bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY31-03: Global signaling mechanisms that regulate autophagy
Authors: Yi Caroline , Yuan Junying 
Published: May 2019

Abstract
Apoptosis is an evolutionally conserved cellular suicide mechanism that can be activated in response to a variety of stressful stimuli. Increasing evidence suggests that apoptotic regulation relies on specialized cell death signaling pathways and also integrates diverse signals from additional regulatory circuits, including those of cellular metabolism. Cell metabolism is exquisitely linked to multiple aspects of cell physiology relevant for cancer development, including cell proliferation, growth, and death. However, the mechanism by which cellular metabolism controls apoptotic sensitivity is unknown. We conducted a genome-wide RNA interference screen to systematically identify regulators of apoptosis induced by DNA damage in Drosophila melanogaster cells. This screen identified 47 double- stranded RNAs that target a functionally diverse set of genes, including several with a known function in promoting cell death. Further characterization uncovers 10 genes that influence caspase activation upon the removal of Drosophila inhibitor of apoptosis 1 (DIAP1). This set includes the Drosophila initiator caspase Dronc and, surprisingly, several metabolic regulators, and an N-acetyltransferase, ARD1. Importantly, several of these genes show functional conservation in regulating apoptosis in mammalian cells. Our data suggest a previously unappreciated fundamental connection between various cellular processes and caspase-dependent cell death. We have further explored the functional role and the mechanism by which ARD1 regulates apoptotic sensitivity in mammalian cells. We found that a reduction of N-alpha-acetylation mediated by ARD1 leads to inhibit apoptosis by blocking the interaction of a caspase with its activating complex. We further demonstrate the levels of protein N-alpha-acetylation is controlled by the availability of acetyl-CoA, a key intermediate metabolite. Our study provides a mechanistic link between cellular metabolism and apoptotic sensitivity and suggests that targeting the mechanism of protein N-alpha-acetylation may provide a new therapeutic approach for anti-cancer drug development.
Citation Format: Caroline Yi, Junying Yuan. Global signaling mechanisms that regulate autophagy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY31-03
Abstract 2099: Apo-10’-lycopenoic acid functions as a peroxisome proliferator-activated receptor gamma activator and inhibits cell growth both in vitro and in vivo ob/ob mice treated with diethylnitrosamine
Authors: Hu Kang-Quan , Wang Yan , Smith Donald E. , Russell Robert M. , Wang Xiang-Dong 
Published: May 2019

Abstract
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is involved in controlling metabolism, cell growth, inflammatory responses and tumorigenesis. Specific PPAR-gamma agonists, such as rosiglitazone, inhibit growth and induce differentiation in several different cancer cell lines including liver cancer cells. Lycopene has been shown to decrease the initiation of hepatic preneoplastic foci induced by diethylnitrosamine (DEN) in rats. Recently, we showed that apo-10’-lycopenoic acid, an enzymatic metabolite of lycopene, suppresses carcinogenesis in a mouse model. However, the underlying mechanism(s) is not well defined. In the present study, we examined the effects of apo-10’-lycopenoic acid treatment on cell growth and apoptosis, as well as PPAR-gamma activation in both human liver cells and in livers of ob/ob mice treated with DEN. We reported that apo-10’-lycopenoic acid dose-dependently increased the mRNA expression and protein levels of PPAR-gamma in human THLE-2 liver cells. Apo-10’-lycopenoic acid (from 5 µM to 20 µM) produced concentration-dependent increases in luciferase activity, as compared with PPAR-gamma agonist rosiglitazone in cells co-transfected with constructs containing PPAR-gamma and PPRE-luciferase reporter construct. Additionally, apo-10’-lycopenoic acid dose-dependently inhibited cell growth and induced apoptosis in THLE-2 liver cells by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing activation of c-Jun NH2-terminal kinase (JNK) and cyclin D1 gene expression. However, human HepG2 liver cancer cells were less sensitive to apo-10’-lycopenoic acid treatment, as compared with THLE-2 cells. We further examined the effect of apo-10’-lycopenoic acid treatment (120 mg/Kg diet) in ob/ob mice administered intraperitoneally with a single-dose of DEN (30 mg/Kg body weight). After eight weeks, we found lower expression of PPAR-gamma but higher levels of tumor necrosis factor-alpha and phosphorylated JNK in the liver of ob/ob mice injected with DEN, as compared with controls. Furthermore, apo-10’-lycopenoic acid supplementation prevented DEN-down-regulated expression of PPAR-gamma in the liver of ob/ob mice and significantly inhibited DEN-induced expression of proliferating cell nuclear antigen and cyclinD1. In addition, apo-10’-lycopenoic acid supplementation inhibited DEN-induced tumor necrosis factor-alpha expression and JNK activation in the liver of ob/ob mice. Together, our findings indicate that apo-10’-lycopenoic acid produced from lycopene metabolism may function as a natural ligand of PPAR-gamma and as a potential chemopreventive agent against hepatic tumorigenesis.
