bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5477: Multiple BH3 mimetics antagonize anti-apoptotic MCL1 by inducing the endoplasmic reticulum stress response and upregulating the BH3-only protein NOXA
Authors: Albershardt Tina C. , Salerni Bethany L. , Soderquist Ryan S. , Bates Darcy J P , Pletnev Alexandre A. , Eastman Alan R. 
Published: June 2012

Abstract
Many small molecules have been designed or discovered that mimic the binding of BH3-only proteins to the hydrophobic groove of anti-apoptotic BCL2 proteins and thus have potential as anticancer agents. For example, ABT-737 preferentially binds and inhibits BCL2 and BCL-XL but not MCL1. It is generally believed that specific inhibitors of anti-apoptotic BCL2 proteins should induce apoptosis in a BAX/BAK-dependent manner. While this is true for ABT-737, many other purported BH3 mimetics have been shown to kill cells in a BAX/BAK-independent manner leading to the conclusion that they function through alternative undefined targets. The selectivity of these BH3 mimetics for BCL2, BCL-XL, or MCL1 has been established in vitro; whether they inhibit these proteins in cells has not been rigorously investigated. In this study, we used a panel of leukemia cell lines to assess the ability of seven putative BH3 mimetics to affect the interaction of BCL2 family members in a cell-based system. We show that ABT-737 is the only BH3 mimetic that inhibits BCL2 in cells as assessed by displacement of BAD from BCL2. The other six BH3 mimetics activated the endoplasmic reticulum (ER) stress response and induced ATF3 resulting in induction of NOXA which binds to and inhibits the anti-apoptotic MCL1 protein. The fact that 6 different compounds, all of which are thought to be BH3 mimetics, can induce ER stress suggests that they may interact with a common target although whether this is a BCL2 family member remains to be established. In most cancer cells, inhibition of either BCL2/X or MCL1 does not acutely induce apoptosis. However, by combining two BH3 mimetics, one that inhibits BCL2 and one that induces NOXA, apoptosis is induced within 6 h in a BAX/BAK-dependent manner. As MCL1 is a major mechanism of resistance to ABT-737, these results suggest a novel strategy to overcome this resistance. In summary, these results identify a novel signaling pathway through which many BH3-mimetics inhibit MCL1 and suggest the potential use of these agents as adjuvants in combination with various chemotherapy strategies.
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 5477. doi:10.1158/1538-7445.AM2011-5477
Abstract 5486: Combined targeting of the PI3K and MAPK pathways is required for efficacy in treating colorectal cancer of the wild and mutant types
Authors: Hong Seung-Woo , Shin Jae-Sik , Jin Dong-Hoon , Hong Yong-Sang , Lee Jae-Lyun , Ryu Min-Hee , Kim Tae-Won 
Published: June 2012

Abstract
The KRAS oncogene is commonly mutated in human colon cancer. The downstream pathways of mutant KRAS, including the RAF/MEK/ERK, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)-AKT signaling are indispensible in order to understand how to pharmacologically target them when treating colon cancer with the KRAS mutant. However, the heterogeneous responses of these effector pathways remain unclear. Recent studies have indicated that mutational activation of PI3K (PIK3CA) in KRAS mutant tumor cells induces resistance to the inhibition of MEK, one of the MAPK signal cascades. Wild-type p53 also suppresses the oncogenic potential of the MAPK pathway. Our study shows that bortezomib inhibits the PI3K-AKT pathway and that nutlin-3A used as a p53-inducing agent blocks the MAPK pathway. The high doses of bortezomib induced apoptosis through complete suppression of AKT phosphorylation in KRAS and PI3K mutant colon cancer cells. Treating patients using high doses of nutlin-3A resulted in apoptosis by inducing p53 phosphorylation in colon cancer cells with wild-type p53. We also showed that the combination of bortezomib and nutlin-3A exhibited a synergistic effect on KRAS mutant colon cancer cells with PI3K mutant and wild-type p53, whereas there are no combined effect in KRAS mutant colon cancer cells with the p53 mutant. In addition, bortezomib and nutlin-3A exhibited combined effect in KRAS wild-type colon cancer cells with PI3K mutant and wild-type p53, although not in p53 mutant cells. We consistently noted that treatment with bortezomib and nutlin-3A after p53 silencing using small, interfering RNA (siRNA) in p53 wild-type colon cancer cells, resulted in a decrease of the populations of dead cells. Therefore, these results suggest that a combination of bortezomib and nutlin-3A can overcome the heterogeneous responses of the effector pathway in colon cancer with KRAS mutant; they also provide a new basis for the clinical testing of PI3K- and MAPK-targeted 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 5486. doi:10.1158/1538-7445.AM2011-5486
Abstract 552: Targeting brain tumors with PLX3397, an inhibitor of the CSF-1 receptor kinase
Authors: West Brian L. , Tsai James , Nicolaides Theodore , Wong Bernice , Nguyen Hoa , Marimuthu Adhirai , Ibrahim Prabha , Hirth Peter , Bollag Gideon 
Published: June 2012

