bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2766: Targeting heat shock proteins: Novel strategies for treating prostate cancer
Authors: Adelaiye Remi M. , Ellis Leigh , Pili Roberto 
Published: August 2012

Abstract
Prostate cancer (PCa) is the second most common form of cancer in men. Treatment for prostate cancer remains a challenge, particularly for castrate resistant prostate cancer. Hormonal therapy such as androgen ablation often fails as cancer cells utilize alternative mechanisms for survival and eventually progress to castrate resistant PCa. Currently, understanding of molecular mechanisms underlying castrate resistant PCa development is limited. Strong evidence demonstrates that castrate resistant PCa continues to depend on androgen receptor signaling. Novel compounds targeting androgen receptor activity and androgen synthesis are currently under investigation in preclinical and clinical studies; however alternate therapeutic approaches for castrate resistant PCa are needed. Heat-shock protein 90 (Hsp90) is an abundant molecular chaperone and plays a crucial role in structural formation and folding of a variety of proteins including androgen receptor, Akt, and other oncogenic proteins. Inhibition of Hsp90 creates the potential to suppress tumor activity as enforced disassociation induces proteosomal degradation of Hsp90 client proteins. This study utilized four genetically defined murine PCa epithelial cell lines, MYC-CaP (AR+ amplified, Pten +), MYC-Cap css (Castrate resistant, AR= amplified, Pten+), Pten-CaP E2 (Androgen sensitive, AR+, Pten null), and Pten-CaP cE2 (Castrate resistant, AR+, Pten null) to investigate the cellular response to Hsp90 inhibition. Cells were exposed in vitro to NVP-AUY922, a novel Hsp90 inhibitor at increasing concentrations for 24 and 48 hours. Results demonstrated that AUY922 treatment induced reduction in overall growth in all cell lines, with Pten-CaP and castrate resistant Pten-CaP being more sensitive (IC50 = 10nM) than MYC-CaP and MYC-Cap css (IC50 = 25nM) cells. Inhibition of cell growth was also indicated by induced cell cycle arrest in all cell lines, though AUY922 treatment did not result in significant increase in cell membrane permeability. Overall, our preliminary data indicates that AUY922 exhibits strong anti-growth effects in PCa cell lines and warrants further investigation as a potential novel targeted therapy to treat advanced and castrate resistant PCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2766. doi:1538-7445.AM2012-2766
Abstract 2768: IDH1057, A novel, synthetic, small molecule inhibitor of heat shock protein 90(Hsp90)
Authors: Kwon Jin-Sun , Moon An-Na , Park Joon-Tae , Hong Soo-Jung , Jeong Jin-Ah , Kwon Sung-Wook , Lee Myong-Jae , Jang Hyeon-Soo , Yeon Seung-Woo , Lee Hong-Sub , Kang Jae-Hoon 
Published: August 2012

