bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B102: 19-Substituted benzoquinone ansamycins: Decreasing the toxicity of the benzoquinone ansamycin class of Hsp90 inhibitors.
Authors: Chang Chuan-Hsin , Kitson Russell , Reigan Philip , Siegel David , Moody Christopher J. , Ross David 
Published: June 2012

Abstract
Benzoquinone ansamycins (BQAs) were the first class of Hsp90 inhibitors developed but members of this class, particularly geldanamycin, demonstrated hepatic toxicity. One major mechanism of toxicity of the BQA class is manifested via the electrophilic properties of the quinone and arylation of cellular nucleophiles at the 19-position of the ansamycin ring. Using selective halogenation and palladium-catalyzed coupling, we have synthesized a number of novel 19-substituted BQAs in the geldanamycin, 17-AAG and 17-DMAG series as a means to prevent arylation of cellular nucleophiles and have validated this approach using model thiols including N-acetylcysteine and glutathione. 19-Substituted BQAs did not react with thiols at the 19-position while marked reactivity could be detected using their parent quinones. 19-Substituted BQAs were tested for their ability to inhibit recombinant yeast Hsp90 and 19-substitution did not block the capacity of these novel molecules to inhibit the ATPase activity of the Hsp90 chaperone. This result was confirmed by molecular modeling of 19-substituted derivatives in the active site of human Hsp90 demonstrating that 19-substitution did not block entry of the molecule into the active site. The addition of NAD(P)H:quinone oxidoreductase 1 (NQO1) potentiated inhibition of recombinant yeast Hsp90 by 19-substituted BQAs confirming our previous data demonstrating increased inhibitory efficacy of the hydroquinone ansamycin relative to its parent quinone. Cellular effects of 19-substituted BQAs were examined in MDA468 breast cancer cells and the isogenic MDA468/NQ16 cell line which over-expresses NQO1. Growth inhibitory effects were observed using 19-substituted BQAs and were potentiated by the presence of NQO1 in the MDA468/NQ16 line. Hsp90 inhibition in MDA468 and MDA468/NQ16 cells was confirmed using decreases in the Hsp90 client protein Raf1 and a compensatory increase in Hsp70 as biomarkers. In summary, these data demonstrate that 19-substituted BQAs do not react with thiols at the 19-position but retain their Hsp90 inhibitory capacity using purified enzyme and in cells suggesting that they should undergo further translational evaluation as therapeutic candidates (Supported by CA51210 and the Parkinsons Disease Society UK).
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 B102.
Abstract B104: Tid1 as a novel target for HSP-directed therapy in NSCLC.
Authors: Chen Chi-Yuan , Jan Chia-Ing , Lo Jeng-Fan , Hong Tse-Ming , Yang Pan-Chyr 
Published: June 2012

Abstract
Molecular chaperones, commonly known as heat shock proteins (HSPs), are essential for mammalian cells to maintain homeostasis. HSPs may interact with diverse co-chaperones and induce an ATPase-coupled structural change in client proteins and regulate critical signaling networks. More than 200 client proteins have been identified which may serve as important therapeutic targets in human diseases. The human tumorous imaginal disc 1 (Tid1) protein, a member of the DnaJ domain protein family, is a tumor suppressor and is known to promote ubiquitin-mediated degradation of oncogenic kinases. The Tid1 is a heat shock protein and function as molecular chaperone. In this work, we investigated the role of Tid1 in the tumorigenesis of non-small-cell lung cancer (NSCLC). The expression of two alternatively spliced isoforms of Tid1 (Tid1L and Tid1S) as well as EGFR was examined with RT-PCR and immunohistochemistry (IHC) in tumors from NSCLC patients. The expression of Tid1 was reduced in the majority of NSCLCs and an inverse correlation was observed for the expression of Tid1 and EGFR. Furthermore, we demonstrated that Tid1L, EGFR, HSP70, and HSP90 interacted with each other, and this interaction is dependent on functional DnaJ domain of the Tid1L. Overexpression of the Tid1L in lung cancer cells in vitro inhibited cell proliferation, anchorage-independent growth, and induced apoptosis. We further showed that overexpression of the Tid1L in lung cancer cells attenuated EGFR signaling activity and inhibited the activation of AKT, ERK and STAT3. In contrast, knockdown of Tid1 in EGFR-transfected lung cancer cells markedly increased the stability of EGFR. Taken together, our results support that Tid1L may play a critical role in regulating EGFR signaling in NSCLC; raising the possibility that Tid1 may be a novel target for HSP directed therapy.
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 B104.
Abstract B107: Characterization of a small molecule selective androgen receptor downregulator: A novel approach for the treatment of castration-resistant prostate cancer.
Authors: Loddick Sarah A. , Brave Sandra , Campbell Hayley , Gaughan Luke , Growcott Jim , Lahan Natalie , Mouchet Elizabeth , O'Neill Daniel , Robson Craig , Shaheen Fadhel , Thomason Andrew , Trueman Dawn , Walker Graeme , Brooks Nigel 
Published: June 2012