Abstract
Cancer growth in the brain incites a neuroinflammatory response that becomes a defining feature of the brain tumor microenvironment. Microglia and macrophages provide important functions that support the invasiveness of glioblastoma. Other cancer types that become metastatic to brain also rely on the microenvironment to support angiogenesis.
PLX3397 is a potent inhibitor of the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). The CSF-1R is required for the differentiation and activation of microglia and macrophages. Oral administration of PLX3397 to mice at 20 mg/kg qd significantly reduces the microglia/macrophage marker, Iba1, as determined by western blotting.
PLX3397 penetrates the blood-brain barrier, as determined through pharmacokinetic analysis, with brain levels reaching substantial fractions of the concurrent plasma levels. PLX3397 is highly bound to plasma albumin, and therefore the levels attained in the brain likely affect Iba1 levels through a local inhibition of brain microglia and macrophages, although a peripheral effect may also contribute.
Culture of glioblastoma cell lines including U87, and treatment with chemotherapeutic agents or radiation, was found to cause a 4-fold elevation of the two CSF-1R ligands, CSF-1 and IL-34, as quantified by QPCR. This indicates that glioma cells can recruit and stimulate microglia and macrophages, and that current standard therapies likely exacerbate this stimulation. Other cancer types that are known to form metastases to brain, including melanoma and breast cancer, show similar abilities to produce these cytokines in response to standard therapies.
The rat 9L glioblastoma line forms an aggressive tumor when tested as an orthotopic model in syngeneic Fisher rats. Seven days after implantation, PLX3397 was administered via rodent chow for 14 days, reducing the tumor growth by 44% as determined by MRI.
These results provide preclinical evidence that PLX3397 may show a clinical benefit in brain cancers, either as a single agent or in combination with standard chemo- or radiation therapies. PLX3397 is nearing completion of a successful Phase 1 dose-escalation safety trial in solid tumor cancer patients.
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 552. doi:10.1158/1538-7445.AM2011-552
Abstract 5522: Increase of Th1/Treg ratio in peripheral blood of breast cancer patients with autologous formalin-fixed tumor vaccine
Authors: Kuranishi Fumito 
Published: June 2012

Abstract
Introduction: Autologous formalin-fixed tumor vaccine (AFTV) containing formalin-fixed and/or paraffin-embedded tumor fragments is able to induce tumor specific CTL and suppresses recurrence of hepatocellular carcinoma after resection (Clin Cancer Res 2004; 10: 1574-9). We have used delayed-type hypersensitivity (DTH) test as a parameter of cellular immune response. We also found that slight but consistent population change has occurred in peripheral blood T lymphocytes after AFTV treatment.
Method: Thirty two breast cancers were operated in our hospital. AFTV was injected intradermally. DTH response to the tumor fragments without any adjuvant was determined if erythema was 10mm or more.
Results: After operation, standard chemotherapy, and enough time have passed to recover immunological function, we examined change of peripheral blood T-cell population in 32 cases with breast cancer. Among them, 27 cases turned DTH response from negative to positive after AFTV injection. In these patients, WBC counts increased 1.11 times; lymphocytes, 1.09 times; Th1 in CD4+ T cells, 1.07 times; regulatory T cells (Treg) in CD4+ T cells, 0.95 times, and Th1/Treg ratio, 1.17 times (statistically significant, 95%CI was 1.060-1.284).
Conclusion: AFTV probably strengthen the cellular immune response against cancer by improving Th1/Treg ratio in peripheral blood.
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 5522. doi:10.1158/1538-7445.AM2011-5522
Abstract 5548: Comparison of gene expression profile in chromate transformed BEAS-2B cells
Authors: Hong Sun , Clancy Harriet A. , Kluz Thomas , Zavadil Jiri , Costa Max 
Published: June 2012