Abstract
Backgroud: The molecular chaperone Heat shock protein 90(Hsp90) governs the stabilization and activity of an array of over 100 ‘client proteins’, many of which are key signaling molecules involved in cell proliferation, survival, and transformation. A significant number of these client proteins are oncogenic in nature, including the protein kinases Her2, C-Raf, B-Raf, and AKT. We report here that IDH1057 is structurally distinct from a geldanamycin derivative, tanespimycin(17-AAG) as a novel and potent small molecule Hsp90 inhibitor that binds to the NH2-terminal ATP-binding pocket of Hsp90. Results: IDH1057 exhibited superior binding affinity for the ATPase domain of Hsp90(IDH1057, human Hsp90α FP IC50&lt;150 nM) compared to 17-AAG(IC50 =456.3 nM) in vitro. IDH1057 also markedly inhibited proliferation in a broad panel of human tumor cell lines(IC50α100 nM) and depleted Her2 in SKBR3 breast cancer cells(IC50&lt;50 nM). 10 NSCLC cell lines were relatively sensitive to IDH1057, irrespective of EGFR, Her2 or KRAS mutational status. IDH1057 was also highly effective against cell lines that displayed resistance to erlotinib. IDH1057 efficiently inhibited cell proliferation in 8 breast cancer cell lines including triple-negative breast cancer(TNBC) cell lines such as BT-20, Hs578T and MDA-MB-231. Exposure to IDH1057 led to a rapid and dramatic degradation of key signaling molecules in BT474 cells. Based on these results, we examined in vivo anti-tumor activity of IDH1057 in BT474 breast cancer xenografts. Following once daily oral dosing of IDH1057 at 200mg/kg on a weekly 5-day-on and 2-day-off schedule for 4 weeks, this compound showed statistically significant tumor growth inhibition(TGI=84.5%) and was well-tolerated with no observable body weight loss. A2780 ovarian cancer xenografts in mice treated orally with IDH1057 also resulted in potent tumor growth inhibition. More importantly, IDH1057 displayed favorable oral PK profiles in mice. Additionally, we performed in vitro ADME assays to characterize a new series of small molecule inhibitors. IDH1057 exhibited high metabolic stability in liver microsomes from human, mouse and beagle(≥60%). Five human CYP isoforms were not significantly inhibited by IDH1057 at 10uM. IDH1057 had moderate permeability in MDCK permeability assay(Papp=4.7x10−6 cm/sec). Conclusion: Our results indicate that IDH1057 is a novel and fully synthetic Hsp90 inhibitor with strong anti-tumor activity in vitro and in vivo. IDH1057 is a promising and orally active drug candidate for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2768. doi:1538-7445.AM2012-2768
Abstract 2777: Suppression of multiple myeloma via non-canonical inhibition of NF-κB
Authors: Hovde Stacy , Lansdell Theresa A. , Azevedo Lauren , Tepe Jetze J. , Henry Ronald W. 
Published: August 2012

Abstract
Multiple myeloma is a deadly disease for which treatment has significantly improved with the introduction of the proteasome inhibitor bortezomib. The mechanism of cell death invoked by proteasome inhibition is unknown, but likely involves multiple pathways, including downregulation of NF-κB activity, stabilization of pro-apoptotic factors, and induction of the unfolded protein response, which may be especially critical for apoptosis of B-cell tumors. However, most patients ultimately experience disease relapse, and novel treatments are clearly necessary. We have developed a novel class of proteasome inhibitors called trans-imidazolines that target the proteasome differently from bortezomib and exhibit substantial anti-inflammatory properties when tested in mouse models of rheumatoid arthritis. The purpose of the current studies was to determine the efficacy of these small molecule anti-inflammatory agents for inhibition of multiple myeloma proliferation and survival. For these studies, trans-imidazoline efficacy was initially determined in vitro against a panel of multiple myeloma cell lines with effects on apoptotic induction determined by fluorescent activated cell sorting analysis. Subsequent studies were expanded to examine multiple myeloma tumor growth in mouse xenograft assays. Component levels of the NF-κB pathway were examined by Western blot analyses and immunofluorescent staining after challenge with exogenous cytokines. The biochemical mechanism of trans-imidazoline function was further explored in vitro using proteasome assays of fluorescently tagged peptide substrates. Our data indicates that trans-imidazolines impede IαBβ turnover in response to TNFα treatment and are consequently effective inhibitors of NF-κB activity for transcriptional activation. As NF-κB mediates key pro-survival roles in multiple myeloma, these compounds were found to induce apoptosis in multiple myeloma cells as rapidly as bortezomib, and demonstrated impressive inhibition of RPMI-8226 tumor growth in mice. Importantly, trans-imidazolines are equally effective inhibitors of bortezomib-resistant tumor cell proliferation. Consistent with these observations, we found that trans-imidazolines inhibit proteasome activity via a non-competitive mechanism that is distinct from the active site competitive inhibition mechanism displayed by bortezomib. As acquired resistance to bortezomib often occurs via increased expression of its proteasome target, trans-imidazolines thus offer an alternative treatment option for recurrent disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2777. doi:1538-7445.AM2012-2777
Abstract 2783: Inhibition of prosurvival autophagy by the BH3-mimetic obatoclax sensitizes antiestrogen-resistant breast cancer cells to apoptosis
Authors: Schwartz Jessica , Shajahan Ayesha , Liu Minetta , Clarke Robert 
Published: August 2012