Abstract
The androgen receptor (AR), an important molecular target in the aetiology and progression of prostate cancer, has been found recently to drive key signalling responses in castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed. Here we describe the biological characterisation of a novel and selective small molecule AR downregulator and propose this mechanism as a potential new approach for the treatment of CRPC. The compound is a derivative of a novel AR binding core with selectivity over other nuclear hormone receptors, and causes a reduction of AR protein in human LNCaP prostate cancer cells in vitro. The reduction in AR protein is observed in steroid depleted serum (CSS) conditions and demonstrates a differential mode of action from a classical AR antagonist (bicalutamide) which has no effect on AR protein expression. This AR downregulation translates into functional activity in vitro and in vivo. In cell viability assays in vitro the compound has activity in cells expressing wild-type (VCaP) and mutated (T877A) AR, but is inactive in AR-negative PC3 and DU145 prostate cancer cells, indicating a dependency on AR for efficacy. We have also observed a reduction in PSA synthesis in vitro, consistent with the inhibition of AR signalling. The compound also reduced AR protein expression, PSA synthesis and cell viability in LNCaP-Casodex™-Resistant and LNCaP-Androgen-Independent cells in vitro. We investigated in vivo activity using the Hershberger castrated rat assay where oral dosing (100mg/kg twice-daily for 7 days) resulted in a significant inhibition of testosterone-induced growth of sexual accessory organs. In summary we describe data supporting our hypothesis that a selective AR downregulator offers a novel approach for delivering therapeutic benefit in CRPC.
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 B107.
Abstract B135: Treatment with the MEK inhibitor PD0325901 modulates expression of key members of the MEK pathway in BRAFV600E but not BRAFWT thyroid cell lines.
Authors: Dorris Emma R. , Smyth Paul , O'Leary John J. , Sheils Orla 
Published: June 2012

Abstract
Introduction: The MEK/ERK pathway is mutated in approximately 7% of human cancers. Extracellular ligands signal via RAS to recruit RAF kinase and activate MEK and its downstream effectors. This pathway is involved in a range of biological pathways including cell proliferation, differentiation and senescence. The BRAF isoform is the most potent activator of MEK and is frequently mutated in cancer. A single thymine to adenine base pair change at position 1799 accounts for greater than 95% of somatic mutation in BRAF. BRAFV600E can gain 500-fold increased activation, stimulating the constitutive activation of the MEK/ERK pathway in the absence of extracellular signalling. The strategic position of MEK within the pathway makes it a promising target for drug development. Although MEK is downstream of both RAF and RAS, RAF but not RAS mutation has been demonstrated to predict sensitivity to MEK inhibition.
Materials and Methods: Human thyroid cell lines were SNP typed for the T1799A mutation using a custom TaqMan® SNP genotyping assay. The optimal IC50 and length of treatment for the MEK inhibitor PD0325901 for each cell line were determined via a series of MTT assays. Each cell line was subjected to PD0325901 treatment and surviving cells were harvested for mRNA and protein extraction. A comparative study for relative expression of MAP2K1 (MEK1), MAP2K2 (MEK2), MAPK3 (ERK1), MAPK1 (ERK2) and the downstream target ELK1 was performed using TaqMan assays with GAPDH as the endogenous control.
Results: Human thyroid cell line 8505c carries the T1799A mutation and N-Thy-Ori cell lines carry wild type BRAF. BRAFV600E cells had visually evident patches of inhibition following PD0325901 treatment which were not evident in media-only treated controls or in the BRAFWT cell line. In BRAFV600E, all 5 genes were down-regulated in PD0325901 treated cells compared to their media-only treated counterparts. This pattern was not seen with the BRAFWT cells. BRAFV600E cells exhibited this pattern following both a single treatment and two successive treatments with PD0325901.
Discussion: This pattern of gene expression is consistent with the hypothesis that resistance to small molecule MEK inhibition occurs via upregulation of an alternative pathway or activation of a redundant signalling pathway rather than through reactivation off the BRAF/MEK/ERK pathway. It also reinforces the theory that MEK inhibition induces differential effects in target cells dependent upon BRAF status.
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 B135.
Abstract B148: The miRNA-200 family regulates cell migration and metastasis in lung adenocarcinoma.
Authors: Blat Irene C. , Winslow Monte M. , Jacks Tyler E. 
Published: June 2012