Abstract 2545: Response to a preventive HER2/neu peptide (E75) vaccine based on HER2/neu status
Authors: Benavides Linda C , Gates Jeremy D , Carmichael Mark G , Holmes Jarrod P , Hueman Matthew T , Mittendorf Elizabeth A , Patil Ritesh , Stojadinovic Alexander , Craig Dianna , Ponniah Sathibalan , Peoples George E 
Published: May 2019

Abstract
Background: HER2/neu is a source of immunogenic peptides and is over-expressed in 30% of early stage breast cancer (BCa) patients. We have conducted clinical trials with the HER2/neu E75-peptide vaccine in node-positive and node-negative BCa patients demonstrating all levels of HER2/neu expression.
Methods: A subset analysis review was performed of 165 BCa patients enrolled in our E75 vaccine trial based on the level of HER2/neu expression. Patients were HLA typed; HLA-A2+/A3+ patients were vaccinated (V); HLA-A2-/A3- patients served as controls (C). HER2/neu over-expressers (OE) were defined as FISH &gt;2.0 and IHC 3+ HER2/neu tumors. Low-expressers (LE) included patients with IHC ranging from 0 to 2+. These 2 groups were assessed by clinicopathologic factors, immunologic response (in vivo DTH reactions and in vitro HLA-A2:IgG dimer assay) to the vaccine, and post-vaccine clinical responses (recurrence and survival).
Results: Of 165 patients assessed; 94 were vaccinated (30 OE = 32%, 64 LE = 68%) and 71 were controls (22 OE = 31%, 49 LE = 69%). HER2/neu over-expressers were similar regarding prognostic and treatment factors, except a statistically larger number of V-OE patients were hormone receptor negative (ER/PR-; p=0.02) and node-negative (p=0.007). Clinicopathologic factors were not significantly different between control and V-LE patients. Immunologic responses were similar as measured by DTH reactions (post DTH V-OE=12.7+1.9 vs. V-LE=15.1+1.8; p=0.6), but V-OE demonstrated a decreased number of E75-specific CD8+ T cells when compared to V-LE post-vaccination (V-OE vs. V-LE Dimer: 0.6+0.06% vs. 0.8+0.07%; p=0.08; V-OE vs. V-LE Max Dimer: 1.5+0.1% 1.9+0.1%; p=0.04). At 30 months median follow-up, disease recurrence rates (RR) were similar between V-OE and C-OE patients (V-OE vs. C-OE RR: 4.3% vs. 5.6%; p=0.7); however there was a 50% reduction in mortality rate (MR) among patients that recurred (V-OE vs. C-OE MR: 25% vs. 50%; p=NS). RR was reduced for vaccinated patients with low HER2/neu expression (V-LE vs. C-LE RR: 6.4% vs. 11.3%; p=0.3). Importantly, MR among those that recurred was 0% vs. 38% (p=0.2) for V-LE and C-LE BCa patients, respectively.
