bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5481: Antitumor activity of a novel JAK/Stat3 inhibitor, NSC-743380
Authors: Guo Wei , Wu Shuhong , Fang Bingliang , Wang Li , Liu Xiaoying 
Published: June 2012

Abstract
We recently developed two compounds, NSC-741909 and NSC-743380, which were highly active against a subset of NCI-60 cancer cell lines. This study investigated the in vivo activities of NSC-743380 and NSC-741909 in human tumor xenografts in nude mice and the mechanism of NSC-743380 antitumor activity. In vitro antitumor activity was determined by sulforhodamine assay of cell viability. In vivo antitumor activity was determined in xenograft tumors established from the human renal cancer cell line A498. NSC-743380-induced apoptosis and changes in gene expression levels and signaling pathway activities were identified by Western blot analyses, flow cytometric analyses, or both. The role of Stat3 in NSC-743380-induced antitumor activity was determined by enforced expression of a constitutively active Stat3 construct in sensitive cancer cells. NSC-743380 is highly active against a subset of cancer cell lines derived from lung, colon, ovary, kidney, and breast cancers and has an antitumor spectrum similar to that of NSC-741909 in the NCI-60 cancer cell line panel. The in vivo study revealed that NSC-743380 has an improved toxicity profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused tumor regression at all three dose levels, and a portion of animals at all three doses were tumor free. Mechanistic studies revealed that treatment with NSC-743380 inhibited JAK/Stat3 phosphorylation and this inhibition was dependent on both dose and time. Our results demonstrate that NSC-743380 is a novel JAK/Stat3 inhibitor that has selective antitumor activity against a subset of cancer cell lines and has favorable in vivo antitumor activities.
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 5481. doi:10.1158/1538-7445.AM2011-5481
Abstract 5485: mTOR inhibition promotes autophagy that reduces chemosensitivity and is partially restored by chloroquine
Authors: Huang Shengbing , Yu Chunrong , Sinicrope Frank A. 
Published: June 2012

Abstract
BACKGROUND. The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. We determined whether mTOR inhibition can induce cytoprotective autophagy resulting in anti-cancer drug resistance, and whether inhibition of autophagy using the lysomotrophic agent, chloroquine, can restore chemosensitivity.
EXPERIMENTAL METHODS. Inhibition of mTOR was accomplished in human colon cancer cells (HT-29, DLD1) using lentiviral shRNA or by AZD8055, a TORC1 and TORC2 kinase inhibitor. These cells were then incubated with 5-FU (0-100 µM) or CPT-11 (0-20 µM) alone and in combination with chloroquine. LC3I/II expression, phospho-histone H2A.X (a DNA damage marker), and caspase cleavage were analyzed by Western blotting using highly specific antibodies, and clonogenic survival assays were also performed.
RESULTS. AZD8055 was shown to attenuate caspase-3 and -9 cleavage and to suppress the expression of phospho-histone H2A.X induced by 5-FU or CPT-11 in colon cancer cells. AZD8055 was also found to antagonize the ability of 5-FU to inhibit clonogenic survival. Similarly, shRNA knockdown of mTOR attenuated 5-FU-induced caspase cleavage and phospho-histone H2A.X expression. Inhibition of mTOR by AZD8055 or shRNA enhanced the conversion of the autophagosome-associated protein light chain 3 (LC3) from a cytosolic (LC3I) to a membrane-bound (LC3II) form, consistent with induction of autophagy. Inhibition of autophagy by chloroquine was shown to attenuate the ability of AZD8055 to suppress 5-FU-induced caspase cleavage. Consistent with this result, chloroquine sensitized DLD1 cells to AZD8055 and 5-FU in a clonogenic survival assay.
CONCLUSION. Inhibition of mTOR can protect colon cancer cells from DNA damage induced by cytotoxic chemotherapy. This cytoprotection was due, in part, to induction of pro-survival autophagy since chloroquine was able to partially restore chemosensitivity.
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 5485. doi:10.1158/1538-7445.AM2011-5485
Abstract 5488: Novel death pathway in a p53 null human leukemia cell line treated with PNC-27
Authors: Fenelus Maly , Mathew Sheena M. , Zolkind Paul A. , Adler Victor , Yazdi Ehsan S. , Michl Josef , Pincus Matthew R. , Bowne Wilbur B. 
Published: June 2012

