bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2569: Combination of the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin produces complete remissions in an ovarian A2780 xenograft model
Authors: Kratz Felix , Fichtner Iduna , Graeser Ralph 
Published: June 2012

Abstract
INNO-206, the (6-maleimidocaproyl)hydrazone of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that has demonstrated superior antitumor efficacy in eight murine tumor models compared to doxorubicin. After intravenous administration, INNO-206 rapidly binds to the cysteine-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. It has shown objective responses in a phase I study, and phase II studies are planned for 2011 at the recommended dose of 260 mg/m2 i.e. an approximate 4-fold increase over the standard dose for doxorubicin.
Interestingly, in contrast to free doxorubicin, which primarily locates in the nucleus, INNO-206, mainly accumulates in the cytoplasm. Furthermore, the binding of INNO-206 to albumin and the resulting EPR-mediated accumulation and distribution in the tumor will differ from the distribution of free doxorubicin which will be mediated by diffusion. There might thus be a rationale to combine the two drug formulations for obtaining an optimal antitumor effect. Indeed, in cell culture experiments using A2780 cells, a moderate synergy was found at a 5:1 ratio of free Doxo : INNO-206.
In a next step, we therefore tested whether a combination of suboptimal doses of INNO-206 with doxorubicin improved the therapeutic efficacy of INNO-206 or doxorubicin at their respective maximum tolerated doses (MTDs) in the mouse model. We treated nude mice with subcutaneously growing ovarian A2780 xenografts on a weekly schedule with 2 × 8 mg/kg doxorubicin (MTD), 3 × 24 mg/kg INNO-206 (doxorubicin equivalents) (MTD) and a combination of 3 × 12 mg/kg INNO-206 (doxorubicin equivalents) and 3 × 4 mg/kg doxorubicin. In the combination protocol, INNO-206 was administered 6 h prior to doxorubicin treatment. Doxorubicin showed a very moderate effect and a body weight loss of -21 %, whereas INNO-206 and also the combination produced complete remissions. The combination, however, was much better tolerated causing a body weight loss of -12 % compared to -31 % for INNO-206. The surprising result of this experiment is that the doses used in the combination regimen were able to induce complete remission and the best tolerability considering that when dosed individually at these doses, neither doxorubicin or INNO-206 would have produced such an impressive antitumor response. This work is an impetus for investigating further combinations of albumin-binding prodrugs with clinically established anticancer agents.
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 2569. doi:10.1158/1538-7445.AM2011-2569
Abstract 257: Targeted inhibition of mutant k-ras by siRNA in pancreatic cancer cells results in increased sensitivity to anti-EGFR therapy
Authors: Jabbari Neda , Daneker George W. , McDonald John F. 
Published: June 2012

Abstract
Cancer patients are frequently resistant to anti-epidermal growth factor receptor (EGFR) therapy due to secondary mutations in k-ras. This is particularly true for pancreatic cancer patients where the frequency of k-ras mutations is exceptionally high. A variety of therapeutic strategies to target RAS effector pathways have been pursued with limited success. We report here on the use of small interfering RNA (siRNA) to silence oncogenic k-ras in a pancreatic cancer cell line with the goal of sensitizing the cells to anti-EGFR chemotherapies. The AsPC-1 pancreatic cancer cell line expresses EGFR and is homozygous for the mutant k-ras GAT (GGT to GAT in codon 12) allele resulting in the constitutive activation of downstream pathways and reduced apoptotic function. We independently transfected (lipofectamine 2000) AsPC-1 with two siRNAs, one targeted to the mutant (si-k-ras GAT) and one to the wild type (si-k-ras GGT) alleles. We found that levels of k-ras expression (RT-PCR) were significantly reduced after si-k-ras GAT transfection but not after si-k-ras GGT transfection indicating target specificity against the mutant allele. As a preliminary test of the potential clinical utility of si-k-ras GAT mediated inhibition, we measured the relative viability (Tox-8 assay) of AsPC-1 cells transfected with si-k-ras GAT and the EGFR inhibitors Gemcitabine and Erbitux. The results demonstrate a significant increase in sensitivity to both drugs in cells transfected with si-k-ras GAT. We conclude that siRNA mediated inhibition of mutant k-ras may be a promising method by which to sensitize pancreatic cancer cells to anti-EGFR therapy.