Abstract
miRNAs are post-transcriptional regulators of genes involved in such canonical signaling pathways as the TGF-β and EGF pathways, both of which are frequently altered in tumor cells. miRNA downregulation results in upregulation of its target genes and ultimately aberrant signaling of pathways involved in invasion and migration, for example. To better understand how alterations in miRNA expression could lead to metastasis, we used a lung adenocarcinoma mouse model in which a lentivirus expressing the Cre recombinase activates oncogenic K-Ras and deletes p53, giving rise to primary lung tumors (T) and metastases (M). We performed miRNA expression profiling on 30 T and M derived cell lines and identified three members of the miR-200 family - miR-200b, miR-200c, miR-429 - to be significantly downregulated in the M lines compared to their related T line. To explore the functional contribution of the miR-200s to metastasis, we designed a miRNA sponge to stably inhibit endogenous miR-200 levels in T cell lines. We found miR-200 depletion promoted wound healing and cell migration towards either serum or EGF. Transplantation of the sponge-expressing lines via tail vein led to in vivo formation of more invasive, metastatic tumors compared to controls. Previously, the miR-200 family has been shown to inhibit the TGF-β target gene and EMT mediator, Zeb1. We have identified another miR-200 target, Epidermal Growth Factor Receptor Substrate 8 (Eps8), which mediates actin based cell motility. In miR-200 low (M) cells, Eps8 is expressed three-fold higher than in corresponding miR-200 high (T) cells. Additionally, exogenous expression of Eps8 in T lines promotes wound healing and cell migration, relative to control cells. Thus, our findings implicate the miR-200s as a class of metastasis regulators that modulate expression of genes functionally relevant in tumor cell dissemination and provide new targets for therapeutic intervention of late stage lung adenocarcinoma.
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 B148.
Abstract B151: Src inhibitor dasatinib reduces the metastatic phenotype of breast cancer cells.
Authors: Saffran Veronica , Siemann Dietmar 
Published: June 2012

