy of CXCL8 signaling upon HIF-1 and NF-B transcription was also greater in magnitude and duration in PTEN-null prostate cancer cells or following siRNA-mediated PTEN knockdown. Increased expression of the orthologous murine chemokine KC was elevated in atypical cytological features of PTEN+/− prostate tissue relative to normal epithelium in PTENWT glands. Attenuation of CXCL8 signaling using siRNA oligonucleotides or shRNA vectors in cell-based models of partial or complete PTEN-loss significantly decreased cell viability. Furthermore, attenuation of CXCL8 signaling modulates the response of PTEN-depleted prostate cancer cells to clinically-relevant doses of ionizing radiation.
Conclusion: PTEN loss promotes a selective up-regulation of CXCL8 signaling and increases the efficacy of CXCL8 signaling in prostate cancer cells. Functionally, this selective induction of CXCL8 signaling acts to maintain cell viability as an essential adaptation to the genetic instability arising from PTEN loss.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B200.
Abstract B205: Therapeutically targeting redundant, growth factor-induced prosurvival signaling with MM-141, a novel bispecific antibody targeting IGF-1R and ErbB3.
Authors: Lugovskoy Alexey , Johnson Bryan , Baum Jason , Adams Sharlene , Tang Jian , Kohli Neeraj , Rennard Rachel , Xu Lihui , Jiao Yang , Nilesen Ulrik , Fitzgerald Jonathan 
Published: June 2012

Abstract
Monoclonal antibodies have significantly advanced our ability to treat cancer, but most patients do not have durable responses to therapy. We find that the majority of tumor cell lines are responsive to activation by two or more growth factors. In particular cell lines grown in culture and in mice appear to frequently rely on Insulin-like growth factor 1 (IGF-1) and Heregulin (HRG) signaling to redundantly support their proliferation. Using a Network Biology approach, we have designed, constructed and optimized a novel bispecific antibody, MM-141, for simultaneous targeting and inhibition of ErbB3 and IGF-1R. MM-141 blocks IGF-1, IGF-2, and heregulin-induced AKT signaling, inhibits growth of multiple cancer cell lines, and is active in xenograft models of human pancreatic cancer (BxPC-3) and human prostate cancer (DU145). MM-141 does not bind the insulin receptor, thus strongly reducing the risk of metabolic side effects. MM-141 has favorable CMC and pharmacokinetic profiles and is being advanced into preclinical development. Taken together, these results suggest that MM-141 has the potential to be an effective therapeutic for treatment of patients with solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B205.
Abstract B211: Augmentation of Fas (CD95) signaling pathway sensitizes non-small cell lung cancer (NSCLC) cells.
Authors: Chiu Huan-Chih , Huang Chin-Ting , Chang Teng-Yuan , Hsu John T.-A. 
Published: June 2012

Abstract
Epidermal growth factor receptor (EGFR) is a proven therapeutic target to treat a subset of NSCLC harboring activating mutations within the EGFR gene. However, many NSCLC patients are not sensitive to EGFR kinase inhibitors, suggesting that other factors may play a role in determining survival of NSCLC cells. Signal transducers and activators of transcription 3 (Stat3) functions as a transcription factor to mediate cell survival and differentiation and the dysregulation of Stat3 has been described in numbers of cancers. Our previous report showed that suppression of Stat3 activity by a pharmacological approach, WP1066, sensitized NSCLC cells. Along with Stat3 inhibition, we also found that WP1066 treatment up-regulated the expression of Fas, a death receptor, regulating numbers of physiological and pathological process of cell death. Although Fas-mediated apoptosis pathway has been studied mostly in the immune system, the identification of Fas mutations in non-lymphoid malignancies, such as NSCLC, suggests its implication in the pathogenesis of non-lymphoid malignancies as well. Results from this study showed that levels of Fas were increased in cells with down-regulated Stat3 by small interfering RNA (siRNA), suggesting that Stat3 may play an inhibitory role to regulate the expression of Fas. To examine whether the Fas pathway is responsible for the WP1066-mediated cytotoxicity, Fas apoptosis signaling was induced by anti-Fas antibody and Fas ligand. Our results revealed that NSCLC cells showed different degrees of sensitivity to anti-Fas antibody but resistance to Fas ligand. However, augmentation of Fas expression by WP1066 remarkably increased the sensitivity of NSCLC cells to both anti-Fas antibody and Fas ligand. Taken together, our findings suggest that regulation of the Fas system may be a potential strategy to treat NSCLC and the combined use of a Fas inducer, such as WP1066, may further strengthen its efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B211.
Abstract B244: The small molecule focal adhesion kinase inhibitor Y15 decreases human glioblastoma cell viability, clonogenicity, and tumor growth.
Authors: Golubovskaya Vita M. , Grace Huang , Ho Baotran , Yemma Michael , Morrison Carl , Song Liu , Hu Qiang , Cance William 
Published: June 2012

Abstract
Introduction: Glioblastomas are the third most frequent cause of cancer-associated deaths due to the cancer cell rapid growth and high invasion and novel therapeutic approaches are needed for this disease. Focal adhesion Kinase (FAK) is known to be highly expressed and activated in glioblastoma and plays significant role in tumorigenesis.
Experimental procedures: In this report we tested FAK autophosphorylation inhibitor, Y15 (called also Inhibitor 14) or 1,2,4,5-Benzenetetraamine tetrahydrochloride) that specifically decreased Y397-FAK autophosphorylation in DBTRG and U87 glioblastoma cells. To test Y15 we used the following in vitro assays: viability, clonogenicity, detachment, apoptosis, invasion, immunostaining, Western blotting and microarray analysis of gene expression; and in vivo assay: xenograft tumor growth model.
Results: Y15 significantly decreased viability and clonogenicity of DBTRG and U87 cells in a dose-dependent manner. Y15 inhibitor increased detachment, apoptosis and inhibited cell invasion in a dose-dependent manner. In addition, Y15 decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Moreover, we tested the effect of Y15 on gene expression by Illumina Human HT12v4 microarray assay and among 34, 694 genes affected by Y15 there we 8087 and 6555 genes either up- or down-regulated in DBTRG and U87 cells, respectively (p&lt;0.05). Moreover, Y15-treated DBTRG and U87 cells changed expression of 237 common genes more than 1.5 fold, p&lt;0.05 that play role in survival signaling, cell growth and motility. In addition, combination of temozolomide with Y15 significantly decreased viability and clonogenicity in both cell lines. In addition, Y15 inhibitor delivered orally significantly decreased DBTRG xenograft tumor growth. The tumors from Y15-treated mice expressed decreased Y397-FAK autophosphorylation, activated PARP and caspase-3.
Conclusion: Inhibition of FAK autophosphorylation with the oral small molecule inhibitor Y15 can be an effective therapy approach to block glioblastoma tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B244.