bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C73: Anticancer effects of a novel phosphoinositol 3-kinase inhibitor in human hepatocellular carcinoma.
Authors: Lee Ju-Hee , Lee Hyunseung , Yun Sun-Mi , Seo Ju-Hyeon , Jung Kyung Hee , Li Guang-Yong , Hong Sang-Won , Hong Soon-Sun 
Published: June 2012

Abstract
The phosphatidylinositol 3-kinase (PI3K) is one of the most important regulators of cancer cell growth, survival, motility, and metabolism. As PI3K is activated in a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. Recently, we have designed and synthesized a new series of imidazo [1,2-a] pyridine derivatives as PI3Ka inhibitors. In this study, we investigated the effect of HS-196 [ethyl 6-(5-(2,4-difluorophenylsulfonamido) pyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxylate] in human hepatocellular carcinoma (HCC) cells. HS-196 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt, mTOR, p70S6K and glycogen synthase kinase 3b (GSK3b) by western blotting and immunofluorescence staining. And HS-196 showed anti-proliferative effects in variety of HCC cells in a dose-dependent manner. Interestingly, HS-196 didn't affect the normal liver cell line (HL-7702), while sorafenib and doxorubicin showed cytotoxicity at the same concentration. Also, HS-196 induced apoptosis by increasing the proportion of sub-G1 apoptotic cells, and caused cell cycle arrest at G0/G1 phase. HS-196 increased the expression of p27 and p21 and decreased that of cyclin D1 associated with cell cycle arrest. The induction of apoptosis by HS-196 was confirmed by DAPI and TUNEL staining, and the increases of the cleaved PARP, caspase-3, caspase-9 were observed. Furthermore, HS-196 decreased the expression of hypoxia-inducible factor-1a(HIF-1a) and vascular endothelial growth factor (VEGF) and inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs), which were confirmed by Matrigel plug assay performed in BALB/c nude mouse. Taken together, these results demonstrated that HS-196 exhibited its anticancer activity through disrupting the PI3K/Akt pathway, causing cell cycle arrest and consequently inducing apoptosis, and inhibiting angiogenesis in human HCC cells. We suggest that HS-196 may be a potential new candidate for targeted HCC 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 C73.
Abstract C78: A variant of the oncogene RET might be a molecular target in BRAFwt melanoma cells.
Authors: Amato Carol M. , Coffey David , Kounalakis Nicole , Robinson Steven , Su Lih-Jen , Robinson William A. 
Published: June 2012

Abstract
Desmoplastic malignant melanomas (DMM) are clinically, pathologically, and molecularly different from other melanomas. Patients with this subset of melanoma are generally older, with tumors exhibiting deeper levels of invasion, a low incidence of nodal involvement, and tend to track along nerves. Previous studies indicate that DMM tumors have a low prevalence of BRAFV600E mutations making them ineligible for targeted therapies with BRAF inhibitors. The oncogene RET is a tyrosine kinase receptor mainly associated with neuroendocrine cancers and is activated by the ligand glial cell-derived neurotrophic factor (GDNF). Numerous studies suggest that given the neurotrophic features of DMM, a variant of RET (G691S, designated RETp) may be a potential molecular target. We examined human melanoma cell lines for RETp and the BRAFV600E mutation and demonstrated that these molecular changes were usually discordant suggesting that RETp might be an attractive molecular target in BRAFwt cells. Further we hypothesized that in tumors with the RETp genotype, certain TKIs may be more effective in inhibiting cell growth in environments rich with GDNF. We screened various melanoma cell lines with and without the RETp genotype and determined their response to clinically available small molecular weight inhibitors. The cell viability effects were accessed in the presence and/or absence of the RET co-receptor, GFRa1, and ligand, GDNF. We show that in cell lines carrying the RETp genotype, GDNF alone increases cell proliferation, and certain small molecular weight inhibitors may be more effective at inhibiting melanoma cell growth in environments rich in GDNF.
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 C78.
Abstract C84: Inhibition of proteasome deubiquitinating activity as a novel cancer therapy.
Authors: D'Arcy Padraig , Brnjic Slavica , Olofsson Maria H. , Fryknas Marten , Lindsten Kristina , De Cesare Michelandrea , Perego Paola , Sadeghi Behnam , Hassan Moustapha , Larsson Rolf , Linder Stig T. 
Published: June 2012