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 257. doi:10.1158/1538-7445.AM2011-257
Abstract 2570: Combination studies of EC145 with approved anti-cancer drugs for ovarian cancer
Authors: Reddy Joseph A. , Bloomfield Alicia , Nelson Melissa , Dorton Ryan , Leamon Christopher P. 
Published: June 2012

Abstract
EC145, a potent folate-targeted Vinca alkaloid conjugate, is currently being evaluated in a phase 2 study of EC145 + DOXIL® compared with DOXIL® alone, in women with platinum-resistant ovarian cancer. Since EC145's toxicity profile is appearing to be non-overlapping with many of the existing approved drugs for ovarian cancer, we tested the effects of combining EC145 with some of these drugs. Thus, EC145 was evaluated in combination with cisplatin, carboplatin, docetaxel, topotecan or DOXIL® against folate receptor (FR)-positive human tumor xenograft models in vivo. In these studies, EC145 was purposely administered at a non-curative dose level while the non-targeted combination drugs were given at ∼50-75% of their MTD values. When tested as single agents against the FR-positive KB tumor model, partial anti-tumor responses were typically observed. In contrast, significantly greater anti-tumor activity with no detectable increase in toxicity was observed when EC145 was tested in combination. For example, 100% cures resulted when EC145 was combined with cisplatin or docetaxel, 80% cures with carboplatin or DOXIL®, and 40% cures with topotecan. Overall, these data provide support for the evaluation of EC145 in combination with numerous agents with different mechanisms of action for the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2570. doi:10.1158/1538-7445.AM2011-2570
Abstract 2571: ABT-737, a small molecule Bcl-2/Bcl-xL antagonist, increases docetaxel-mediated apoptosis in human prostate cancer cells
Authors: Parrondo Ricardo , de las Pozas Alicia , Reiner Teresita , Perez-Stable Carlos 
Published: June 2012

Abstract
Castration-resistant prostate cancer (CRPC) express high levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL, resulting in drug resistance and association with poor prognosis. Docetaxel (Doc), an antimitotic drug that is the first-line treatment strategy for CRPC, is known to provide a small survival benefit but patients eventually become resistant to Doc with little hope for survival. It is apparent that Doc chemotherapy alone is not enough to counteract the high levels of Bcl-2/Bcl-xL present in CRPC. ABT-737 is a small molecule that binds to Bcl-2/Bcl-xL with high affinity and disrupts their interaction with pro-apoptotic Bax/Bak, thus enhancing pro-apoptotic signals when combined with other drugs. We investigated whether ABT-737 can increase Doc-mediated apoptosis in CRPC cells. Our results in androgen-dependent LNCaP and CRPC PC3 cell lines indicate that ABT-737 (1 μM) increases Doc (1 nM)-mediated cell death and caspase-dependent apoptosis, as determined by trypan blue exclusion, annexin-FITC/propidium iodide flow cytometry, and Western blot analysis. Our data suggests that Doc's anti-cancer effect results from prolonged cyclin B1/Cdk1 activation and inactivation of Bcl-2/Bcl-xL by phosphorylation, resulting in increased apoptosis. We show a correlation between high phosphorylation (P) of Bcl-2(Ser70)/Bcl-xL(Ser62) and increased apoptosis by Doc and Doc + ABT-737 treatments. Furthermore, the Cdk1 inhibitor purvalanol A blocks Doc + ABT-737-mediated increases in P-Bcl-2/P-Bcl-xL and subsequent apoptotic cell death. Lentivirus pLKO.1 shRNA stable knockdown of Bax but not Bak lowers cell death LNCaP and PC3 cells after treatment with Doc + ABT-737. In contrast to LNCaP and PC3, the CRPC DU145 cell line is null for Bax, expresses high levels of anti-apoptotic Mcl-1, and is more resistant to ABT-737. Retrovirus pBABE stable expression of Bax in DU145 cells restores sensitivity to Doc + ABT-737 compared to the empty vector control cells. We conclude that ABT-737 can sensitize CRPC cells to Doc treatment and may provide an important combination chemotherapy strategy for improving overall survival.