Abstract
Subsequent to escaping the primary tumor, a successful metastatic tumor cell has to survive in the bloodstream, invade normal tissue at a secondary site, proliferate, and induce angiogenesis. Src is a non-receptor tyrosine kinase that is frequently over-expressed in malignances, and increased Src activity may be associated with poor patient prognosis. Src is well known to contribute to the metastatic phenotype of tumor cells through conferral of increased motility, migration, and invasion. Since these cellular functions are key components of the metastatic cascade, Src may be a novel target for breast cancer therapy. The present studies were undertaken to investigate whether molecular intervention in Src associated signaling could impact the metastatic phenotype of tumor cells. Specifically, we evaluated the in vitro and in vivo efficacy of the potent, selective and orally available Src inhibitor Dasatinib (BMS 354825) in the highly metastatic 4T1 murine mammary adenocarcinoma cell line.
Dasatinib was evaluated in vitro for the ability to inhibit migration and invasion in the 4T1 cell line. The results showed that Dasatinib treatment (50–100 nM) significantly inhibited both migration and invasion in a dose dependent manner (6- to 10-fold for the doses studied). To examine the effect of Dasatinib on tumor cell-induced angiogenesis in vivo, an intradermal angiogenesis assay was used. Briefly, 4T1 tumor cells were inoculated intradermally on the ventral surface of athymic nude (Ncr nu/nu) mice and 3 days later the mice were euthanized and skin flaps were removed for visual quantification of the number of blood vessels intersecting each inoculate. Mice received daily doses of either Dasatinib (5 to 15 mg/kg) or vehicle by oral gavage. The results showed that Dasatinib treatment inhibited 4T1 tumor cell-induced angiogenesis by up to 60%.
In summary, Dasatinib was found to significantly inhibit multiple cell functions critical to the successful dissemination of 4T1 breast cancer cells. The results suggest that Dasatinib may be useful in the reduction of breast cancer metastasis, and studies examining its impact on 4T1 metastases formation are currently ongoing.
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 B151.
Abstract B154: A first-in-human trial of GDC-0068: A novel, oral, ATP-competitive Akt inhibitor, demonstrates robust suppression of the Akt pathway in surrogate and tumor tissues.
Authors: Yan Yibing , Wagle Marie-Claire , Punnoose Elizabeth , Musib Luna , Budha Nageshwar , Nannini Michelle , Lin Kui , Liederer Bianca M. , Murli Sumati , Ramakrishnan Vanitha , Patel Premal , Cervantes Andrs , Tabernero Josep 
Published: June 2012

Abstract
GDC-0068 is a highly selective ATP-competitive small molecule that inhibits all three isoforms of Akt with IC50 values of 5 to 30 nM. GDC-0068 selectively inhibits cancer cells with activated Akt signaling (e.g. via PTEN loss or PIK3CA mutations). Patients with advanced solid tumors were treated with GDC-0068 using a 3+3 escalation design. GDC-0068 was dosed PO QD on a 21-day on, 7-day off schedule; endpoints included safety, pharmacokinetics (PK) and determination of pathway knockdown. Pharmacodynamics (PD) endpoints in surrogate tissue [platelet rich plasma (PRP)] were evaluated in all patients. In addition, at least two patients per cohort had pre- and on-treatment (day 15) tumor biopsies at doses ≥100mg QD. The tumor tissue samples were evaluated using reverse phase protein array (RPPA).
Thirty patients were enrolled across 7 cohorts (25, 50, 100, 200, 400, 600 and 800 mg QD). GDC-0068 was generally well-tolerated at doses ≤ 600 mg. Preliminary PK analyses show a dose proportional increase in exposure over the dose range tested. In addition, clinical exposures at doses ≥ 200 mg QD met or exceeded GDC-0068 exposures associated with tumor stasis in multiple PTEN null preclinical xenograft models. PK/PD evaluation showed dose-dependent Akt pathway inhibition in the PRP assay, with ≥70% inhibition of pGSK3 in all patients at doses ≥ 200 mg QD. Pre- and on-treatment tumor biopsies showed ≥50% decrease in pPRAS40 and cyclin D1 in multiple patients at doses of 200 mg QD and higher. In addition, evidence of feedback activation of the MAP kinase pathway after treatment with GDC-0068 was observed in biopsy samples. One patient with PTEN low/ PIK3CA H1047R/ KRAS wt CRC had prolonged stable disease and showed Akt pathway suppression by multiple downstream markers.
GDC-0068 is well tolerated at doses ≤ 600 mg with a favorable safety profile and dose proportional pharmacokinetics. Treatment with GDC-0068 results in substantial pathway knockdown in both surrogate and tumor tissues at doses ≥ 200 mg QD.
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 B154.
Abstract B155: A phase I study of the MEK inhibitor GSK1120212 (GSK212) in combination with PI3K/mTOR inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors.
Authors: Grilley-Olson Juneko E. , Bedard Phillip , Fasolo Angelica , Blackman Samuel C. , Cartee Leanne , Baker-Neblett Katherine L. , Sun Peng , Infante Jeffrey R. 
Published: June 2012

