bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2530: The anticancer kinase inhibitor dovitinib (TKI258/CHIR258) may have multiple modes of action because it also binds DNA and inhibits topoisomerase I and topoisomerase IIα
Authors: Wu Xing , Yalowich Jack C. , Hasinoff Brian 
Published: June 2012

Abstract
Dovitinib (TKI258/CHIR258) is a kinase inhibitor in phase II development for the treatment of renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. Dovitinib is thought to exert anticancer effects through its binding to and kinase inhibition of fibroblast growth factor receptor 3 (FGFR3). It also strongly inhibits a number of other kinases that are members of the RTK superfamily, including the vascular endothelial growth factor receptor (VEGFR); fibroblast growth factor receptor 1 (FGFR1); platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3 (FLT3); stem cell factor receptor (c-KIT) and colony-stimulating factor receptor 1 (CSF1R) all of which may also contribute to its anticancer activity. In terms of its chemical structure dovitinib is a benzimidazole-quinolinone compound. Thus, structurally it resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could be reasonably accommodated in the minor groove. Dovitinib was shown to bind to DNA by its ability to increase the DNA melting temperature. Changes in the visible absorbance and fluorescence spectrum of dovitinib that occurred upon addition of DNA were also consistent with DNA binding. Because DNA binders are often topoisomerase I and topoisomerase II inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited both the decatenation activity and the ATPase activity of topoisomerase IIα in the low micromolar concentration range. Dovitinib was also able to stabilize the topoisomerase IIα-cleavage complex and act as a topoisomerase IIα poison with activity comparable to etoposide as measured by its ability to induce formation of linear DNA. Dovitinib was also examined for its ability to increase phosphorylation of H2AX in K562 cells to determine if it could act as a cellular topoisomerase II poison and induce double strand DNA breaks. Dovitinib was also able to inhibit the topoisomerase I-catalyzed relaxation of DNA. In conclusion, the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also from its ability to target topoisomerase I and topoisomerase IIα. Support: CIHR and a Canada Research Chair in Drug Development to BBH and an NIH grant (CA090787) to JCY.
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 2530. doi:10.1158/1538-7445.AM2011-2530
Abstract 2535: PrevOnco® exhibits anti-tumor activity in in vitro and in vivo human tumor models: Combination therapy (PrevOnco® / Doxorubicin) demonstrates a better efficacy profile with enhanced survival rate in a liver cancer model
Authors: Incardona Francesca , Dines Kevin , Damaj Bassam , Martin Richard , Hachicha Mohamed 
Published: June 2012

Abstract
Background: The investigational anti-neoplastic agent PrevOnco® (know as Prevacid® /Lansoprazole®) is entering Phase II clinical trials in the US for hepatocellular carcinoma.
Objectives: This study examined the efficacy of PrevOnco® in both in vitro and in vivo human tumor models. The optimal oral formulation, pharmacokinetic parameters and its combination therapy with doxorubicin were evaluated.
Methods: Cytotoxicity was assessed in vitro by MTT analysis. In vivo efficacy was assessed in nude mice in 2 survival models of the pediatric kidney-derived G401 and SR leukemia, and one ectotopic HepG2 model.
Results: In MTT assays, PrevOnco® demonstrated a concentration-dependent cytotoxic effect against a number of cancer cell lines (MC116, HOP-62, MOLT4, HCT-15, JMI, RPMI6666, RS 1184, STA 486, SF539, U251, SF295, UACC-62). Synergistic activity was observed with doxorubicin but not with cisplatin. PrevOnco® was significantly more effective than Omeprezole or SCH-28080. Pharmacokinetic analysis in nude mice showed 10% PEG400 to be a better vehicle than carboxy-methyl cellulose. A mean maximum concentration (Cmax) of 20,242 ng/mL was detected at 0.5 hours (Tmax) with the mean dose adjusted area under the curve (AUC) determined to be 846.5 nM*hr/mg. The half life (T1/2) of the compound was 0.9 hours. PrevOnco® at 100 mg/kg given orally significantly prolonged the survival rate in the G401 kidney xenograft by 60% at day 70 whereas all mice in vehicle treaded group died. At study end (day 83) 26% of the mice remained alive in the treated group. SR leukemia xenograft treated with PrevOnco® survived through the end of the study with &gt;80% of the mice remaining alive. PrevOnco® induced a dose-dependent reduction in tumor growth in hepG2 model. A synergestic antitumoral effect was obtained with the combination treatment of PrevOnco® at 30 mg/kg and doxorubicin at10 mg/kg. PrevOnco® levels in hepG2 tumors following 100 mg/Kg BID treatment for 3 consecutive days indicated accumulation of the drug into tumor tissue.
Conclusion: PrevOnco® exhibited anti-neoplastic activity in both in vitro and in vivo, enhancing survival and inhibiting tumor growth. Synergistic activity was obtained with doxorubicin in xenograft model of liver cancer, suggesting a potential new combination therapy for the treatment of liver cancer with less toxicological liability.
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 2535. doi:10.1158/1538-7445.AM2011-2535
Abstract 2539: Antitumor effects of oral paclitaxel DHP107 on gastric cancer xenografts
Authors: Na Young-Soon , Jung Kyung-Ah , Yang Soo-Jin , Kim Seung-Mi , Kim Hye Youn , Hong Yong Sang , Ryu Min-Hee , Lee Jae-Lyun , Son Woo-Chan , Jin Dong-Hoon , Kim Tae Won 
Published: June 2012

