bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3255: MLN0128, an investigational selective TORC1/2 kinase inhibitor, demonstrates potent antitumor activity in preclinical models of soft tissue sarcoma.
Authors: Patwardhan Parag , Deraje Shyamprasad Vasudeva , Tap William D. , De Stanchina Elisa , Schwartz Gary K. 
Published: August 2014

Abstract
Sarcomas, cancers of mesodermal origin, represent a heterogenous group of malignancies with limited treatment options currently available. The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, consists of two distinct multi-protein complexes, TORC1 and TORC2, which regulate protein synthesis, cell proliferation, and metabolism. Rapamycin, a TORC1 inhibitor, and its analogs (rapalogs) have been disappointing in sarcoma clinical studies but inhibitors of TORC1/2 kinase have the potential of resulting in better outcomes. MLN0128, an investigational potent small molecule TORC1/2 inhibitor, has shown promising results in preclinical studies of breast and other cancer types. We tested the in vitro anti-proliferative activity of MLN0128 in a panel of sarcoma cell lines including malignant peripheral nerve sheath tumor, synovial, Ewing's and osteosarcoma. Our results indicate that when compared to rapamycin, MLN0128 is highly efficient in blocking proliferative activity of all the sarcoma cell lines tested at nanomolar concentrations irrespective of the tumor subtype. We also carried out western blot analysis to test the efficacy of MLN0128 in blocking TORC1/2 signaling pathway. Inhibition of TORC1 pathway by rapamycin in sarcomas has been shown to release negative feedback inhibition of receptor tyrosine kinases like IGF1-R and activate AKT (p-AKT). Our data suggest that MLN0128, unlike rapamycin, effectively blocks both the phosphorylation of S6 and 4EBP1, the downstream substrates of TORC1, and specifically inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2. This superior in vitro activity of MLN0128 may be attributed to its apparent improved TORC1 inhibition. Taken together, our data supports further clinical research of MLN0128 in sarcoma. Targeting TORC1/2 pathways using MLN0128 either alone or in combination with inhibitors of receptor tyrosine kinases could provide a new therapeutic approach in this disease.
Citation Format: Parag Patwardhan, Shyamprasad Vasudeva Deraje, William D. Tap, Elisa De Stanchina, Gary K. Schwartz. MLN0128, an investigational selective TORC1/2 kinase inhibitor, demonstrates potent antitumor activity in preclinical models of soft tissue sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3255. doi:10.1158/1538-7445.AM2013-3255
Abstract 3263: Evaluation of the activity of rigosertib, an inhibitor of PI3K and MAPK pathways, in a preclinical model of colorectal cancer.
Authors: Purkey Alicia , Song Eun-Kee , Quackenbush Kevin , Bagby Stacey , Arcaroli John J. , Jimeno Antonio , Messersmith Wells 
Published: August 2014