Abstract
Background: This is a Phase I, open-label, dose escalation, pharmacokinetic (PK), pharmacodynamic (PD) and safety study in patients (pts) with advanced solid tumors exploring the combination of the investigational drugs GSK458 and GSK212. GSK212 is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinases 1 and 2 (MEK1 and MEK2). GSK458 is a potent, reversible, ATP-competitive, pan-phosphoinositide-3 kinase (PI3K) inhibitor, which also inhibits the mammalian target of rapamycin (mTOR), and the common activating mutations of catalytic isoform p110α. The MTD for daily, continuous dosing of monotherapy GSK458 is 2.5mg and GSK212 is 2.0mg.
Methods: The study consists of two parts: dose escalation in Part 1 (ongoing) uses a zone design (3+3 rules) to study safety, tolerability, PK, PD and clinical activity, and to establish the maximum tolerated doses (MTDs) and schedules for the combination. Adult pts with relapsed or refractory solid tumors are receiving oral doses of GSK458+GSK 212 once daily until disease progression or toxicity. Efficacy is assessed using RECIST 1.1. Part 2 will examine safe dose combinations from Part 1 in patients with tumors likely to respond to MEK/PI3K pathway inhibition. Genetic and protein profiles collected from blood and tumor samples will be used to explore relationships between predictive biomarkers of response and efficacy.
Results: 34 pts(45% female) with a mean age of 58y (range 37–82y) have enrolled. Safety data includes31 subjects who have received ≥1 dose of GSK458+GSK212. Most commonly reported drug-related AEs &gt;10%, n=31) include rash (68%; G3/4, 3%), diarrhea (42%; G3/4, 6%), nausea (29%; G3/4, 0%), vomiting (23%; G3/4, 3%), decreased appetite (19%; G3/4, 0%), stomatitis (13%; G3/4, 3%) and fatigue (13%; G3/4; 3%). Of 21 serious adverse events (SAEs) reported in 14 pts, 3 were considered related to study drug. Stable disease has been observed in several patients with the longest being at 6 months (renal cell carcinoma and colorectal cancer).

The combination of GSK458 0.5 mg + GSK212 2.0 mg exceeded the MTD. However, once daily and continuous combination dosing of GSK458 (0.5, 1.0 or 1.5mg) + GSK212 ≤ 2.0 mg were well tolerated.
Conclusions: The preliminary safety profile and anti-tumor activity of this combination warrants further investigation in continued dose escalation and planned expansion cohorts.
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 B155.
Abstract B160: PWT33597 promotes apoptosis in tumor cells through balanced dual inhibition of PI3K alpha and mTOR.
Authors: Matthews David J. , Ventura Richard , Tai Albert , Holst Charles , O'Farrell Marie 
Published: June 2012

Abstract
Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) serve as critical nodes in an intracellular signaling network that regulates cell growth, proliferation and survival, and dysregulation of this signaling network is frequently found in tumor cells. PWT33597 is a novel, balanced, dual inhibitor of PI3K alpha and mTOR currently in clinical development. To dissect the relative contribution of PI3K and mTOR pathways to activity, we explored the effects of various mono versus dual PI3K and mTOR inhibitors on intracellular signaling pathways, proliferation and apoptosis in cancer cell lines harboring PI3K alpha mutations. The panel of inhibitors used includes compounds that are highly selective for PI3K (GDC-0941), molecules that are highly selective for mTORC1/2 (AZD8055), as well as dual inhibitors such as PWT33597, BEZ235, PF-04691502 and GSK2126453.
Our results indicate that compounds predominantly inhibiting PI3K have modest effects on phosphorylation of pathway proteins downstream of mTOR (in particular 4EBP), and do not lead to sustained induction of apoptosis markers such as PARP. Conversely, compounds that predominantly target mTORC1/2 produce feedback activation of PI3K signaling, resulting in increased phosphorylation of AKT (T308) and very limited effects on cell death. Dual PI3K/mTOR inhibitors produce more significant inhibition across the pathway, in particular leading to sustained inhibition of pAKT (S473 and T308) and p4EBP (T37/46), decreased release of normal feedback loops within the pathway, and an increased percentage of apoptotic cells as measured by percent population in sub-G1 phase of the cell cycle. In particular, PWT33597 produces potent and sustained pathway inhibition both for PI3K and mTOR-dependent readouts (pAKT S473, pAKT T308 and p4EBP T37/46), and maintains induction of apoptotic markers, resulting in cell death.
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 B160.