Abstract
Background: PNC-27 is a p53-derived peptide from the human double minute binding domain (HDM-2). This peptide has been shown to induce rapid tumor cell necrosis of selected cancer cells, while sparing their normal cellular counterparts (PNAS 2010; 107: 1918-1923). PNC-27 binds to HDM-2 in the cancer cell membrane, causing pore-formation and permeabilization of the membrane. We now propose an additional target for PNC-27 involving mitochondrial membrane-bound B-cell lymphoma-2 (Bcl-2), which contains a BH3 protein-protein interaction domain. BH3 serves as a potent mediator of cell death in pro-apoptotic proteins (such as Bax and Bad), as well as anti-apoptotic proteins, Bcl-2 and Bcl-XL. These Bcl-2 proteins have been proposed to control function and stability of the outer mitochondrial membrane.
Methods: The anti-cancer activity and mechanism of PNC-27 (p53 aa12-26-penetratin) was studied against p53 null K562, a human leukemia cancer cell line. Necrosis was determined by measuring lactate dehydrogenase (LDH), while apoptosis was determined by measuring early markers of apoptosis (caspases 3, 7). Co-immunoprecipitation (IP) was performed between PNC-27 and subcellular components to identify potential targets for PNC-27 in K562 cells. HDM-2, Bcl-2, Cytochrome C, and ATP synthesis in PNC-27-treated cells were studied.
Results: We found that PNC-27, but not control peptide PNC-29, is cytotoxic to K562 cells, inducing nearly 90% inhibition of proliferation with LDH release. PNC-27 peptide induced Cytochrome C release as well as downregulation of ATP synthesis. Furthermore, endoge$$nous HDM-2 and Bcl-2 was found to IP with exogenous PNC-27 in K562 cells, inducing downregulation of HDM-2 and Bcl-2.
Conclusions: P53 N-terminal derived peptide (PNC-27) potentially alters the mitochondrial membrane of K562 cells via induction of outer membrane permeabilization; with resultant down-regulation of Bcl-2, induction of Cytochrome C release, and decreased ATP synthesis. Our results suggest a second target and mechanism of cell death using PNC-27 in a p53 null K562 cell line; a p53 derived peptide that also targets Bcl-2 leading to rapid tumor cell necrosis.
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 5488. doi:10.1158/1538-7445.AM2011-5488
Abstract 5493: Lethal mutagenesis of cancer cells by nucleoside analogs
Authors: Fox Edward J. , Shen Jiang-Cheng , Loeb Lawrence A. 
Published: June 2012

Abstract
The evolution of cancer and RNA viruses is characterized by mutation accumulation facilitating phenotypic plasticity and environmental adaptation. We have demonstrated that serial passage of virus from HIV-infected human lymphoblastoid cells in the presence of mutagenic nucleosides results in mutation accumulation, leading to error catastrophe, and viral extinction. In limited phase II clinical studies, administration of a cytidine analog, KP-1461, to individuals infected with HIV results in increased viral mutations. We hypothesize that cancer cells treated with mutagenic nucleoside analogs will progressively accumulate mutations until the error threshold for viability is exceeded and the tumor ablated. We have serially passaged mismatch repair proficient and deficient colon cancer cells in the presence of 36 different mutagenic deoxynucleoside analogs and established a new protocol for measuring both mis-incorporation and repair during DNA synthesis in cells. DNA templates, purified from phage, are blocked with terminal non-hydrolysable nucleotides to prevent degradation by cellular nucleases. After transfection of double-stranded DNA into human cells, we can recover &gt;50,000 molecules/cell. After transfection of single-stranded DNA molecules hybridized to a 5′-biotin labeled primer, extended primers are recovered on streptavidin beads; the frequency of misincorporation into the newly synthesized DNA varies from 10-3 to 10-6, depending on the genetic background of the tranfected cells. The versatility of this assay will facilitate studies on the efficiency of DNA repair, the role of different human DNA polymerases in DNA synthesis and bypass of DNA damage, and the stratification of individuals with respect to DNA repair capacity and fidelity. Enhancing the mutation frequency of cancer cells represents a new avenue for treatment, particularly for patients with tumors that have accumulated large numbers of mutations and/or who failed extensive chemotherapy.
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 5493. doi:10.1158/1538-7445.AM2011-5493
Abstract 5497: An inhibitor of phosphatase PP2A enhances in vivo anticancer activity of a phospho (ADP-ribosyl) polymerase inhibitor (PARPi) combined with temozolomide (TMZ)
Authors: Lu Jie , Ikejiri Barbara , Yang Chunzhang , Thompson Eli , Mushlin Harry , Kovach John S. , Lonser Russell , Zhuang Zhengping 
Published: June 2012