Abstract
Tumor cells display enhanced sensitivity to disruptions in the ubiquitin-proteasome system making this an attractive target for the development of anti-cancer therapies. Ubiquitin-tagged substrates are degraded by the 26S proteasome; a multisubunit complex comprising a proteolytic 20S core particle (20S CP) capped by 19S regulatory particles (19S RP). The 20S CP has evolved as an important target for anti-cancer drug development, resulting in the approval of bortezomib (Velcade®) for the treatment of multiple myeloma. Here, we describe the characterization of the small molecule b-AP15 as a novel class of proteasome inhibitor that functions by abrogating the deubiquitinating (DUB) activity of the 19S RP. b-AP15 inhibits the activity of two 19S RP-associated DUBs, UCHL5 and USP14. Consistent with DUB inhibition, treatment with b-AP15 caused the accumulation of polyubiquitinated proteins in treated cells with higher molecular weight compared to bortezomib treatment and induced a stronger proteotoxic response. Importantly, apoptosis induction by b-AP15 differed from that of bortezomib by being insensitive to disruptions of the p53 tumor suppressor and insensitive to overexpression of the intrinsic apoptotic suppressor Bcl-2. Finally, we show that treatment with b-AP15 inhibited tumor progression in human and mouse tumor in vivo models of breast, lung, colon, head & neck carcinoma and inhibited organ infiltration in an acute myeloid leukemia (AML) model. Our results suggest that inhibiting the DUB activity of the 19S RP may be a novel target for the treatment of 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 C84.
Abstract C99: Beyond bortezomib: Development of Millennium's next-generation proteasome inhibitors.
Authors: Tsu Christopher A. , Blank Jonathan , Garcia Khristofer , Liu Jane , Bruzzese Frank , Lee Edmund , Kao Yueying , Bannerman Bret , Fitzgerald Michael , Fleming Paul , Ciavarri Jeffrey , Hales Paul , Yu Jie , Yang Yu , Berger Allison , Sintchak Michael , Kupperman Erik , Manfredi Mark , Dick Lawrence 
Published: June 2012

Abstract
Bortezomib (Velcade®) is a proteasome inhibitor that has been approved by the U.S. Food and Drug Administration for the treatment of patients with multiple myeloma or relapsed mantle cell lymphoma. It is currently available in more than 90 countries worldwide. The molecule is an N-capped dipeptidyl boronic acid and its molecular mechanism involves slow-tight binding to the chymotrypsin-like (β5) sites of the 26S proteasome. In the development of Millennium's next generation inhibitors, we have investigated several parameters affecting the drug's activity in biological systems. These include tissue proteasome concentration, blood/plasma partitioning and the kinetics of proteasome inhibition in cultured cells. We find that the abundance of the proteasome (approx. 1–5 μM β5 active site concentration) in cells and tissues together with the slow rate of dissociation of bortezomib from the proteasome (110 min. half-life) led to partitioning of the inhibitor in red blood cells, thereby limiting its distribution to potential sites of therapeutic action. Based on the hypothesis that more rapid dissociation from the proteasome should improve tissue distribution, we have developed an investigational, dipeptidyl boronic acid proteasome inhibitor (MLN9708). MLN9708 displays comparable potency (i.e. similar Ki) to bortezomib for the β5 site of the proteasome but a shorter (18 min.) half-life of dissociation. This affects rapid recovery of proteasome activity in tissue culture cells upon washout of the drug as well as reduced blood/plasma partitioning in mice, supporting the hypothesis that a more rapid equilibrium proteasome inhibitor can improve tissue distribution. MLN9708 is currently in phase 1 clinical trials.
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 C99.
Abstract CN08-02: Androgens, biomarkers, and abiraterone.
Authors: de Bono Johann S. 
Published: June 2012

Abstract
We have recently reported positive Phase III trial results for abiraterone acetate (de Bono, Logothetis et al, NEJM 2011), a drug designed and developed at The Institute of Cancer Research and The Royal Marsden Hospital, now approved for the treatment of CRPC patients in the post-docetaxel setting. We have also described the OS benefit associated with cabazitaxel (de Bono, Oudard et al, The Lancet 2010). These agents have improved the outcome of men with CRPC and enabled us to control this disease for long periods of time. Nevertheless, despite these advances, most patients progress with a rising PSA, suggesting that the biological mechanisms causing treatment resistance are associated with reactivation of androgen receptor (AR) signalling (Attard, Cooper & de Bono 2009). Continued AR signalling is implicated as a common determinant of resistance and has become a key target for prostate cancer drug development. Several molecular mechanisms have been proposed to explain AR reactivation in CRPC including gene amplification or overexpression, selection of gain of function mutations, increased expression of constitutively active AR splice variants and upregulation of cross-talk signal-transduction pathways such as AKT. AR mutations usually occur in the ligand-binding domain and widen the specificity of AR to other steroid hormones like estrogens or progestins, to adrenal steroids and/or to exogenous ligands (e.g. anti-androgens or steroids commonly used to treat CRPC). AR signalling can also occur in the complete absence of ligand due to the expression of truncated AR splice variants that contain an intact N-terminal domain (NTD) and DNA binding domain (DBD), but lack the ligand-binding domain (LBD) (Luo, Hu et al. 2009). AR activating phosphorylations through the Ras/MAPK and PI3K/Akt pathways have been also implicated in the restoration of AR activity (Weber, Bakin et al. 2003; Carver, Chapinski et al. 2011). We are developing further rational therapeutic strategies to reverse these mechanisms of resistance and further improve outcome from this disease.
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 CN08-02.
Abstract PL08-04: New ways to impact glutamine metabolism in cancer.
Authors: Cerione Richard A. 
Published: June 2012