Abstract
Background: Hexavalent chromium [Cr(VI)] is a potent human carcinogen. Occupational exposure has been associated with increased risk of respiratory cancer. Multiple mechanisms have been shown to contribute to Cr(VI) induced carcinogenesis, including DNA damage, genomic instability, and epigenetic modulation, however, the molecular mechanism and downstream genes mediating chromium's carcinogenicity remain to be elucidated.
Methods/Results: We established chromate transformed cell lines by chronic exposure of normal human bronchial epithelial BEAS-2B cells to low doses of Cr(VI) followed by anchorage-independent growth. These transformed cell lines not only exhibited consistent morphological changes but also acquired the ability to form tumors in nude mice. Interestingly, the gene expression profiles of six Cr(VI) transformed cell lines were remarkably similar to each other yet differed significantly from that of either control cell lines or normal BEAS-2B cells. A total of 409 differentially expressed genes were identified in Cr(VI) transformed cells compared to control cells. Genes related to cell-to-cell junction were upregulated in all Cr(VI) transformed cells, while genes associated with the interaction between cells and their extracellular matrices were down-regulated. Additionally, expression of genes involved in cell proliferation and apoptosis were also changed.
Conclusion: This study is the first to report gene expression profiling of Cr(VI) transformed cells. The gene expression changes across individual chromate exposed clones were remarkably similar to each other but differed significantly from the gene expression found in anchorage-independent clones that arose spontaneously. Our analysis identified many novel gene expression changes that may contribute to chromate induced cell transformation, and collectively this type of information will provide a better understanding of the mechanism underlying chromate carcinogenicity.
(This work was supported by grant numbers ES000260, ES014454, ES005512, ES010344 from the National Institutes of Environmental Health Sciences, and grant number CA16087 from the National Cancer Institute)
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 5548. doi:10.1158/1538-7445.AM2011-5548
Abstract 5557: Steady DNA adduct accumulation by dibenzo[a,l]pyrene implants
Authors: Jeyabalan Jeyaprakash , Aqil Farrukh , Ravoori Srivani , Vadhanam Manicka V. , Gupta Ramesh C. 
Published: June 2012

Abstract
The past and current trends in determining the DNA-damaging and carcinogenicity potential of environmental toxicants rely largely on treatment of rodents with single or multiple bolus doses. To simulate the human scenario where the exposure is generally continuous to low doses, we have developed polymeric implants embedded with carcinogens. When grafted subcutaneously, polymeric implants provide continuous (“24/7”) low dose exposure. In this study we report the effects of sustained low doses of a highly potent environmental carcinogen, dibenzo[a,l]pyrene (DBP) on DNA adduct accumulation. Different size DBP implants (10 – 20 mm long, 1.4 – 2.4 mm dia; 5% DBP load) were tested first in a pilot study using female A/J mice to optimize the implant surface area. Two 20-mm implants (1.4 mm dia), which produced maximal lung DNA adducts, were used subsequently. Groups of female A/J mice (n = 4 – 6) were grafted with sham or DBP implants. For comparison, animals were also treated in parallel with a bolus carcinogenic dose of DBP intraperitoneally (6 mg/kg) or vehicle alone. Animals from both the treatment groups were euthanized at different time intervals and selected tissues were collected. Analysis of the target (lung) DNA adducts by 32P-postlabeling showed qualitative identical adduct patterns by the two routes of administration; the sham treatments showed no detectable adducts. As expected, the bolus dose treatment resulted in higher DNA adducts (in adducts /109 nucleotides) (72 ± 18) compared with the implant group (33 ± 17) one week post-treatment. However, 3 weeks later, adduct levels in the implant group increased (54 ± 17) but a significant declined occurred in the i.p treatment group (19 ± 13). The adduct levels after 4 weeks in the implant group (66 ± 19) were somewhat higher than the 3 week group, suggesting that the adduct levels plateaued. The steady accumulation of DNA adducts was consistent with continuous release of DBP from the implant (about 10 µg/day based on in vitro release). The study is ongoing to determine if the low-dose continuous exposure which provides steady accumulation of DNA adducts in the target tissue will be tumorigenic. In summary, the steady-state adduct level reflect human exposure scenario and this approach will be ideal to determine both carcinogenicity and biological/pathological changes due to low-dose exposure as well as for screening potential chemopreventive agents. This exposure system has been used to determine efficacy of chemopreventive agents (accompanying abstracts by Aqil et al.; Gupta et al.) (Supported from CA-118114, KLCRP and Agnes Brown Duggan Endowment).
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 5557. doi:10.1158/1538-7445.AM2011-5557
Abstract 5564: Lack of efficacy of metformin in several standard prevention models: Methylnitrosourea rat mammary (ER+), MMTV-Neu/p53 mouse mammary (ER−) and the Min mouse colon
Authors: Lubet Ronald A. , Clapper Margie , Bode Ann , Steele Vernon , Grubbs Clinton 
Published: June 2012