Abstract
We previously showed that a novel inhibitor of PP2A enhances the in vivo activity of TMZ against human glioblastoma xenografts (Lu et al, PNAS 2009;104:11697-11702). Several mechanisms underlie this effect of PP2A inhibition and include an increased rate of cancer cell entry into DNA synthesis, inhibition of cell cycle arrest at G1 and G2/M, and a marked reduction in p53. Because inhibitors of PARP1 have been shown to enhance the activity of cytotoxic cancer drugs by inhibiting repair of single-strand breaks in cells with impaired mechanisms for double-stranded DNA repair (BrCa mutants, triple negative breast cancer cells), we reasoned that blocking other types of DNA-damage defense mechanisms by PP2A inhibition might further enhance the activity of a PARPi combined with TMZ in cancers, not necessarily already deficient in DNA repair. We treated mice bearing xenografts of human melanoma, line A2058, with single agent LB-100, a novel water soluble PP2A inhibitor (Lixte Biotechnology Holdings, Inc., East Setauket, NY; Lu et al, J Neurosurg 2010; 113: 225-233) at 1.5mg/kg by continuous intraperitoneal (i.p.) infusion for 21 days and TMZ at 80mg/kg i.p. days 3,6,9,12,15,18. LB-100 and TMZ were given alone and in combination with each other and in 2-drug combinations with the PARPi, ABT-888 (Sigma), at 6.25 mg/kg i.p. on days 3,6,9,12,15,18, and all three drugs were given together at the same doses and schedules as when used alone or in 2-drug combinations. (ABT-888 was inactive as a single agent and was not used alone). The combination of LB-100 + TMZ was more inhibitory to the xenografts at 21 days than ABT-888 + TMZ, but the 3-drug regimen was most effective and no more toxic than any of the 2-drug regimens. Histologic analysis of xenografts 24 hours after treatment of animals with each of the single agents, each 2-drug regimen, and the 3-drug regimen showed increased apoptosis and necrosis by the 3-drug combination compared to the two-drug regimens, which in turn were more effective that the single agents. Similar results were found in vitro by flow cytometric analysis of A2058 cells 24 hours after exposure to the single agent and 2- and 3-drug regimens. Inclusion of a PP2A inhibitor may increase and extend the effectiveness of cytotoxic regimens containing a PARPi to cancers without acquired mutations in DNA repair.
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 5497. doi:10.1158/1538-7445.AM2011-5497
Abstract 5502: Absence of ERCC1 expression is predictive of complete pathologic response to platinum-based therapy for women with triple negative breast cancer
Authors: Cioffi-Lavina Maureen , Hurley Jude , Jorda Merce , Walker Gail , Gomez-Fernandez Carmen 
Published: June 2012