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 2571. doi:10.1158/1538-7445.AM2011-2571
Abstract 258: The role of EGFR on RAF inhibitor resistance in B-RAFV600E melanoma and colon tumors
Authors: Yen Ivana , Sideris Steve , Song Kyung , Liu Bonnie , Schmidt Stephen , Koeppen Hartmut , Belvin Marcia , Friedman Lori , Hatzivassiliou Georgia , Malek Shiva 
Published: June 2012

Abstract
Constitutive activation of the RAS, RAF, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK) pathway is a common finding in many human cancers. Activating mutations in K-RAS or B-RAF constitute over 30% of all mutations in human tumors. It has been demonstrated that RAF inhibitors selectively inhibit B-RAFV600E tumors and not RAS mutant tumors, despite functioning as one of the key effector enzymes downstream of RAS and upstream of MEK. Recent Phase I clinical data with RAF inhibitors has demonstrated a significant response rate (81% response rate) in metastatic melanoma patients with B-RAFV600E-positive tumors (N Engl J Med. 2010 363:809-19). In contrast, the response rates in B-RAFV600E-positive colon tumors have been relatively low. In this work we examine the molecular mechanism of EGFR pathway activation as a mechanism of resistance by comparing the effects of RAF inhibitors against a panel of B-RAFV600E, mutant K-RAS, and WT RAS/RAF tumor lines in the presence and absence of EGF stimulation. We demonstrate that in B-RAF WT lines, pathway induction is observed for RAF inhibitors as evidenced by increases in phospho-MEK and phospho-ERK levels. RAF-inhibitor induced pathway activation in this setting mimics the kinetics and mechanism of EGF-induced pathway stimulation where RAS-GTP levels, C-RAF kinase activity and pERK levels are elevated. Upon stimulation with EGF or serum in B-RAF WT or K-RAS mutant lines, RAF inhibitor induced pathway activation is attenuated. In contrast in B-RAFV600E tumor lines, RAF inhibitors effectively block the MAPK pathway under basal conditions but become ineffective in a subset of B-RAFV600E lines when cells are stimulated with EGF. Additional studies across a broader panel of colon and melanoma mutant B-RAF lines demonstrate that B-RAFV600E lines with high basal levels of EGFR tend to be more resistant to selective B-RAFV600E inhibitors. Immunohistochemistry of colorectal tumor patient samples with either wildtype B-RAF or B-RAFV600E illustrates that colorectal B-RAFV600E tumors are associated with a higher percentage of membrane EGFR. Taken together, these results provide insight into the therapeutic utility of MAPK pathway inhibitors, and emphasize not only the importance of targeting defined genetic backgrounds in cancer treatment but the value in assessing other key pathway markers (such as EGFR) in B-RAFV600E-positive tumor subsets as a factor in sensitivity or resistance to therapy.
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 258. doi:10.1158/1538-7445.AM2011-258
Abstract 2593: A novel small molecule drug (LWKS) for pancreatic cancer therapy
Authors: Wang Yan , Maeda Yoshiko , Qin Sheng , Lam Kit , Liu Ruiwu , Kumaresan Pappanaicken R. 