Abstract
Antiestrogens (AEs) have long been a standard treatment for estrogen receptor-positive (ER+) breast cancer patients. However, antiestrogen resistance, either de novo or acquired, is a major hurdle for effective therapy in breast cancer patients. To address this, the underlying mechanisms of antiestrogen resistance must be understood. One common mechanism by which AE resistant cells thrive is by overexpressing BCL2 and its antiapoptotic family members, which allows cancer cells to survive under conditions that would normally cause apoptosis. We discovered that the BH3-mimetic, obatoclax (GX15-070), significantly reduces cell proliferation and, in combination with fulvestrant or tamoxifen, results in a synergistic inhibition of cell growth in AE resistant breast cancer cells. Obatoclax exhibits potency against BCL2, BCL-XL, BCLW, MCL1, and A1 and is currently being used in clinical trials directed at lymhomas and leukemia. However, the molecular mechanisms of cell death by obatoclax are unclear. We show that obatoclax induces apoptosis and autophagosome formation in AE-resistant breast cancer cells. To compensate for the increase in autophagosomal formation as measured by LC3, obatoclax also induces lysosome formation to prepare for cellular breakdown. This study is the first to show that obatoclax inhibits prosurvival autophagy by preventing the degradation of LC3 and p62 through a cathepsin-dependent mechanism. Furthermore, overexpression of BCL2 in breast cancer cells “primes” the cells with BH3-only proteins and renders the cancer cell sensitive to treatment with obatoclax. Collectively, these data support exploration of clinical trials combining an AE and the BCL2 inhibitor, obatoclax, for the treatment of AE-resistant breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2783. doi:1538-7445.AM2012-2783
Abstract 290: A Twist1 code of p53 inactivation
Authors: Piccinin Sara , Tonin Elena , Sessa Sara , Pivetta Flavia , Rosano Camillo , Rossi Sabrina , Tos Angelo Paolo Dei , Doglioni Claudio , Maestro Roberta 
Published: August 2012

Abstract
Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we identified an unprecedented mechanism of destabilization of p53. We show that Twist1 and MDM2 overexpression are mutually exclusive in these tumors and provide evidence that, by physically hindering p53 key phosphorylation, Twist1 facilitate MDM2:p53 complex formation and p53 degradation. This study suggests the existence of a Twist code of p53 inactivation in sarcomas and provides the proof of principle that targeting the Twist:p53 interaction may offer additional avenues for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 290. doi:1538-7445.AM2012-290
Abstract 2906: Preclinical systems to study the biodistribution of nanoparticle delivery in pancreatic ductal adenocarcinoma
Authors: Collisson Eric A. , Zuckerman Jonathan , Wang Donghui , Phojanakong Paul , Gale Aaron B. , Choi Chung Hang J. , Hann Byron , McCormick Frank , Davis Mark 
Published: August 2012

Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is a deadly disease, with no effective available treatment. Primary chemoresistance is common and has been attributed to the hypovascularity characteristic of the disease and the dense desmoplastic response that accompanies virtually every case of PDA. Effectively delivering therapeutic anticancer agents to PDA cells is therefore a specific, difficult and understudied problem in PDA that must be resolved for successful treatments to emerge. With the goal of eventually delivering drug payloads via nanoparticles (NP), we used well-defined mouse models of the disease to iteratively test NP distribution to both the cancerous and normal pancreas. Minimal deposition was observed in normal pancreas after intravenous or intraperitoneal administration of a variously sized (25nm or 40nm) NP. Surprisingly, abundant NP deposition was seen in both syngenic xenografted and autochthonous KPC models of PDA. NP deposition tended to be greater with IP administration and was enriched in stoma rich tumor regions. These findings have encouraging ramifications for delivery of depot or novel (e.g. siRNA, radiopharmaceutical, etc.) agents in this deadly disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2906. doi:1538-7445.AM2012-2906
Abstract 2908: Biological evaluation of paclitaxel-peptide conjugates as a model for MMP2-targeted drug delivery
Authors: Yamada Roppei , Xu Shili , Neamati Nouri 
Published: August 2012