Conclusions: Patients with HER2/neu over-expressing breast cancer (FISH amplified (&gt;2.0) and IHC 3+) respond well to the E75 vaccine immunologically and have a 50% absolute reduction in mortality compared to controls. Unexpectedly, patients with low-expressing (0 - 2+ on IHC) HER2/neu tumors show better response not only immunologically, but clinically with decreased breast cancer recurrence and 0% mortality following E75 peptide vaccination.
Abstract 5832: Overexpression of ODC1 is associated with poor outcome in childhood neuroblastoma and represents an important therapeutic target
Authors: Haber Michelle , Cheng Ngan , Smith Janice , Murray Jayne , Hogarty Michael D. , London Wendy B , Marshall Glenn M , Norris Murray D. 
Published: May 2019

Abstract
MYCN gene amplification is a powerful predictor of poor clinical outcome in neuroblastoma, the most common solid tumor of young children. The mechanism by which MYCN amplification influences the prognosis of this disease has not been well defined. MYCN is a known transcription factor and available evidence indicates that ornithine decarboxylase (ODC1) is a critical downstream target for this oncoprotein. ODC1 is the rate-limiting enzyme in the synthesis of polyamines and overexpression of this gene has been observed in a range of tumor cells, including neuroblastoma. In particular, a number of studies have provided evidence for the oncogenic and transforming abilities of ODC1. To investigate the role of ODC1 in neuroblastoma, we used Real-Time PCR to analyze ODC1 expression in a large cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in this cohort. ODC1 expression was significantly higher in MYCN-amplified tumors by comparison with non-amplified tumors (p&lt;0.0001). Kaplan-Meier survival analysis indicated that high levels of ODC1 expression were strongly predictive of both event-free-survival (p&lt;0.001) and overall survival (p&lt;0.001) in this cohort as well as in patients whose tumors lacked MYCN amplification (p=0.01). Furthermore, a functionally important single nucleotide polymorphism within the ODC1 promoter (G316A) that has been shown previously to influence gene transcription rates, was found to be significantly associated with outcome in patients whose tumors lacked MYCN amplification (p&lt;0.05). These data suggest that inhibiting ODC1 activity would have therapeutic advantage in treating neuroblastoma. To test this hypothesis, MYCN transgenic mice that spontaneously develop neuroblastoma closely mimicking the human disease, were treated either with cisplatin alone or in combination with the ODC1 inhibitor, Î±-difluoromethylornithine (DFMO). Importantly, DFMO therapy, either concomitant with or following cisplatin treatment, resulted in prolonged tumor-free survival (p&lt;0.01) in these mice, by comparison with cisplatin administered alone. Similar results were obtained with cyclophosphamide treatment in combination with DFMO. No overt toxicity attributable to DFMO therapy was noted in treated mice. Collectively, these findings provide strong evidence that ODC1 contributes to the malignant phenotype of neuroblastoma and suggest that targeting this oncogene for suppression of polyamine synthesis is potentially a valuable therapeutic approach for inhibiting neuroblastoma growth.
Abstract LB-201: Updated results from a Phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and -3 tyrosine kinase inhibitor, in patients with advanced solid tumors
Authors: Eskens Ferry A.l.m. , de Jonge Maja J.a. , Esteves Brooke , Cotreau Monette , Bhargava Pankaj , Ryan John , van Doorn Leny , Isoe Toshiyuki , Hayashi Kunihiko , Ekman Lena , Burger Herman , Verweij Jaap 
Published: May 2019

Abstract
Background: AV-951 inhibits phosphorylation of VEGF receptors (VEGFR)-1, -2, and -3 at picomolar concentrations (IC50 of 0.21, 0.16, and 0.24 nM, respectively) and inhibits c-Kit and PDGFR at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM, respectively). In a dose-escalation study of AV-951 given orally on a 4 week on, 2 week off schedule, the maximum tolerated dose (MTD) was determined to be 1.5 mg/day and clinical activity was observed in renal (RCC), colon, and lung cancers [Proc ASCO 2006;24(18S):2034]. Thereafter, the study was amended to enroll an additional 10 patients at 1.0 mg/day in order to compare the safety profile, pharmacokinetics (PK), effects on tumor blood flow, and antitumor activity across all dose levels.
