bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 600: The HSV-2 oncolytic virus ΔPK induces multiple death and inflammatory programs associated with inhibition of melanoma tumor growth
Authors: Colunga Aric , Li Biquan , Aurelian Laure 
Published: June 2012

Abstract
Metastatic melanoma is a highly aggressive and drug resistant cancer. Oncolytic virotherapy is a novel therapeutic strategy designed to circumvent cancer resistance through virus replication-induced cancer cell lysis. Unfortunately, its clinical efficacy is modest, apparently related to poor virus replication within the tumors and the failure to stimulate inflammatory/immunotherapeutic pathways. The growth compromised herpes simplex virus type 2 (HSV-2) mutant ΔPK causes metastatic melanoma cell death through activation of multiple non-redundant death pathways. Activation of calpain and caspases-3 and -7 provide the bulk of the death programs, as evidenced by the finding of 80% protection in cells treated with the combination of calpain (PD150606) and pancaspase (zVAD-fmk) inhibitors. In addition, ΔPK upregulates the autophagy proteins Beclin-1 and LC-II and the autophagy inhibitor 3-methyladenine (3-MA) reduces ΔPK-induced cell death by 15-17%. Cell death is further decreased (to a total of 28-34%) by treatment with 3-MA together with the JNK inhibitor SP600125, indicating that JNK signaling and autophagy contribute independently to ΔPK-induced cell death. Inflammatory-related pathways contribute to ΔPK-induced melanoma cell death, as evidenced by caspase-1 activation, interleukin (IL)-1β release into the conditioned medium and upregulation of pro-apoptotic/stress signaling molecules and pro-inflammatory cytokines and chemokines identified by microarray analysis. These include BAD, BIK, BOK, NLRC4, CIDEB, IL-1β, IL-6, IL-8, IL-12α, IL-12β, LTα, CXCL-10, c-JUN and caspases-4, -5, -6, -8, and -10. Tumor burden is significantly reduced by intratumoral injection of ΔPK and xenografts generated from a fresh clinical isolate, were completely eliminated for a period of 1 year following treatment. Growth inhibition is associated with activation of calpain and caspases-3, -7 and -1 and expression of the inflammatory cytokine TNF-α. Collectively, the data indicate that ΔPK eliminates tumor burden through the simultaneous activation of multiple non-redundant death programs and pro-inflammatory signaling, providing a distinct and promising virotherapeutic approach.
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 600. doi:10.1158/1538-7445.AM2011-600
Abstract 602: Silencing BRG1 in human cancers
Authors: Reisman David R. , Gramling Sarah , Wright Tracy 
Published: June 2012

Abstract
BRG1 is a novel tumor suppressor that serves as the major catalytic subunit of the SWI/SNF complex. Because this complex is central to the function of a number of transcription factors and key cellular proteins and it is required for a plethora of signal transduction pathways, its loss can have devastating effects on cellular function. We know that BRG1 is not only lost in lung cancer but also in a variety of tumor types: between 10-40%. Hence, the loss of this protein plays an important role in cancer development and progression. In cell lines, it has been well document that BRG1 is mutated or altered in the vast majority of cell lines, but in primary lung cancer mutations are not found. Our analysis has led us to believe that BRG1 is epigenetically silenced like its homolog BRM. Hence, it may be possible to restore its expression in cancer cells. The loss of BRG1 impacts the sensitivity to Cisplatin by making cells more sensitive to the DNA damaging effects of this agent. Similarly, this loss also impacts sensitivity to EGFR inhibitors by making cells more resistant. Hence, the loss of BRG1 can help to explain the reciprocal sensitivity to these drugs seen in cancers. Hence, the BRG1 protein can play the role of a biomarker for chemotherapy sensitivity as well as being a potential target for therapy. Further research will reveal how this gene can best be integrated into clinical practice.
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 602. doi:10.1158/1538-7445.AM2011-602
Abstract 604: Nek2 is a promising target for triple negative breast cancer treatment strategies
Authors: Lee Jaehyung , Gollahon Lauren 
Published: June 2012