Abstract
Our laboratory has a long-standing interest in understanding the involvement of Rho GTPases in cell growth and migration, which recently led to our discovery of a novel signaling connection between these GTPases and elevated glutamine metabolism in cancer cells. This was based on our identification of a small molecule inhibitor that blocks the transformation of fibroblasts by oncogenic Dbl (for Diffuse B cell lymphoma), a Rho GTPase-activator, as well as inhibits the growth of human breast cancer and B lymphoma cells, and shrinks tumors induced by these cancer cells in mice. The effects of the small molecule inhibitor are specific for transformed/cancer cells, as it does not inhibit the growth of normal fibroblasts or mammary epithelial cells. We identified the target of this inhibitor to be an isoform of the metabolic enzyme glutaminase (GLS1), which catalyzes the hydrolysis of glutamine to glutamate. Transformed/cancer cells show markedly elevated levels of GLS1 activity, due to post-translational modifications (phosphorylation) that are dependent on the activation of Rho GTPases and NFκB, and are blocked by the small molecule inhibitor. Recently, we have shown that an important outcome of the metabolic changes exhibited by cancer cells, that can be prevented by the inhibitor, is the generation of vesicular structures (oncosomes) that contain signaling proteins, metabolic enzymes, RNA transcripts and microRNA. Oncosomes, by transferring these components to recipient cells, are capable of conferring transformed properties on to their acceptor cells and thus have been suggested to play important roles in cancer progression. Collectively, these results shed new light on how glutamine metabolism is elevated during tumorigenesis in order to satisfy the ‘glutamine addiction’ of cancer cells, as well as demonstrate the consequences of such metabolic changes and how they might be interrupted. The hope is that these insights will highlight new strategies for therapeutic intervention.
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 PL08-04.
Abstract PR-1: Acquired resistance to RAF inhibitors is mediated by splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.
Authors: Poulikakos Poulikos I. 
Published: June 2012

Abstract
Tumors with mutant BRAF(V600E) are dependent on BRAF/MEK/ERK (ERK signaling) for their growth. ATP-competitive RAF inhibitors suppress ERK signaling in cells with mutant BRAF, but paradoxically enhance ERK signaling in cells with wild-type BRAF. We have shown previously the mechanistic basis of this phenomenon: active RAS promotes homo- and heterodimerization of RAF. When RAF exists in dimers, drug binding to one protomer transactivates the other unbound protomer. In BRAF(V600E) tumors, RAS is not activated, RAF is predominantly monomeric and ERK signaling is inhibited by the drug. These results predict that RAF inhibitors will be effective in tumors in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumor activity than MEK inhibitors. Confirming these predictions, RAF inhibitors have shown remarkable clinical activity in patients with melanomas that harbor mutant BRAF(V600E), however, resistance invariably develops. The mechanism of action of these drugs indicates that promotion of RAF dimerization (by lesions that activate RAS, or other means) could lead to drug resistance in mutant BRAF tumors. Indeed, RAS mutation has been reported as a mechanism of resistance in a subset of patients that progressed on the RAF inhibitor PLX4032 (vemurafenib). In order to identify novel mechanisms of resistance, we generated cell lines resistant to PLX4032. We found that a subset of cells resistant to PLX4032 express a 61kd splicing variant form of BRAF(V600E) that lacks exons 4–8, a region that encompasses the RAS-binding domain (p61BRAF(V600E)). p61BRAF(V600E) exhibits enhanced dimerization as compared to full length BRAF(V600E) in cells with low levels of RAS activation. In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signaling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to PLX4032, indicating that dimerization status of BRAF(V600E) determines the effects of the drug. We detected BRAF splicing variants in tumors collected at the time of progression on PLX4032, but not in matched pre-treatment tumors, supporting the clinical relevance of this mechanism and its potential utility as a therapeutic target. These data support the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.
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 PR-1.
Abstract 1300: Evaluating the relative bioavailability of a new formulation of navitoclax (ABT-263) in both cancer patients and healthy volunteers
Authors: Yang Jianning , Xiong Hao , Krivoshik Andrew , Holen Kyle , Pradhan Rajendra , Chiu Yi-Lin , Nada Adel , Tolcher Anthony , Awni Walid , Humerickhouse Rod 
Published: June 2012