Abstract
Background: Platinum-based chemotherapy exerts its cytotoxic effects by forming intra-strand DNA adducts that inhibit replication. Excision Repair Cross Complementing group 1 protein (ERCC1) plays a critical, yet undesirable, role in repair of DNA damage induced by platinum. Absence of immunohistochemical expression of ERCC1 has been shown to be associated with response to platinum-based chemotherapy regimens in non small cell lung carcinomas. Experimental data suggests that triple negative breast cancers may have increased sensitivity to platinum-based chemotherapy, particularly in BRCA1 mutation carriers, whose cancers cluster among the basal-like subtype, as defined by gene expression profiling. We investigated the immunohistochemical expression of ERCC1 in relation to response to neoadjuvant platinum-based chemotherapy in a cohort of patients with triple negative breast cancers.
Materials and Methods: We reviewed the diagnostic core biopsies of 32 triple-negative breast cancer patients treated with neoadjuvant docetaxel plus platinum-based salts at our institution between 1999 and 2007. Fifteen (46.9%) study patients had pathologic complete response (pCR), defined by the absence of invasive carcinoma in the breast and axilla. Immunohistochemistry for ERRC1 (ABCAM) was performed in all cases using the LSAB method. A nuclear immunohistochemical reaction in &gt;1% of the tumor cells was scored as positive for ERCC1. Fisher's exact test was used to compare pCR rates by ERCC1 status.
Results: Sixteen of 32 (50%) triple negative breast carcinomas were positive for ERCC1 by immunohistochemistry. Reactivity was present in 10 to 50% of the tumor cell nuclei. The remaining 16/32 (50%) carcinomas were definitively negative for ERCC1. Significantly higher pCR rates were found in patients with ERCC1(−) tumors, 11/16 (68.8%), compared to 4/16 (25%) patients with ERCC1(+) tumors, p=0.032. Findings were similar for pCR confined to the breast (75.0 v 31.3%, p=0.032), and for pCR in the axilla (75.0 v 43.8%), although the latter result lost statistical significance, p=−0.149.
Conclusion: Absence of immunohistochemical expression for ERCC1 is predictive of pathologic complete response to platinum-based neoadjuvant chemotherapy for patients with triple negative breast cancers.
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 5502. doi:10.1158/1538-7445.AM2011-5502
Abstract 5506: Trabedersen (AP 12009) for the treatment of patients with advanced tumors: A phase I/II study
Authors: Oettle Helmut , Hilbig Andreas , Seufferlein Thomas , Luger Thomas , Schmid Roland , von Wichert Götz , Endlicher Esther , Garbe Claus , Kaehler Katharina C. , Hauschild Axel , Kiessling Peter , Schmaus Susanne , Heinrichs Hubert , Schlingensiepen Karl-Hermann 
Published: June 2012

Abstract
Background: Transforming growth factor-beta 2 (TGF-β2) regulates key mechanisms of carcinogenesis, in particular immunosuppression and metastasis. The antisense oligonucleotide trabedersen (AP 12009) specifically inhibits TGF-β2 expression. A randomized and active-controlled phase IIb study in high-grade glioma patients showed a clear survival benefit for intratumoral treatment with trabedersen over standard chemotherapy. In this study we evaluate the maximum tolerated dose (MTD), safety, pharmakokinetics, and efficacy of intravenous trabedersen treatment in patients with advanced solid tumors.
Methods: In the open label, multicenter, Phase I/II study, 33 patients with advanced pancreatic carcinoma (PancCa, stage III/IV, N=23), malignant melanoma (stage III/IV, N=5), or colorectal carcinoma (stage III/IV, N=5) were enrolled in cohorts for dose-escalation. Patients were treated intravenously with trabedersen as 2nd to 4th-line therapy as monotherapy with escalating doses in 2 treatment schedules (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). After completion of dose-escalation, further patients were enrolled for the treatment with one defined dose in the Phase II part of the study.
Results: Trabedersen showed excellent safety and tolerability. The only expected adverse reaction identified is non-serious, transient and moderate thrombocytopenia. Within the 1st schedule, MTD was established at a dose of 160 mg/m2/d. In the 2nd schedule (4d on, 10d off) a well tolerated dose (140 mg/m2/d) was identified and subsequently further 14 PancCa patients were treated with this regimen. The median overall survival of PancCa patients treated 2nd-line with the 2nd schedule-140 mg/m2/d regimen (N=9) has not yet been reached and currently is 9.2 months (status Oct 2010). Further promising efficacy data include: one PancCa patient had a complete, sustained response of liver metastases and is alive 61 months after monotherapy with trabedersen; another patient is alive 31 months after treatment start (status Oct 2010). Promising efficacy was also observed in malignant melanoma patients with a current median overall survival of 13.8 months.
Conclusions: Currently the study continues with the treatment of 12 patients with malignant melanoma with the 2nd schedule-140 mg/m2/d regimen. A randomized, active-controlled study in PancCA patients is in preparation.
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 5506. doi:10.1158/1538-7445.AM2011-5506
Abstract 5507: Immunological findings in a phase II immunotherapy study using allogeneic lung cancer cells modified to express alpha(1,3)galactosyltransferase in advanced non-small cell lung cancer (NSCLC)
Authors: Rossi Gabriela R. , Vahanian Nicholas N. , Morris John C. , Ramsey Jay W. , Tennant Lucinda , Link Charles J. 
Published: June 2012