Results: 40 patients (26M/14F), were enrolled at AV-951 doses of 1 (n=16), 1.5 (n=16), and 2.0 mg (n=8). At 2 mg DLTs consisting of grade 3 proteinuria, grade 3 ataxia, and grade 4 intracranial hemorrhage were seen in one patient each. The primary toxicity across all dose levels was hypertension (HTN), as listed in Table 1. HTN was dose-dependent, and could be controlled with standard anti-hypertensive agents. Only two patients, both at 1.5 mg, required dose reduction to 1.0 mg for control of HTN. PK analysis revealed dose dependent drug exposure and peak plasma concentrations. DCE-MRI analysis indicated a decrease in tumor perfusion in selected patients. Among 9 patients with RCC, there were 2 confirmed partial responses at 2.0 mg (n=1) and 1.5 mg (n=1) lasting 128 weeks and 42 weeks, respectively, and 7 patients with stable disease (lasting &gt;12 wks) at 1.0 mg (n=5), 1.5 mg (n=1), and 2.0 mg (n=1). Clinical activity was observed in multiple tumor types.
Conclusions: AV-951 could be safely administered at 1.0 and 1.5 mg doses. The primary toxicity was dose-dependent HTN, a biomarker of VEGFR inhibition. Clinical activity was observed across all dose levels. In future combination studies, AV-951 may be administered at a dose of either 1.0 mg or 1.5 mg.
Table 1.Primary toxicity of AV-951 across all dose levelsHypertensionAV-951 DoseGrade 1-2Grade 3Grade 4All Grades1.0 mg (n=16)6% (n=1)31% (n=5)0%37% (n=6)1.5 mg (n=16)0% (n=0)56% (n=9)0%56% (n=9)2.0 mg (n=8)25% (n=2)75% (n=6)0%100% (n=8)
Abstract LB-238: Immunotransplant filters out regulatory T cells and cures large lymphoma tumors.
Authors: Brody Joshua D , Goldstein Matthew J , Levy Ronald 
Published: May 2019

Abstract
Background: The potency of transferring ex vivo activated tumor-infiltrating lymphocytes into lymphodepleted recipients has been demonstrated in clinical trials, though the use of in vivo vaccine-primed anti-tumor lymphocytes could make this approach sufficiently feasible for broad clinical application. We previously described a vaccination maneuver against murine B-cell lymphoma combining chemotherapy (CTX) and intra-tumoral injection of an immunostimulant CpG, which induced T-cell immunity and eradicated established tumors. An ongoing clinical trial of this maneuver has demonstrated complete and partial responses in lymphoma patients, though immune-regulatory factors such as regulatory T cells (Tregs) and limiting amounts of “homeostatic” cytokines might block even more powerful antitumor immunity. Transfer of tumor-specific lymphocytes into lymphodepleted recipients may eliminate these immune-regulatory obstacles.
Methods: Splenocytes and bone marrow from CpG/CTX vaccinated mice were transplanted into lethally irradiated recipients, i.e., “immunotransplant.” Recipients received high dose tumor challenge with A20 murine B-cell lymphoma and followed clinically for tumor growth and for tumor-specific CD8 T cell IFNγ responses by multi-color flow cytometry.
Results: We observed selective filtering against Tregs, doubling of the transferred Teffector:Treg ratio, and preferential expansion of transferred tumor-specific CD8 T cells in immunotransplant recipients. Immunotransplant cures large subcutaneous (&gt;100 mm2) and metastatic tumors in 100% of recipients and enhances tumor-specific T cell memory. The addition of a vaccine “boost” to the immunotransplant maneuver results in an additional 3-fold increase in tumor-specific immunity and the use of cured recipients as subsequent donors in serial immunotransplant experiments demonstrated even greater tumor protection.