Published: June 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC) currently stands at approximately 29,000 new cases per year in North America and lack of effective therapies leads to an extremely poor prognosis. Since pancreatic cancers respond poorly to chemotherapy, more effective and less toxic treatment is a crucial need. We have employed a biological assay (MTS assay) to identify small molecular compounds that induce cytotoxicity specifically in pancreatic cancer cells and not in normal cells by screening large number of compounds from various combinatorial chemical library. Commercially available PDAC cells derived from various stages of pancreatic cancer were used for screening. For normal cells, immortalized epithelial cells isolated from pancreatic duct (h-tert HPNE) were used. One of the compounds, LWKS (MW: 547.94) kills pancreatic cancer cells and not the normal HPNE cells. LWKS kills pancreatic cancer cells isolated from all the four stages and the EC50 is in the range of 2 – 10 µM, whereas for normal cells is 70 µM. Maximum tolerated dose is 80 mg/kg of body weight. At 20 mg/Kg body weight, it showed significant tumor shrinkage in human PDAC xenografts mice model when compared to PBS controls. The tumor reduction was monitored by measuring the tumor volume for two times per week for 8 weeks. All the animal safety procedures were followed as described by AALAC. At this dosage level no toxicity was observed in the mice model.
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 2593. doi:10.1158/1538-7445.AM2011-2593
Abstract 2611: Inhibition of the immunoproteasome subunit LMP2 by UK-101 leads to apoptosis and cell cycle arrest in pancreatic cancer
Authors: Jang Eun Ryoung , Thakkar Nilay , Kim Kyunghwa , Lee Eun Y. , Kim Kyung-Bo , Lee Wooin 
Published: June 2012

Abstract
Background: The immunoproteasome is an alternative form of the constitutive proteasome and it has been increasingly shown to play an important role in a number of diseases including cancer and inflammatory diseases. We have previously developed ‘UK-101’, a small molecule that selectively inhibits the immunoproteasome catalytic subunit LMP2. In our present study, we investigated the therapeutic potential of the immunoproteasome-targeting approach in pancreatic cancer using UK-101 as a lead compound.
Methods: The expression of LMP2 was assessed in primary pancreatic cancer tissues and established pancreatic cancer cell lines via immunohistochemical (IHC) and immunoblotting analyses. Using pancreatic cancer cells expressing LMP2, we have investigated the effects of UK-101 (an LMP2 inhibitor), general proteasome inhibitors (bortezomib and carfilzomib) and gemcitabine on cell survival, apoptosis and cell cycle progression. We also examined the effects of UK-101 on various molecular markers associated with apoptosis and cell cycle control.
Results: Our immunoblotting and IHC analyses indicated that the LMP2 levels are substantially upregulated in primary pancreatic cancer tissues as well as established pancreatic cancer cell lines compared to nonmalignant pancreatic tissues. The IHC staining on a tumor tissue array demonstrated positive immunostaining for LMP2 in approximately 53% of pancreatic cancer specimens evaluated (n=23 out of 43) while the normal pancreatic duct showed a negative LMP2 staining (n=11). Using Panc-1 (gemcitabine-resistant) and BxPc-3 (gemcitabine-sensitive) cells, we observed that the UK-101 treatment leads to a covalent modification of LMP2, a decreased proteasomal proteolytic activity as well as apoptotic cell death and cell cycle arrest.
Conclusion: Our results show that LMP2 is upregulated in pancreatic cancer and that the targeted inhibition of LMP2 using UK-101 induces apoptotic cell death and cell cycle arrest. Taken together, these results suggest that the immunoproteasome may be a potential therapeutic target that can be exploited for pancreatic cancer where the existing therapy including gemcitabine shows limited efficacy.