Abstract
Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated considerable interest as a potential preventive agent for a variety of cancers. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. The preventive efficacy of metformin was examined in three commonly employed in rodent prevention models of breast and intestinal cancers. Treatment of female Sprague-Dawley rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers. This model has been highly responsive to a wide variety of agents or hormonal alterations that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, and ovariectomy). Metformin was administered by gavage (7x/week) at either 150 or 50 mg/kg BW/day; beginning seven days after MNU treatment and continuing for the duration of the study. Metformin failed to decrease mammary cancer incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53 KO mice (which spontaneously develop ER− cancers) was evaluated. In this study, metformin was administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and continued for 10 months. This study similarly showed no efficacy of metformin (average tumors/mouse: 2.7 in both controls and metformin-treated mice). Finally the effect of metformin was examined in the Min model of intestinal neoplasia, in which mice have a germline APC mutation. Again, we failed to observe any efficacy of metformin. In contrast, naproxen (a non-specific NSAID) was highly effective in this model when used as a positive control. Thus, these initial studies failed to detect any chemopreventive efficacy of metformin in three commonly employed prevention models. One major caveat to these studies is that the animals were not diabetic nor were they administered an altered diet containing high fat or carbohydrates. Supported by NCI contract number HHSN261200433001C.
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 5564. doi:10.1158/1538-7445.AM2011-5564
Abstract 5574: mTOR is a target for omega-3 fatty acid modulation of prostate cancer progression
Authors: Apte Shruti A. , Cavazos David , Hursting Stephan , Nogueira Leticia , deGraffenried Linda A. 
Published: June 2012

Abstract
Prostate cancer is the second leading cause of cancer related deaths in men. The primary obstacle in effective treatment of prostate cancer is the progression of the disease from a hormone-dependent to a hormone-independent state. Previous studies indicate that activation of the mammalian Target of Rapamycin (mTOR) signaling pathway may be involved in progression of prostate cancer to androgen independence. Recent data indicate that the combination of androgen deprivation with mTOR inhibition provides an additive anti-tumor effect in vivo. mTOR activity is regulated by both growth factors and nutrients, suggesting that certain dietary interventions may have anti-cancer effects through regulation of mTOR. Epidemiological studies indicate an inverse relation between dietary intake of omega-3 fatty acids and prostate cancer risk. Omega-3 fatty acids have been shown to inhibit prostate cell growth both in vitro and in vivo. Preliminary data from our laboratory demonstrated that treatment of LNCaP prostate cancer cells with omega-3 fatty acids, specifically docosahexaonoic acid (DHA), delayed development of androgen independence in vitro. This delay correlated with a decrease in protein expression of downstream targets of mTOR regulation, including phosphorylated S6, Bcl-2, and cyclin D. We hypothesize that omega-3 fatty acids may prevent prostate cancer progression to a hormone independent phenotype in part through modulation of mTOR. To test this hypothesis, we established stable transfectant LNCaP cell lines that express a constitutively active mTOR. These clones displayed less sensitivity to hormone deprivation, resembling the response observed in our previously generated hormone refractory LNCaP cell line. Importantly, these clones with constitutively active mTOR also showed resistance to the inhibitory effects of DHA. Ongoing studies are using these clones to determine if omega-3 fatty acids mediate their effect on mTOR in an Akt-independent manner to delay progression of prostate cancer to a hormone refractory phenotype. We will investigate alternative pathways through which mTOR activity is modulated in prostate cancer signaling, These studies indicate that mTOR is critical for cellular response to hormone ablation, and that mTOR may be a viable target for delaying progression to a hormone refractory disease.
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 5574. doi:10.1158/1538-7445.AM2011-5574
Abstract 561: Tumor-associated fibroblast-induced head and neck squamous cell carcinoma invasion can be abrogated by c-Src and c-Met inhibition
Authors: Shi Huifang , He Gouqing , Joyce Sonali , Thomas Sufi M. 
Published: June 2012

Abstract
Purpose: Mortality from head and neck squamous cell carcinoma (HNSCC) is usually associated with locoregional invasion of the tumor into vital organs including the airway. There are currently no treatments that abrogate HNSCC tumor invasion. HNSCC tumors are frequently associated with reactive fibroblasts. Our preliminary data demonstrate that stromal fibroblasts in the vicinity of the tumor induce phosphorylation of c-Src and induce HNSCC invasion. We reported that tumor-associated fibroblasts (TAF) secrete HGF that binds to the c-met receptor on HNSCC activating downstream signaling contributing to the invasive phenotype. In addition we have previously reported that c-Src plays an important role in mediating HNSCC invasion. We hypothesize that blocking c-Met and c-Src in HNSCC cells will abrogate TAF induced HNSCC invasion.
Experimental design: Inhibition of c-Met and c-Src was achieved by a combination of small molecule inhibitors and dominant negative approaches. The effect of inhibition of c-Met and c-Src on invasion of HNSCC cells was assessed in an in vitro Matrigel coated transwell invasion assay.
Results: We demonstrate that inhibition of c-Met or c-Src with inhibitors or using dominant-negative constructs attenuated TAF-stimulated HNSCC invasion. Combined inhibition of c-Met and c-Src resulted in further attenuation of HNSCC cell invasion in vitro.Conclusions: These cumulative results suggest that TAF-induced signaling through c-Met and c-Src contribute to HNSCC invasion and that targeting these pathways may be a novel strategy to prevent tumor invasion and metastasis in HNSCC.
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 561. doi:10.1158/1538-7445.AM2011-561