Abstract
Oral paclitaxel DHP107 (Daehwa, Seoul Korea), an antineoplastic agent, is effectively absorbed through the gastrointestinal tract via the lipid uptake mechanism, which is currently under clinical investigation. Oral capecitabine generates 5-fluorouracil (5-FU) by thymidine phosphorylase, preferentially in tumor tissue. Taxanes, such as paclitaxel and docetaxel, have the ability to up-regulate levels of thymidine phosphorylase which show the its increased activity in tumors compared with that of normal tissue. Accordingly, combination treatment using taxanes with capecitabine is effective in several tumors, especially in gastric cancer. In this study, we investigated the antitumor effect of DHP107 combined with capecitabine and compared the effects of DHP107 and Taxol in gastric cancer xenografts. DHP107 in combination with capecitabine dramatically inhibited tumor growth without additive toxicity compared with each agent used alone in gastric xenografts. The expression of the level of thymidine phosphorylase in tumor was markedly increased four hours after treatment with DHP107. The apoptotic effects, assessed using TUNEL and soft agar colony-formation assay on xenograft tumors, were greater with combined treatment than with either agent used alone. The antitumor effects of DHP107 were similar to those of Taxol in gastric cancer xenografts. These data indicate that DHP107 combined with capecitabine had enhanced antitumor effects in human gastric tumor xenografts and that DHP107 had antitumor effects in gastric cancer models, both of which provide support for future clinical trials of DHP107.
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 2539. doi:10.1158/1538-7445.AM2011-2539
Abstract 2545: Roles of BIM induction and survivin down-regulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification
Authors: Tanizaki Junko , Okamoto Isamu , Fumita Soichi , Okamoto Wataru , Nakagawa Kazuhiko 
Published: June 2012

Abstract
Breast cancer is the leading cause of cancer death among women worldwide. Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 25 to 30% of breast cancers, and HER2 is thus an attractive target for the development of therapeutic drugs. Lapatinib, a dual tyrosine kinase inhibitor of HER2, is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism of this antitumor action has remained unclear, however. Although lapatinib improved the overall outcome for such patients, not all patients benefited from the treatment. Characterization of the molecular basis of the response to lapatinib will thus be important to maximize the clinical efficacy of this drug. Mutations in PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been identified in 8 to 40% of breast cancers. Although a positive correlation between HER2 overexpression and the presence of PIK3CA mutations has been described, the relation between the efficacy of lapatinib and such mutations has remained unclear. We have now investigated the effects of lapatinib in HER2 amplification-positive breast cancer cells with or without an activating PIK3CA mutation. By using immunoblot analysis and Annexin V assay, we found that lapatinib induced apoptosis in association with up-regulation of the proapoptotic protein BIM through inhibition of the MEK-ERK signaling pathway in breast cancer cells with HER2 amplification. RNA interference-mediated depletion of BIM inhibited lapatinib-induced apoptosis, implicating BIM induction in this process. The proapoptotic effect of lapatinib was less pronounced in cells with a PIK3CA mutation than in those without one. Lapatinib failed to inhibit AKT phosphorylation in PIK3CA mutant cells, likely because of hyperactivation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by the mutation. Depletion of PIK3CA (a catalytic subunit of PI3K) by si-RNA revealed that survivin expression is regulated by the PI3K pathway in these cells, suggesting that insufficient inhibition of PI3K-survivin signaling is responsible for the limited proapoptotic effect of lapatinib in HER2 amplification-positive cells with a PIK3CA mutation. Consistent with this notion, depletion of survivin by RNA interference or treatment with a PI3K inhibitor markedly increased the level of apoptosis in PIK3CA mutant cells treated with lapatinib. Our results thus suggest that inhibition of both PI3K-survivin and MEK-ERK-BIM pathways is required for effective induction of apoptosis in breast cancer cells with HER2 amplification.
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 2545. doi:10.1158/1538-7445.AM2011-2545
Abstract 2549: Efficacy of the Chk1 inhibitor PF-00477736 and pemetrexed in human mesothelioma
Authors: Blasina Alessandra , Hallin Jill F. , Tan Wei , Los Gerrit , Jani Jitesh P. 
Published: June 2012

Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy with the median survival of less than 1 year from diagnosis. Pemetrexed (PTX), a multi-targeted antifolate drug in combination with cisplatin, has been used as front-line treatment. PTX-treatments causes S-phase cell cycle arrest allowing cancer cells to repair damaged DNA critical for cell survival and proliferation. The Chk1 kinase, a central regulator of cell cycle progression and a principal mediator of cell cycle checkpoints in response to genotoxic stress is overexpressed in mesothelioma. We evaluated the in-vitro activity of the Chk1 kinase inhibitor, PF-00477736, in combination with PTX in MPM. PF-00477736 treatments abrogated the PTX-induced S-phase cell cycle arrest and enhanced cytotoxicity of PTX in a dose-dependent manner (∼81% cell proliferation inhibition, vs. ∼13% with PTX alone). PTX and PF-00477736 treatments alone enhanced the levels of γH2AX (6% and 16%, respectively), however, their combination had significantly higher effect (∼60% increase) compared to control cells. These results suggest that when Chk1 is inhibited, PTX-induced replication stress is converted into additional DNA damage due to checkpoint abrogation and lack of DNA repair. The sensitization of mesothelioma cells to PTX by PF-00477736 was also associated with a marked increase in apoptosis (∼11-fold increase compared to PTX of PF-00477736 treatments alone). Collectively, these results show a therapeutic potential of combining Chk1 inhibitors and PTX for the treatment of mesothelioma.
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 2549. doi:10.1158/1538-7445.AM2011-2549
Abstract 255: GRB7 – a novel target in triple-negative breast cancer
Authors: Giricz Orsi , Pero Stephanie C. , Krag David N. , Sparano Joseph A. , Kenny Paraic A. 
Published: June 2012

Abstract
Triple-negative breast tumors lack expression of estrogen and progesterone receptors and HER2, rendering them non-responsive to the most effective targeted therapies in breast cancer. These tumors are typically more aggressive than other breast cancer subtypes and, consequently, have a poor prognosis. In a clinical trial of triple-negative breast cancer patients treated with anthracyclines and taxanes, we and others have recently determined that high levels of GRB7 are predictive of tumor recurrence. GRB7 is a cytoplasmic adaptor protein that interacts with receptor tyrosine kinases and integrins, transducing information to their downstream signaling cascades.
In this study, we have tested the hypothesis that triple-negative breast cancer cell lines are dependent on GRB7 for migration, invasion and colony formation in 3D culture. Using a highly specific peptide inhibitor (G7-18NATE), we found that the GRB7 inhibition significantly impaired each of these phenotypes in four triple-negative breast cancer cell lines: MDA-MB-468, MDA-MB-231, HCC70 and T4-2. In addition, we have tested whether GRB7 inhibition may sensitize these cell lines to the chemotherapies used in the initial clinical trial. Combination treatment with G7-18NATE and doxorubicin or docetaxel resulted in cooperative cell growth inhibition in each of the four cell lines. Co-treatment lowered the IC40 of both chemotherapeutic agents, and it proved to be synergistic in all cases (Combination Index values &lt;1)
These data implicate GRB7 as a key mediator of migration, invasion, colony growth and chemoresistance of triple-negative breast cancer cells and suggest that GRB7 itself, or GRB7-dependent pathways, may prove to be important targets therapeutic.
This work was supported in part by Susan G. Komen for the Cure (KG091136).
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 255. doi:10.1158/1538-7445.AM2011-255
Abstract 2560: The CK2 inhibitor CX-4945 enhances the antitumor activity of EGFR-targeted agents by attenuating signaling in the PI3K/AKT/mTOR pathway
Authors: Bliesath Josh , Drygin Denis , Streiner Nicole , Ho Caroline , Siddiqui-Jain Adam , Proffitt Chris , Omori May , Huser Nanni , O'Brien Sean , Anderes Kenna 
Published: June 2012