Abstract
Although the anticancer drugs paclitaxel and doxorubicin are commonly used to treat many types of solid tumors, their effectiveness is highly variable due to tumor cell resistance. Therefore, it is important to find mechanisms that can be targeted to increase the sensitivity of cancer cells to antitumor agents such as paclitaxel and doxorubicin. NIMA related kinase 2 (Nek2), a serine/threonine kinase is emerging as an important oncogene because of its regulatory role in mammalian cell mitosis. Thus, regulation of the Nek2 expression levels may prove important as a target for cancer treatment. In this study, we investigated whether drug sensitivity was increased in the triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 by using antisense oligonucleotides (ASOs) and siRNA against Nek2. MDA-MB-231 and MDA-MB-468 breast cancer cells transfected with Nek2 siRNA or ASO were exposed to various concentrations of paclitaxel and doxorubicin. Cell viability, cell cycle distribution, and apoptosis were evaluated. We observed that drug susceptibility in these transfected cells was dramatically increased compared with either agent alone. Interestingly, the cell proliferation of the Nek2 ASO transfected breast cancer cells was much lower than the Nek2 siRNA transfected breast cancer cells. Our FACS data showed paclitaxel treated cells transfected with ASOs arrested in G2/M phase as expected due to Nek2 regulatory function in centrosome duplication. We observed that ASOs and siRNA against Nek2 work with paclitaxel and by arresting cells at G2/M and progressing the cells to apoptosis. Our results suggest that these drugs in combination with Nek2 siRNA or ASO treatment greatly improve the sensitivity of cancer cells. Thus, these results provide a possible new strategy for the treatment of breast 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 604. doi:10.1158/1538-7445.AM2011-604
Abstract 610: Regression of spontaneous non-small cell lung cancers in P53 mutant transgenic mice following exposure to PRIMA-1
Authors: Duan Wenrui , Gao Li , Vereb Gregory , Wu Xin , Otterson Gregory A. , Villalona-Calero Miguel A. 
Published: June 2012

Abstract
P53 mutations are common in lung cancer, thus restoration of p53 function in tumor cells have the potential to be an important approach for lung cancer therapy. The small molecule PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) has been shown to induce apoptosis in human tumor cells containing mutant p53 by restoration of tumor suppressor function of p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes.
We have developed a lung tumor model in transgenic mice in which the human mutant p53(273H) is expressed in a lung specific manner, under the control of the surfactant protein C promoter. These mice developed lung adenocarcinomas at an age range of 12-15 months. To evaluate feasibility and preliminary activity of PRIMA-1 on the murine spontaneous lung tumor, we treated SPC-p53-273H lung tumor bearing mice via intraperitoneal injection (i.p) with PRIMA-1 at a dose of 100 mg/kg in 0.2 ml PBS every other day for two weeks. Lung tumor bearing mice were identified with a micro-computed tomography (micro-CT) system and pre- and post-treatment tumor volumes were estimated based on the micro-CT image.
Five mice received the PRIMA-1, and a control group of 4 lung tumor mice received PBS every other day for two weeks. A repeat CT scan was obtained the week after the last treatment. Results of post-treatment with pre-treatment CT volume comparisons are detailed below:

These preliminary results indicate activity of PRIMA-1 in lung tumor bearing P53 mutant transgenics, and suggest the potential feasibility of using p53 restoring activity small molecules to treat lung cancer. Expansion of the sample size, as well as mechanistic and dosing studies is ongoing in order to strengthen the rationale to eventually pursue this strategy in clinical trials.
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 610. doi:10.1158/1538-7445.AM2011-610
Abstract 613: Depletion of Mdm2 and Mdm4 by adenovirus: Molecular mechanism and anticancer therapeutic implication
Authors: Liao Daiqing , Zhao Lisa Y. , Yang Heng 
Published: June 2012

Abstract
Mdm2 and Mdm4 are two paralogous proteins. They contain a conserved p53-binding domain in the N-terminal region and a RING-finger domain in the C-terminal part. Both proteins physically bind p53 and prevent p53 activation. Biochemically, Mdm2 acts as an E3 ubiquitin ligase of p53 and promotes ubiquitin-dependent p53 degradation. Mdm4 does not appear to have intrinsic E3 ubiquitin ligase activity and may negatively control p53 function through suppressing p53-mediated transactivation of gene expression. Mdm2 and Mdm4 also form heterodimer, which suggests that Mdm2 and Mdm4 might cooperatively control p53 activity. In vivo, both Mdm2 and Mdm4 have an essential but non-redundant function in suppressing p53 activity to enable embryonic development. Mdm2 and Mdm4 are overexpressed in several types of human cancer such as breast cancer and osteosarcoma. In transgenic mouse models, overexpression of Mdm2 or Mdm4 leads to tumorigenesis. Thus, both Mdm2 and Mdm4 are bona fide oncogenes. Several small molecules that disrupt the interaction between p53 and Mdm2 and Mdm4 have been shown to induce p53 activation, cell cycle arrest and apoptosis. These compounds also cause tumor repression in preclinical animal models. Thus, they have clinical potentials for treating various types of human cancer. Biological agents that specifically target Mdm2 and Mdm4 have not been described. We found that adenovirus infection of diverse type of cancer cells results in dramatic downregulation of both Mdm2 and Mdm4. Adenovirus E1B-55K binds specifically both Mdm2 and Mdm4 in cells and in vitro, demonstrating specific interactions between E1B-55K and Mdm2 or Mdm4. Cotransfection experiments indicated that E1B 55K alone was sufficient to deplete Mdm2 and Mdm4. E1B-55K is known to form a functional E3 ubiquitin ligase consisting of Cul2 or Cul5. Thus, it is likely that E1B-55K targets Mdm2 and Mdm4 for ubiquitin-mediated proteosomal degradation. Based on these observations, we hypothesize that adenovirus is effective for treating cancers with overexpression of Mdm2 or Mdm4. We are currently testing whether adenoviral therapy is efficacious on treating such cancers in cell culture and animal models. (This work was supported by Bankhead-Coley Cancer Research Program of the Florida Department of Health.)
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 613. doi:10.1158/1538-7445.AM2011-613
Abstract 614: Efficacy of metformin in two mouse models of Li-Fraumeni syndrome
Authors: Kunnumakkara Ajaikumar B. , Memmott Regan M. , Maier Colleen R. , Kawabata Shigeru , Quinn Brendan , Gills Joell , Dallos Matthew , Hollander Christine M. , Dennis Phillip A. 
Published: June 2012