Abstract
Background: Rigosertib is an inhibitor of the PI3K and MAPK kinase pathways and is currently being evaluated in clinical trials for pancreatic cancer and hematologic diseases. The PI3K/AKT and MAPK (RAS/RAF/MEK/ERK) signaling pathways have been identified to play a central role in the development and progression of CRC by modulating many different downstream targets that are essential for enhancing cellular survival and proliferation. Mutations in the PI3K (PIK3CA) and MAPK (RAS) pathways have been identified and their importance is well-established in oncogenesis and as drivers of tumor growth. The objective of this study is to determine the anti-proliferative and anti-tumor effects of rigosertib in a preclinical model of colorectal cancer (CRC).
Experimental Design: We used colorectal cancer cell lines and a patient-derived explant model to investigate the growth inhibitory activity of rigosertib. We treated 25 CRC cell lines with rigosertib for 72 hours and measured the effect on proliferation by a sulforhodamine B (SRB) assay. We treated 5 patient-derived CRC explants with rigosertib (250 mg/kg/day-daily) for 28 days to determine anti-tumor activity in vivo. A tumor growth inhibition inhibition (TGI) ≥ 50% was considered sensitive.
Results: Twenty-four CRC cell lines were sensitive to rigosertib with an IC50 &gt; 1μM. The cell lines MIP-101, Lovo, and Caco-2 were the most sensitive reaching an IC50 at 0.0625 μM. The Colo678 cell line was resistant to rigosertib with an IC50 &gt; 1μM. There was no association between mutational status in PIK3CA or RAS and sensitivity to rigosertib. Zero out of 5 CRC explants showed sensitivity to rigosertib.
Conclusion: Rigosertib is a potent growth inhibitor in vitro of the majority of CRC cell lines tested with an IC50 &lt; 1μM. Our upcoming studies will test the inhibitory effects of rigosertib on an additional 15 CRC explants in an attempt to develop biomarkers of sensitivity or resistance.
Acknowledgements: The work was supported by a grant from Onconova Therapeutics® Inc.
Citation Format: Alicia Purkey, Eun-Kee Song, Kevin Quackenbush, Stacey Bagby, John J. Arcaroli, Antonio Jimeno, Wells Messersmith. Evaluation of the activity of rigosertib, an inhibitor of PI3K and MAPK pathways, in a preclinical model of colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2013-3263
Abstract 3270: Improved response of mitogen activated protein kinase kinase 1/2-dependent tumors using combination drug therapy.
Authors: Andersen Nicholas John , Boguslawski Elissa , Froman Roe , Duesbery Nicholas 
Published: August 2014

Abstract
Mitogen activated protein kinase kinase 1/2 (MEK1/2) inhibitors have failed to demonstrate a sustained clinical benefit for the treatment of melanoma or other MEK1/2 dependent cancers. We hypothesize combined treatment with inhibitors of MEK1/2 plus another cancer pathway would provide a more durable tumor response for MEK1/2 driven cancers. To test this we examined in vitro synergy between MEK1/2 inhibitor PD0325901 and inhibitors to eleven common cancer pathways using MEK1/2-driven melanoma cell lines and canine hemangiosarcoma cell isolates. Combination indices (CI) were calculated following the methods of Chou and Talalay (Chou and Talalay, 1984). Of the combinations tested, tyrosine kinase receptor inhibitors sorafenib and dasatinib, and the dual PI3 kinase and mTOR inhibitor rapamycin showed synergy (CI&lt;0.7) with PD0325901. To validate these results we subsequently tested synergy for PD0325901 plus sorafenib in vivo using mouse xenograft models for melanoma and canine angiosarcoma. We conclude dual inhibition of MEK1/2 and receptor tyrosine kinases or mTOR signaling are useful strategies to treat MEK1/2 dependent cancers.
Citation Format: Nicholas John Andersen, Elissa Boguslawski, Roe Froman, Nicholas Duesbery. Improved response of mitogen activated protein kinase kinase 1/2-dependent tumors using combination drug therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3270. doi:10.1158/1538-7445.AM2013-3270
Abstract 3273: TAK1 inhibition sensitizes neuroblastoma cells to chemotherapy.
Authors: Fan Yihui 
Published: August 2014

Abstract
Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-κB activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-κB activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox-induced NF-κB activation and enhanced Dox-induced apoptosis. Moreover, 5Z-7-oxozeaenol could overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, we provide a proof-of-concept that TAK1 inhibition significantly enhances the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk disease. Since the requirement of TAK1 kinase activity in genotoxic stresses-induced NF-κB activation is not limited by cell type, this suggests that TAK1 inhibition may greatly enhance the chemotherapeutic efficacy in other cancers.
Keywords: Neuroblastoma; TAK1 inhibitor; 5Z-7-oxozeaenol; chemotherapy
Citation Format: Yihui Fan. TAK1 inhibition sensitizes neuroblastoma cells to chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3273. doi:10.1158/1538-7445.AM2013-3273
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3279: Enhanced in vivo inhibition of neuropeptide-mediated castration resistant prostate cancer progression by combination therapy with enzalutamide and saracatinib.
Authors: Yang Joy C. , Ngyuen Hao G. , Gao Allen C. , Evans Christopher P. 
Published: August 2014