Abstract
INTRODUCTION: Navitoclax (ABT-263) is a novel, orally bioavailable small molecule that inhibits Bcl-2 family proteins and promotes apoptosis. The current Phase 1 formulation is a lipid solution, which has a short shelf-life. A new lipid solution with improved shelf-life was developed to support Phase 2/3 clinical development. Relative bioavailability studies in patients were expected to have large variability, which would make the interpretation challenging. Meanwhile, the toxicity profile of navitoclax limited an evaluation at the recommended phase II dose in healthy volunteers. Therefore, relative bioavailability studies for the new formulation were conducted in both healthy volunteers (at doses with minimal safety risk) and cancer patients (at therapeutic doses).
METHODS: Two randomized, crossover studies were conducted to evaluate the bioavailability of the new formulation relative to that of the Phase 1 formulation. Study I was conducted in 12 healthy female subjects with non-childbearing potential at a single dose of 25 mg navitoclax. Study II was conducted in 12 cancer patients at a single dose of 250 mg navitoclax. Both studies were conducted under low-fat conditions.
RESULTS: The new lipid solution was bioequivalent to the Phase 1 formulation in healthy subjects. In patients, the point estimates of the bioavailability of the new lipid solution were 30% higher than the Phase 1 formulation; nevertheless, the point estimates were associated with wide 90% confidence intervals indicating high uncertainty in the point estimate. The percent coefficient of variation for navitoclax exposure in patients (49%) was markedly higher than that in healthy subjects (25%).
CONCLUSION: Relative bioavailability assessment in healthy volunteers had substantially lower variability compared to that in cancer patients, therefore served as the primary basis for decision making. However, results from patients provided supportive information at the therapeutic dose levels. Overall results from both studies in healthy subjects and patients provided strong evidence that the new lipid solution has comparable bioavailability as the Phase 1 formulation under low-fat conditions at therapeutic doses, and enabled a decision to select the new lipid formulation without dose modification for Phase 2/3 studies.
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 1300. doi:10.1158/1538-7445.AM2011-1300
Abstract 15: Phosphorylation defective mutant Bcl-xL knockin mice exhibit behavioral abnormalities linked with neurodevelopmental disorders
Authors: Basu Aruna , Casadesus Gemma , Grisham Tina , Chen Yinhuai , Haldar Subrata 
Published: June 2012

Abstract
Bcl-xL, a close homolog of Bcl2, is an important regulator of apoptosis and is overexpressed in many human cancers including neuroblastoma. Previously we have discovered that the regulation of phosphorylation of Bcl-xL on serine 62 residue by tubulin-binding anticancer drugs at mitosis may function as a checkpoint to permit apoptosis of cancer cells. However, the physiological significance of Bcl-xL phosphorylation still remains obscure. With a view to comprehending the functional relevance of Bcl-xL phosphorylation in vivo, we have generated knock-in mice expressing an unphosphorylable ser62 (equivalent to human ser62), by substitution with an alanine residue. Thus placing the phosphorylation-defective mutant of Bcl-xL into the germ line of mice creates opportunities to observe the effects of endogenous phosphorylation in the context of multicellular organisms.
Since Bcl-xL has been shown to be maintained at high level in CNS, initially a full behavioral phenotyping battery was carried out with wild type (WT) and Bcl-xLS62A(+/+) mice. Born at Mendelian ratios, the Bcl-xLS62A(+/+) mice demonstrated reduced startle response and reduced PPI (Prepulse inhibition) at lower PPI amplitudes compared to WT mice. Moreover, cognitive deficits were noted in the passive avoidance task between Bcl-xLS62A(+/+) mice and WT littermates. These data indicate that mutation in the phosphorylation site of Bcl-xL drive a range of functional abnormalities and many of the observed behavioral abnormalities in Bcl-xLS62A(+/+) mice are consistent with neurodevelopmental disorders. In all, our findings suggest that endogenous phosphorylation of antiapoptotic protein Bcl-xL might play a critical role in neurodevelopment and subsequent CNS functional output. Further molecular analysis on the effect of blocking of endogenous phosphorylation of Bcl-xL on neuronal apoptosis will be discussed.
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 15. doi:10.1158/1538-7445.AM2011-15