Abstract
Li-Fraumeni Syndrome (LFS) is a rare autosomal hereditary disorder that is commonly associated with germline mutations in the TP53 gene. People with LFS are at high risk to develop a wide range of malignancies including breast cancer, brain tumors, acute leukemias, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinomas. Although no therapies are approved to treat or prevent LFS, preclinical studies have shown that the anti-diabetic drug metformin is preferentially cytotoxic to p53 null cells in the absence of glucose. This led us to hypothesize that metformin has therapeutic potential in LFS. To confirm the p53 dependence of metformin in vitro, isogenic human and murine cancer cell lines were treated with metformin in the absence or presence of glucose. Metformin induced greater toxicity in p53-deficient cells in a dose-dependent manner. Metformin was then tested in two mouse models that recapitulate the increased tumorigenesis and cancer-related mortality in LFS (p53 mutant mice (p53R172H/+) and p53 null mice (p53-/-)). When administered at 5 mg/ml in drinking water, metformin reached steady state plasma concentrations similar to those in diabetic humans. Biomarker studies showed that oral administration of metformin activated AMPK and inhibited the mTOR pathway in liver tissues. To determine the effects of metformin on overall survival, two sets of studies were performed. For each model, treatment with metformin was begun either late in life (for p53R172H/+, 12 mo; for p53-/-, 4 mo) or early in life (for p53R172H/+, 4 mo; for p53-/-, 1 mo). Mice were treated until death. Long-term oral administration of metformin did not cause weight loss or other discernible toxicity. In the late treatment study, metformin significantly prolonged median survival (for p53R172H/+ mice, 20.6 mo vs. 15.8 mo; p=0.0004)(for p53-/- mice, 9.1 mo vs. 5.3 mo; p=0.0006). Likewise, early treatment with metformin also prolonged median survival (for p53R172H/+ mice, median survival 20.5 compared to 13 months; p=0.0025). The early study with p53-/- mice is ongoing, but median survival is undefined in metformin group, compared to 3.6 mo in control group, p=0.0387). These studies show that metformin is well tolerated and highly effective when given early or late in the life span of two mouse models of LFS. Given that metformin is an inexpensive oral drug that is FDA approved, a pilot clinical trial in LFS is planned.
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 614. doi:10.1158/1538-7445.AM2011-614
Abstract 623: CLU inhibition using OGX-011 is a new adjuvant therapeutic strategy for HSP90 inhibition in prostate cancer
Authors: Lamoureux Francois , Yin Min-Jean , Zoubeidi Amina , Gleave Martin E. 
Published: June 2012

Abstract
Introduction and Objective: Prostate cancer (PCa) responds initially to anti-androgen therapies, however, progression to castration resistant disease (CRPC) frequently occurs. Several small molecule inhibitors of HSP90 show promise in CRPC and other cancers. However, most HSP90 inhibitors (17-AAG or PF-04928473 and its prodrug PF-04929113) trigger the elevation of HSPs (HSP90, 70, 27 and clusterin), which lead to tumor cell survival and treatment resistance. We hypothesized that targeting clusterin (CLU) using siRNA or the antisense drug, OGX-011, may enhance HSP90 inhibitors-induced cell death in PCa.
Methods: Inducible and constitutive CLU and other HSP mRNA and protein levels were measured by real-time RT-PCR and immunoblot assays. The combination of OGX-011 with PF-04928473 or 17-AAG was evaluated in vitro on LNCaP and PC3 cells growth and apoptosis. The HSP90 inhibitor PF-04929113 was evaluated in combination with OGX-011 in vivo in athymic mice bearing castration resistant LNCaP xenografts, while the combination of OGX-011 with 17-AAG was evaluated in PC3 xenografts.
Results: In prostate tumor cell lines, PF-04928473 and 17-AAG induced expression of HSPs in a dose and time dependent manner, and especially CLU at RNA and protein level, by increasing HSF-1 nuclear translocation and transcription activity. In vitro, OGX-011 synergistically enhanced the activity of HSP90 inhibitors on cell growth and apoptosis with increased sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of HSPs, Akt, AR and PSA, and HSF-1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 15mg/kg), potentiated the effect of orally administered HSP90 inhibitors (PF-04929113: 25mg/kg; 17-AAG: 50mg/kg), significantly inhibiting tumor growth by 80% and prolonging survival in PC3 and castrate resistant LNCaP xenograft model compared to the HSP90 inhibitors alone.
Conclusions: These results indicate that HSP90 inhibitor-mediated induction of CLU expression can be attenuated by OGX-011, with synergistic effects on delaying progression of CRPC.
This work was supported by the Canadian Institutes of Health Research fellowship and Association pour la Recherche sur le Cancer, France.
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 623. doi:10.1158/1538-7445.AM2011-623
Abstract 634: Combinatorial targeting in melanoma cell lines with defined and distinct mechanisms of acquired resistance to V600EB-RAF inhibition
Authors: Shi Hubing , Kong Xiangju , Ribas Antoni , Lo Roger S. 
Published: June 2012