Abstract
Introduction: It has been shown that overexpression of the neuropeptides gastrin-releasing peptide (GRP) in LNCaP cells renders the cells castration-resistant through both androgen receptor (AR) activation and intracrine androgen biosynthesis. Aberrant activation of AR by GRP is mediated through Src kinase activation, which may be inhibited by the specific SFK inhibitor saracatinib. Inhibition of cognate AR activation requires anti-androgen. We hypothesize that treatment of this kind of CRPC demands the combination of saracatinib and new generation anti-androgen enzalutamide (MDV-3100).
Materials and methods: LNCaP GRP-Pro cells grown in CS medium were treated with control, saracatinib (2 μM), enzalutamide (10 μM) or the combination. Cell proliferation over 7 days was monitored by MTT assays. Cell cycle distributions over 72 hours of treatment were analyzed by flow cytometry. Cells were collected to prepare nuclear and cytosolic lysates respectively and examined by Western Blotting analysis for AR, pSrc, pAkt, LC-3 and β-actin. Expression of full-length AR and variants were compared by RT-qPCR. Orthotopic injection of GRP-Pro cells into castrated SCID male mice was used as the animal model for drug treatment studies.
Results: Enzalutamide or saracatinib alone only slightly inhibited CR cell growth but the combination brought it down to 27% of the control. Apoptosis was also enhanced with the combination. Enzalutamide only inhibited AR nuclear translocation in regular serum-kept GRP-Pro cells, while saracatinib inhibited the translocation in CS conditions. In the orthotopic model, neither treatments with saracatinib (25 mg/kg/daily) or enzalutamide (10 mg/kg/daily) alone showed any effect on tumor take, tumor weight or serum PSA levels. However, the combination treatment drastically reduced the tumor weights (0.66±0.13 g for controls vs. 0.24±0.07 g for the combo) and serum PSA levels (120.79±27.87 ng/ml vs. 19.19±7.45 ng/ml).
Conclusions: For GRP mediated CRPC growth, neither saracatinib or enzalutamide alone is sufficient to inhibit AR translocation and tumor progression. Combination of the two significantly improved the treatment for the CRPC orthotopic tumor model.
Citation Format: Joy C. Yang, Hao G. Ngyuen, Allen C. Gao, Christopher P. Evans. Enhanced in vivo inhibition of neuropeptide-mediated castration resistant prostate cancer progression by combination therapy with enzalutamide and saracatinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3279. doi:10.1158/1538-7445.AM2013-3279
Abstract 3284: An in vitro synergism between Ganoderma lucidum and Bacillus Calmette Guérin on premalignant transitional cell carcinoma.
Authors: Yuen John W. , Gohel Mayur-Danny I. , Ng Chi-Fai 
Published: August 2014