Abstract
Paclitaxel (PTX) is a highly effective cytotoxic agent widely used for the treatment of several solid tumors. However, PTX shows dose-limiting cytotoxicity and in most cases induces drug resistance followed by failure in treatment. To enhance the therapeutic index of a given drug, various drug delivery methods have been explored to systemically deliver sufficient amount of the drug to the desired site. In the present study, we designed and synthesized two PTX prodrugs by conjugating PTX at different sites with an octapeptide (AcGpLGIaGQ) that can be cleaved by MMP2 at tumor sites. As a result, PTX is expected to be released at the tumor sites, absorbed by the tumor cells, and thereby inhibit the tumor growth. We evaluated the in vitro activities of the two drugs in a panel of drug-sensitive and -resistant cancer cell lines and their in vivo efficacies in a HT1080 fibrosarcoma mouse xenograft model that overexpresses MMP2. Our in vitro results showed that the PTX-AcGpLGIaGQ conjugates inhibited cancer cell proliferation with higher activity compared to that observed for free PTX, both of which were mediated by an arrest of G2/M-phase of the cell cycle. Consistent with the in vitro results, treatment with PTX-octapeptide conjugate resulted in extensive areas of necrosis and a lower percentage of proliferating cells in xenograft tumor sections. Together, our results indicate the potential of the tumor-targeted delivery of PTX to exploit the specific recognition of MMP2, reduce toxicity, and selectively kill tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2908. doi:1538-7445.AM2012-2908
Abstract 2909: Doxorubicin-loaded zirconium phosphate nanoparticles for intracellular anticancer drug delivery to breast cancer cells
Authors: González Millie L. , Diaz Agustin , Cabán Jennifer , Colón Jorge , Báez Adriana 
Published: August 2012

Abstract
Purpose: Doxorubicin (DOX), is an anthracycline antibiotic widely used for the treatment of several solid tumors but its usage is limited by serious side effects to healthy tissues. The purpose of this study was to explore the effectiveness of zirconium phosphate nanoparticles (ZrP) as carrier of anticancer agents (ie. DOX) to tumor cells and potentially reduce side effects to healthy tissue. Methods: Confocal Microscopy (CM) was used to assess internalization and localization of doxorubicin-loaded ZrP nanoparticles (DOX:ZrP) in MCF-7 breast cancer cell line. The cytotoxicity of ZrP and DOX:ZrP in MCF-7 and MCF-10A cells was studied using MTT assay. Results: Co-internalization of DOX and ZrP nanoparticles into the cytoplasm and nucleus of MCF-7 cells was detected using CM. A high fluorescence in cell nucleus demonstrated DOX release from ZrP nanoparticles. ZrP alone is non-toxic to MCF-7 and MCF-10A cells. After a 48-hour treatment of MCF-7 cells with DOX:ZrP or DOX alone the IC50 obtained was 23µM and 24 µM, respectively. DOX cytotoxicity to MCF-7 cells after 72-hour treatment was three times higher than DOX:ZrP with IC50 of 0.74 µM and 3.15 µM, respectively. Conclusion: ZrP nanoparticles are internalized and can effectively deliver DOX to the interior of cancer cells. ZrP nanoparticles might provide a versatile platform for transportation of anticancer agents resulting in improved cancer therapy by reducing the side effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2909. doi:1538-7445.AM2012-2909
Abstract 2913: Identification of GSK2636771, a potent and selective, orally bioavailable inhibitor of phosphatidylinositol 3-kinase-beta (PI3Kα) for the treatment of PTEN deficient tumors
Authors: Rivero Ralph A. , Hardwicke Mary Ann 
Published: August 2012