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 2611. doi:10.1158/1538-7445.AM2011-2611
Abstract 2641: Diversity of anticancer mechanisms of action of tritepenoids derived from betulinic acid
Authors: Dzubak Petr , Rehulka Jiri , Holub Dusan , Ozdian Tomas , Janostakova Anna , Sarek Jan , Vlk Martin , Hajduch Marian 
Published: June 2012

Abstract
Betulinic acid and its derivatives are cytotoxic compounds with the specific effect to the tumor cells. In our betulinic acid derivative chemical library we have identified several potent compounds which were highly active in the wide spectrum of the cancer cell lines and the primary tumour cells as well as. Cell cycle modulating effects of selected compounds were monitored and surprisingly the compounds with different effect on the cell cycle profile were observed. Some derivatives were inhibiting the progression through the early S or G2-M phases and some were rapidly inducing the apoptosis. To identify the mechanisms of the action we have used genomic expressional (Affymetrix) and proteomic profiling (LC-MS/MS, SILAC). Derivatives inducing the rapid induction of the apoptosis were identified to regulate and affect the mRNA expression of the genes and proteins closely related to the oxidative stress and to the detoxification enzymes. Glutathione detoxification pathway and the oxidative phosphorylation cascade (upregulation of glutathion peroxidase, peroxiredoxine, thioredoxin, sulfiredoxine, cytochrome c oxidase, down regulation of glutathion S transferase) were affected and direct interaction of derivatives with cytochrome c was observed. All previously mentioned mechanisms are closely related to the mitochondrion damage. However, derivatives inducing the G2/M block were also increasing the expression of the tubulin chaperone cofactor A (TBCA) and the underexpression of other proteins like chaperonin containing TCP1, subunit 3 (CCT3) related to tubulin polymerization pathway and cell cycle regulation. Tubulin chaperone cofactors were recently suggested to be potential targets for the cancer therapy and current works are showing the upregulation of tubulin chaperone cofactor C correlated to the suppression of the tumor growth and increased chemosensitivity in resistant cancer phenotypes. This work was supported by the GACR 301/09/P433, GACR 305/09/1216 and CZ.1.05/2.1.00/01.0030).
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 2641. doi:10.1158/1538-7445.AM2011-2641
Abstract 2643: Inhibition of calpain disrupts the autophagic response initiated by bortezomib resulting in increased death of myeloma cells
Authors: Landowski Terry H. , Escalante Aluvia M. , McGrath Ryan , Karolak Matthew R. , Henderson Meredith , Perrian Georgia O. , Lynch Ron 
Published: June 2012

Abstract
The proteasome is a multi-subunit enzyme complex that plays a central role in the regulation of proteins controlling many important cellular functions including cell cycle progression, differentiation, gene transcription and apoptosis. Bortezomib is a potent proteasome inhibitor that has recently been approved for use in refractory multiple myeloma. Our previous work demonstrated that bortezomib induces an endoplasmic reticulum (ER) stress response ultimately leading to Ca2+-dependent apoptotic cell death. Intracellular Ca2+ has also been implicated in the cellular stress response known as autophagy. The biochemical events linking the cellular stress response with the induction of autophagy, and the relationship between autophagy and apoptosis are not well understood.
In this study, we investigate the role of the Ca2+ dependent serine protease, calpain, as a mediator of the conversion from autophagic cell survival to accelerated cell death in the ER stress response. Using live cell imaging we demonstrate that bortezomib rapidly initiates autophagy in myeloma cells. Microtubule associated protein 1 light chain 3 beta (LC3) is an autophagic marker that is converted from the inactive form (LC3I) to the autophagosomal membrane-associated (LC3I) form. Simultaneous analysis of the LC3II/I ratio and the polyubiquitin-binding protein, p62/SQSTM1, demonstrates an early elevation in autophagosome formation with an increase in autophagic digestion. Inhibition of the Ca2+-dependent serine protease, calpain, dramatically increases the accumulation of non-functional autophagosomes illustrated by a rise in both the LC3II/I ratio and p62 levels. This effect is accompanied by a significant enhancement or acceleration of cell death. Similarly, elimination of the small catalytic subunit, CAPNS1 using siRNA significantly increased bortezomib-mediated cell death. Our data suggest that inhibition of calpain prevents autophagolysosome maturation, and subverts the survival response thereby enhancing cell death. These data suggest a new therapeutic strategy to enhance the activity of proteasome inhibitors and overcome drug resistance in refractory myeloma and other B cell malignancies.
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 2643. doi:10.1158/1538-7445.AM2011-2643