Abstract
Background: Alpha(1,3)galactose carbohydrate (αGal) epitopes are highly immunogenic in man. In animal models, vaccination with αGal expressing tumor cells induced rejection of tumor and improved survival. In a phase II anti-tumor immunotherapy study, we evaluated the safety, anticancer activity and immunogenicity of allogeneic human lung cancer cells expressing αGal epitopes HyperAcute-Lung (HAL) vaccines. Methods: Patients with advanced NSCLC received intradermal injections of 300 million HAL vaccine cells every 2 weeks for up to eight doses. Anti-αGal (IgG) and anti-CEA antibodies (Ab) were monitored by ELISA. Cellular immune responses were evaluated by ELISPOT assay (IFN-γ and IL-5). Serum was collected before and at several time points post-immunization. PBMC were collected prior to immunization, after the 4th vaccination and after 8 vaccinations. PBMC were cultured with autologous dendritic cells (DC) pulsed with one of 4 irradiated NSCLC cell lines, three of which were the parental (wild type) cell lines used to generate the vaccine. The fourth was a NSCLC line that was not a component of the vaccine. We compared the reactivity of PBMC stimulated with DC pulsed with these tumor cells pre- and post-immunization in 18 patients with available samples. Results: All patients demonstrated anti-αGal Ab prior to immunization and all responded to vaccination by increasing anti-αGal Ab 2 to 100-fold. Thirty-two patients were tested for anti-CEA Ab. Twenty patients showed significant increases in anti-CEA Ab after immunization. IFN-γ release was detected in 10 of 18 patients evaluated. Patients demonstrating IFN-γ release by ELISPOT after immunization had a median overall survival of 92 weeks (range 40 to 157) comparing favorably with 33.5 weeks (range, 12 to 200) in patients that showed little IFN-γ response. The majority of patients tested showed IL-5 induction after vaccination. In both assays, the HAL1 and HAL2 vaccine cell lines induced greater reactivity on ELISPOT. Patients responding with higher levels of IFN-γ and IL-5 also showed reactivity to the NSCLC cell line that was not a component of the vaccine suggesting that reactivity and possibly cross-priming to shared tumor antigens is induced after vaccination with HyperAcute immunotherapy. Conclusion: Hyperacute anti-tumor immunotherapy induced humoral and cellular responses. Cytokine expression, especially IFN-γ, might be predictive for increased 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 5507. doi:10.1158/1538-7445.AM2011-5507
Abstract 5513: An immune-active tumor microenvironment favors clinical response to ipilimumab
Authors: Ji Rui-Ru , Hamid Omid , Chasalow Scott D. , Cogswell John , Alaparthy Suresh , Berman David , Shahabi Vafa 
Published: June 2012

Abstract
Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has shown improvement in overall survival in previously treated advance melanoma patients. As a consequence of blockade of the T cell regulatory molecule CTLA-4, ipilimumab treatment is associated with proliferation and activation of peripheral T cells. An important factor for impacting tumor growth however, is whether these T cells can successfully migrate into the tumor. In order to gain a better understanding of the various tumor-associated components that determine the clinical activity of ipilimumab in melanoma tumors, Affymetrix gene expression profiling and pathway analysis were retrospectively performed on 46 primary or metastatic melanoma tumors, collected in a complete phase II clinical trial in advanced melanoma patients. In biopsies obtained at baseline (before treatment), there were 361 differentially genes expressed (≥ 1.5 fold difference in expression, p ≤ 0.01); most over-expressed transcripts and pathways associated with favorable clinical activity were immune-related. Furthermore, differential analysis of mRNA from pre- and post-treatment tumor biopsies pointed to additional increase in the expression of these genes after treatment. Interestingly, ipilimumab treatment was associated with down-regulation of a number of melanoma-associated transcripts in the tumors within a short time (3 weeks after the first dose). Our preliminary results suggest that high pre-existing immune-activity favors clinical response to ipilimumab. These analyses also provide a list of candidate biomarkers with potential predictive value for response to ipilimumab, to be confirmed in a larger, placebo controlled clinical trial.
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 5513. doi:10.1158/1538-7445.AM2011-5513