Abstract
Dysregulation of the PI3K pathway is one of the most common causes of tumorigenesis. Aberrant pathway activation occurs frequently through loss of the tumor suppressor protein, PTEN. Loss of PTEN protein has been observed in approximately 40% of glioblastoma, 50% of prostate, 57% of endometrial cancers, as well as in a number of other tumor types, including melanoma and breast cancers. Preclinical studies have shown that selective depletion of the PI3Kα isoform inhibits tumorigenesis and reduces downstream PI3K signaling in PTEN deficient tumors. This data presents an opportunity for a clear patient selection strategy based on the presence or absence of PTEN. During an extensive knowledge-based lead identification and optimization effort starting from the reported PI3K beta-selective compound TGX-221, we identified several unique series of potent and selective inhibitors with less than desirable pharmacokinetic properties. Through a combination of structure-based and knowledge-based design, we ultimately identified substituted benzimidazole GSK2636771 as a potent, orally bioavailable, PI3K beta-selective inhibitor. The evolution of our selective inhibitors, leading to the discovery, design, and optimization of GSK2636771 and related analogs, will be described.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2913. doi:1538-7445.AM2012-2913
Abstract 2915: Discovery and characterization of OSI-296, a dual inhibitor of cMET and RON kinases
Authors: Steinig Arno G. , Li An-Hu , Wang Jing , Kleinberg Andrew , Dong Hanqing , Wang Ti , Gavagan Kathryn M. Stolz , Jin Meizhong , Tavares-Greco Paula , Peng Yue , Kahler Jen , Castaldo Linda , McCormack Siobhan , Kan Julie , Albertella Mark , Cooke Andy , Turton Roy , Bittner Mark , Franklin Maryland , Landfair Darla , Gokhale Prafulla , Wild Robert , Pachter Jonathan , Epstein David , Mulvihill Mark J. 
Published: August 2012

Abstract
cMET and RON are receptor tyrosine kinases of the MET proto-oncogene family that are activated by their respective ligands HGF and MSP. Signaling through the cMET/HGF system can be deregulated in cancer by HGF-dependent autocrine activation, gene amplification, and/or the presence of activating mutations, among others, while for RON, constitutively active variants generated by alternative splicing or methylation-dependent promoter usage [short-form RON (sfRON)] have been identified. Approaches to abrogate aberrant cMET and RON signaling that have led to agents in clinical trials include inhibiting their kinase function with small molecules. We report here the discovery and characterization of OSI-296, a dual inhibitor of cMET and RON. The compound exhibited selectivity in a panel of 96 kinases with potent activity against cMET, including common Y1230 mutants, and RON. OSI-296 blocked cMET autophosphorylation in MKN45 cells, resulting in dose-dependent inhibition of downstream ERK, AKT, and STAT3 phosphorylation. It also showed potent cellular activity in ELISA-format sfRON and caRON cell mechanistic assays that we developed, resulting in dose-dependent inhibition of downstream ERK and AKT phosphorylation. OSI-296 showed a PK profile in rodents suitable for oral dosing with &gt;70% bioavailability. In multiple xenografts models (cMET: MKN45, SNU-5, U87MG; RON: caRON), significant tumor growth inhibition was observed upon oral dosing with regression at higher doses. OSI-296 was very well tolerated with little body weight loss and no adverse effects even at the highest tested dose of 300 mg/kg p.o. qdx14. Solid PK/PD/TGI correlations have been established wherein &gt;90% inhibition of cMET or RON phosphorylation sustained over 24 h by OSI-296 translated to 100% TGI. In summary, OSI-296 was shown to be a well tolerated, dual inhibitor of cMET and RON with in vivo activity in mouse xenografts models for both targets upon oral dosing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2915. doi:1538-7445.AM2012-2915