Abstract
Introduction: The major challenge for superficial transitional cell carcinoma (TCC) of the urinary bladder is recurrence. In the past three decades, Bacillus Calmette Guérin (BCG) has been used as an effective adjuvant therapy through the eradication of residual adverse cells following the surgical ablation of TCC tumors. Despite BCG has recently suspended for manufacture and shortage in supply, it provides moderate efficacy by reducing 30-40% of the recurrence cases but has high side effects toll of allergic cystitis. A medicinal mushroom - Ganoderma lucidum (GL) is known for its un-disputed scientific evidences which supporting the therapeutic roles on different cancers including TCC. In our previous reports, the triterpene-enriched ethanol extract of GL (GLe) was found to have similar immunological activities with BCG, in addition to apoptosis and telomerase inhibition. Therefore, BCG and GLe synergism was investigated. Brief Methodologies: The drug-drug interactions between BCG and GLe were assessed in an established carcinogen-sensitive human uroepithelial cell (HUC-PC) line, using two treatment schedules, i.e. co-treatment and pre-treatment with GLe. Outcome measures were cytoxicity and cytokines secretion using automated Vi-CELL cell viability analyzer (Beckman Coulter, USA) and FlowCytomix method (Bender MedSystems, Austria) with flow cytometry, respectively. Treated cells and culture media were harvested for measurements at 24 hours and 5 days upon the completion of the treatment schedules. Results and Discussion: In comparison with BCG, GLe was shown to exhibit immediate cytotoxic effects on the HUC-PC cells following incubation, whereas both drugs were individually active in stimulating the production of interleukin (IL)-6, IL-8 and monocyte chemotactic protin-1 (MCP-1). In both treatment schedules, complete cytostasis by maintaining the baseline cell seeding numbers was demonstrated in 24 hours, and cell eradication processes were progressively executed in the next 5 days in dose-dependent manners. By isobologram analysis, the interaction between BCG and GLe on cytotoxicity was shown to be synergistic. However, the pre-treatment of GLe has also resulted in suppression of all cytokines without influencing its cytotoxic effect. Conclusion: The results suggested that pre-treatment of GLe before BCG incubation could be effective to enhance the efficacy in adverse cells eradication, and potentially useful for counteracting the inflammation-associated side effects.
Citation Format: John W. Yuen, Mayur-Danny I. Gohel, Chi-Fai Ng. An in vitro synergism between Ganoderma lucidum and Bacillus Calmette Guérin on premalignant transitional cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3284. doi:10.1158/1538-7445.AM2013-3284
Abstract 3288: Isolation of anti-neoplastic drug candidates against metastatic breast, lungs and ovarian carcinoma cells.
Authors: Ozes Osman N. 
Published: August 2014

Abstract
Cancer is a leading cause of death in man and women worl-wide. In recent years, wold-wide increase of obesity and diabetes, consumption of food additives and pollution are affecting quality of life and the incidense of all types of cancers are on the rise. Although new treatment regimens are also introduced into clinic war against cancer is still not won.
Treatment of cancer with synthetic chemoterapics come with a unfavorable side effects which often ends therapy. Instead of investing in synthetic compounds, OZES BIOPHARMA is engaged in discovery of anti-neoplastic drug candidates from endemic plants of TURKEY. We have been extracting and analyzing organic compounds from variety of plants consumed as a food. Our search in past two years yielded very enchoraging results and we have discovered 6 novel compounds named OZS 1-6. Our compounds show significant levels of anti-tumor and anti-metastatic activities against human metastatic and non-metastatic breast cancer cells(MDA-231,MCF7), lung cancer cells (A549),
Ovarian cancer cells (A2780) and its cisplatin resistant clone. Currently, we are idientifying the pathways inhibited or activated by our compounds.
Citation Format: Osman N. Ozes. Isolation of anti-neoplastic drug candidates against metastatic breast, lungs and ovarian carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2013-3288
Abstract 3292: The potential chemomodulatory effects of didox and resveratrol on doxorubicin in colon cancer cells.
Authors: Khaleel Sahar A. , Al-Abd Ahmed M. , Ali Azza A. , Abdel-Naim Ashraf B. 
Published: August 2014