Abstract
The epidermal growth factor receptor (EGFR) regulates several oncogenic signaling pathways including PI3K/AKT/mTOR, MEK/ERK, and STAT. A number of EGFR antagonists have been approved for treatment of late-stage tumors of epithelial origin. Despite these advances, there are several limitations to these therapies, including primary and acquired resistance, prompting the need to combine EGFR antagonists with agents that target pathways downstream of EGFR. CK2 modulates multiple pro-proliferative and pro-survival signals through many of these same signaling pathways, and co-overexpression of EGFR and CK2 has been frequently observed in solid tumors. Here we present the combination of EGFR-targeted agents with CX-4945, a first-in-class selective CK2 inhibitor currently under evaluation in a Phase I clinical trial. CK2 phosphorylates several key proteins at multiple levels within the PI3K/AKT/mTOR signaling pathway including AKT, PTEN, and p70S6K1. CK2 also regulates the Hsp90/Cdc37 machinery, whose clients include EGFR, AKT, and Src. We proposed that top-down inhibition of EGFR, combined with lateral inhibition of the PI3K/ATK/mTOR pathway by CX-4945, would result in an improved cancer therapy compared to EGFR antagonism alone. This hypothesis was tested in vitro and in vivo in A431 squamous cell carcinoma (SCC) and non-small cell lung carcinoma (NSCLC) models of various genetic backgrounds. Signaling pathways and induction of apoptosis were analyzed by western blot and cell proliferation was measured in a 96-hour cell viability assay. The combination of CX-4945 and erlotinib resulted in enhanced reduction in phosphorylation of AKT (T308), AKT (S473), PRAS40 (S246), mTOR (S2481), mTOR (S2448), p70S6K1 (T389), S6 (S235/6), S6 (240/4), and 4E-BP1 (T37/46), and decreased Mcl-1 levels. These effects were accompanied by decreased cell proliferation and synergistic induction of apoptosis. CX-4945 plus erlotinib exhibited enhanced antitumor activity in A431 SCC and NCI-H2170 NSCLC xenograft models; moreover, in the erlotinib-resistant NCI-H1975 NSCLC xenograft model, CX-4945 plus cetuximab resulted in enhanced efficacy. These data suggest that CX-4945 in combination with EGFR-targeted agents may improve clinical outcomes in patients with EGFR and CK2-driven cancers by inhibiting multiple nodes of the EGFR signaling pathway.
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 2560. doi:10.1158/1538-7445.AM2011-2560
Abstract 2562: Efficacy of RG7204 (PLX4032), a selective BRAFV600E inhibitor, in combination with pegylated interferon alpha-2a (Pegasys), paclitaxel, carboplatin, and anti-VEGF MAb B20-4.1 in the LOX-IMVI human melanoma xenograft model
Authors: Higgins Brian , Kolinksy Kenneth , Go Zenaida , Char Hing , Lee Richard , Schostack Kathleen , Bollag Gideon , Heimbrook David , Su Fei , Packman Kathryn E. 
Published: June 2012

Abstract
Few drugs are currently approved for the treatment of melanoma, including dacarbazine (chemotherapy) and interferon alpha (immunotherapy). However, only a small fraction of patients with metastatic melanoma respond to dacarbazine and a survival benefit has not been shown with this or any other chemotherapy regimen. Taxanes have demonstrated some activity in melanoma, including modest response rates in combination with carboplatin or bevacizumab. These results contrast with the extraordinary Phase I clinical data reported with the BRAFV600E kinase inhibitor RG7204 (PLX4032), which has demonstrated a remarkable response rate (N Engl J Med 363(9):809-819, 2010). Here we report our preclinical investigation of RG7204 in combination with the biologics interferon alpha-2a (Pegasys) or B20-4.1 (B20) (mouse/ human cross-reactive anti-VEGF MAb), and the chemotherapies paclitaxel and carboplatin in the BRAFV600E mutant LOX-IMVI melanoma model in nude mice.The combination of RG7204 and paclitaxel provided superior survival as compared to either monotherapy. Conversely, the combination of RG7204 plus carboplatin or RG7204 plus B20 did not extend survival as compared to RG7204 monotherapy. When RG7204, paclitaxel, and B20 were given in triplet combination, no improvement in survival was observed over any doublet. Similarly, the triplet combination with RG7204, carboplatin and B20 failed to demonstrate improved survival over any doublets or RG7204 monotherapy. Although complete suppression of tumor growth was readily achieved with either RG7204 or Pegasys monotherapy, the combination provided a remarkable survival benefit with median survival extended by nearly a year as compared to either monotherapy.
Taken together, these data support clinical testing of RG7204 with interferon alpha in melanoma patients harboring BRAFV600E mutation in order to extend survival, and may allow for use of lower dose interferon. Clinical investigation of RG7204 and paclitaxel combination may also be warranted. While our data do not support combined therapy with RG7204 plus anti-VEGF therapy, it should be noted that the LOX model was resistant to B20 monotherapy, and therefore these findings might not apply to tumors with intrinsic sensitivity to anti-VEGF 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 2562. doi:10.1158/1538-7445.AM2011-2562