Abstract
V600EB-RAF mutation is found in 50-60% of melanomas, and its in-human “druggability” has recently been demonstrated using the novel agent PLX4032, which can achieve an unprecedented ∼80% on-target, anti-melanoma response rate. Acquired resistance to PLX4032, however, has been observed in the majority of patients. We have shown previously that melanoma tumors in patients and cell lines in vitro acquire resistance to PLX4032 not by developing secondary mutations in V600EB-RAF but instead by upregulating PDGFRβ (showing MEK inhibitor insensitivity) or N-RAS (showing MEK inhibitor sensitivity). Here we used distinct subsets of melanoma cell lines (resistance derived in vitro) and short-term cultures (resistance derived in vivo) with hitherto characterized mechanisms of acquired resistance to PLX4032 to define the optimal combination of molecular target inhibition necessary to achieve efficient growth inhibition and cytotoxicity. We focused on a set of molecular targets downstream of overexpressed PDGFRβ or mutant N-RAS in each subset and used specific small molecule inhibitors, singly or in combination, to correlate growth inhibitory responses with p-ERK, p-AKT, p-p70S6K levels and apoptotic responses. We found that single inhibitor treatment led to functionally significant compensatory activation or rebound activities, consistent with dynamic network connectivity at key nodes of signaling. In PDGFRβ-upregulated, PLX4032-resistant melanoma cell lines, combined B-RAF, PI3K and TORC1/2 inhibition led to the strongest synergistic growth inhibitory and cytotoxic responses. In N-RAS-upregulated, PLX4032-resistant cell lines, either MEK or dual TORC1/2 inhibition sufficed to yield significant growth inhibition, and combined MEK and TORC1/2 inhibition did not synergize in growth inhibitory or cytotoxic responses. Together, these observations could serve to rationally guide animal model studies and urgently needed clinical testing in pre-identified subsets of patients relapsing on V600EB-RAF inhibitors.
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 634. doi:10.1158/1538-7445.AM2011-634
Abstract 641: Effects of an mTOR inhibitor on immune subpopulations
Authors: Seliger Barbara , Giersberg Corrina , Leich Franziska 
Published: June 2012

Abstract
Immune suppression is frequently detected in renal cell carcinoma (RCC) and might contribute to tumor progression. Recently, receptor tyrosine kinase inhibitors have been shown to revert the frequency of the myeloid-derived suppressor cell (MDSC)-mediated immune suppression, the development of regulatory T cells (Treg), increase the number of NK cells and prevent tumor-specific T cell anergy. The mTOR inhibitors exhibit a unique target profile resulting in both anti-tumor and anti-angiogenic activity. It has been shown that everolimus can induce apoptosis in various cancers of distinct origin. However, the role of everolimus on immune cell subpopulations have not yet been studied in detail. Therefore peripheral blood mononuclear cells as well as human CD3+ T cells obtained from healthy blood donors were either left untreated or stimulated with antibodies or PHA and subjected to multicolour flow cytometry using a large set of antibodies.
We here show that everolimus exerts different effects on peripheral blood mononuclear cells regarding the composition of immune cell subpopulations, their proliferation, activation, cytokine production and degranulation. Upon everolimus treatment the number of stimulated CD3+, CD4+ and CD8+ and CD4+/FoxP3* T cells decreased, whereas the number of NK cells, CD4+/CD8+ CD45RO T cells increased. Furthermore, the T cell proliferation was reduced upon mTOR inhibitor treatment. These data suggest that everolimus modulates the composition of immune cells, their activation and growth properties, which is important for the design of combinatorial therapies.
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 641. doi:10.1158/1538-7445.AM2011-641