Abstract
Resveratrol and didox are polyhydroxy phenols that possess potential anticancer and chemosensitizing effects. The efficacy of doxorubicin in the treatment of colorectal cancer is limited by multi-drug resistance. Herein, we have assessed the chemomodulatory effect of resveratrol and didox on doxorubicin in colorectal cancer cell lines (HCT116 and HT29). Furthermore, we have investigated the molecular aspects of this interaction. Resveratrol was found to possess anti-cancer properties; however with a relatively low potency in HCT116 (IC50 = 17.5 μM) and HT29 (IC50 = 187 μM). IC50 values of Didox in HCT 116 and HT29 was 105 μM and 501 μM, respectively. In terms of Doxorubicin, the IC50-values were 0.96 μM and 0.88 μM in HCT116 and HT29, respectively. Resveratrol combination with doxorubicin significantly reduced its IC50-values to 0.59 μM in HCT116, and to 0.49 μM in HT29. Moreover, Didox combination significantly increased the potency of doxorubicin showing IC50 shift to 0.4 μM in HCT116, and to 0.29 μM in HT29. The combination between doxorubicin and resveratrol/didox in HCT116 and HT29 was found to be additive (combination index ranged from 0.8-1.2). The pro-apoptotic genes, p53 and bax, were markedly elevated after combination of doxorubicin with resveratrol or didox in both HCT116. On the other hand, the anti apoptotic genes, bcl2 and bclx, were downregulated. Caspase-3 concentration revealed marked increase due to combination of didox with doxorubicin in both cell lines. On the other hand, resveratrol combination with doxorubicin showed marginal elevation of caspase-3 concentration in HT-29 cells while marked elevation in HCT116 cells. In conclusion, didox and resveratrol potentiated the efficacy of doxorubicin in colorectal cancer cell lines.
Citation Format: Sahar A. Khaleel, Ahmed M. Al-Abd, Azza A. Ali, Ashraf B. Abdel-Naim. The potential chemomodulatory effects of didox and resveratrol on doxorubicin in colon cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3292. doi:10.1158/1538-7445.AM2013-3292
Abstract 3298: Neotargeting HER2 negative cancer cells with Trastuzumab-based photoimmunotherapy by viral transduction of HER2-extracellular domain.
Authors: Ishida Michihiro , Kagawa Shunsuke , Shimoyama Kyoko , Watamabe Shinichiro , Noma Kazuhiro , Tazawa Hiroshi , Hashimoto Yuuri , Matsuoka Junji , Kobayashi Hisataka , Fujiwara Toshiyoshi 
Published: August 2014

Abstract
The prognosis of HER2 positive breast cancer has been improved by Trastuzumab which features high specificity and limited side effects. Numerous randomized trials have confirmed the efficacy and safety of Trastuzumab in HER2-overexpressing cancers. However, many patients who initially respond to Trastuzumab ultimately develop disease progression. Strategies to overcome Trastuzumab-refractory cancer are sought, and drug-conjugation is one of candidates. Trastuzumab-IR700 which is Trastuzumab conjugated with a near-infrared (NIR) photosensitizer, phthalocyanine dye, IR700, has recently been developed as a new type of molecular-target photoimmunotherapy(PIT). This PIT can induce target-selective necrotic cell death only at the place which have Trastuzumab's target part and where exposure of NIR light. Disappointingly, HER2-targeting therapy is applicable to only Her2-expressig tumors which consist of approximately 20-25% of primary breast cancers. In previous study, we developed the adenoviral vector to express HER2-extracellular domain (HER2-ECD), Ad/HER-ECD, and confirmed that it efficiently induced HER2 expression for HER2 negative and HER2-downregulated human cancer cells. So, we hypothesized that Ad/HER-ECD expand the range of tumor entities suitable for Trastuzumab-based PIT. By using Ad/HER-ECD and Trastuzumab-IR700 with PIT we revealed that the direct cell membrane destruction are induced at HER2 negative cancer cells, similarly at HER2 positive cancer cells, in vitro. These results suggest that combination of virally-transduction of target antigen and an antibody-based PIT would expand and potentiate target therapy even for target-negative or attenuated cancer cells.
Citation Format: Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Shinichiro Watamabe, Kazuhiro Noma, Hiroshi Tazawa, Yuuri Hashimoto, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara. Neotargeting HER2 negative cancer cells with Trastuzumab-based photoimmunotherapy by viral transduction of HER2-extracellular domain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3298. doi:10.1158/1538-7445.AM2013-3298