Conclusions: As hematopoietic stem cell transplantation is a standard therapy for lymphoma patients, pre-transplant vaccination followed by post-transplant transfer of tumor-specific T cells could be tested in clinical trials. Our model suggests that this immunotransplant approach would allow the benefit of cancer vaccines to be revealed and might lead to cure of otherwise resistant malignancies.
Abstract LB-244: A phase 0 trial of riluzole in patients with resectable stage III or IV melanoma.
Authors: Yip Dana , Le Maithao , Lee Jonathan H , Chen Suzie , Goydos James S 
Published: May 2019

Abstract
Recently, our group described a murine model of melanoma that is based on ectopic expression of metabotropic glutamate receptor 1 (Grm1). Grm1 is a normally occurring receptor in the central nervous system of mammals that controls excitatory neural impulses. Ectopic expression of this receptor in melanocytes results in transformation of these cells into a murine form of melanoma indistinguishable from human melanoma. We also found that &gt;60% of human melanoma samples tested ectopically to date express Grm1 while normal skin and melanocytes from the same patients fail to express this protein. Furthermore, stimulation of this receptor in vitro results in downstream upregulation of phosphorylated (activated) ERK, demonstrating that this receptor is involved in the regulation of the MAPK pathway, a pathway in the cell important in melanoma formation and growth. Finally, a murine xenograft model of melanoma treated with riluzole, an oral Grm1 blocking agent, showed decreased tumor growth in the treated mice compared to the untreated controls. The goal of this study was to validate Grm1 as a therapeutic target in humans with melanoma. To accomplish this we enrolled patients with resectable stage III and stage IV melanoma on a Phase 0 NCI Quick Trial of oral riluzole. We performed a pre-treatment biopsy, treated the patients with 200 mg of oral riluzole per day for 14 days, and then resected the patients’ remaining tumors. We compared the level of pERK in the pre- and post-treatment tumor samples to determine if treatment with an oral Grm1 blocking agent results in modulation of the Grm1 signaling pathway in human melanoma. We also assessed overall metabolic activity and proliferation of the tumors pre- and post-treatment, using PET scanning, assessement of pre- and post-treatment mitotic rate of the tumors, and pre- and post-treatment Ki-67 staining intensity. We have accrued 10 of the 15 patients we need for this trial and all 10 appear to express Grm1. Preliminary results demonstrate a significant decrease in pERK in post-treatment tumor samples as compared to pre-treatment samples in 50% of the cases so far (P&lt;0.01). We also found a significant decrease in post-treatment Ki-67 staining in one patient. Three patients had a significant decrease in PET intensity post-treatment while all other patients had similar pre- and post-treatment PET scan findings except for one patient whose post-treatment PET scan revealed progressive disease. Our preliminary data demonstrates that glutamate-blockade with riluzole can inhibit signaling through the MAPK pathway and suppress metabolic activity of melanoma in a significant number of patients. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma and targeting this pathway may be an effective therapy for patients with melanoma.
Abstract LB-305: Soluble CD23 levels increase following lumiliximab dosing in relapsed chronic lymphocytic leukemia patients
Authors: Harris Sarah , Woodworth James , Ranuio-Kelley Julie , Estrellado Annalee , Cesano Alessandra , Mu Hua , Tangri Shabnam 
Published: May 2019

Abstract
Lumiliximab is an anti-CD23 monoclonal antibody under investigation for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL). Lumiliximab binds specifically to human CD23, a glycoprotein expressed on the majority of CLL B cells. CD23 is a trimeric molecule with both membrane-bound (mCD23) and soluble (sCD23) forms. mCD23 is a 45 kD glycoprotein expressed on B cells, monocytes/macrophages, eosinophils, platelets, and dendritic cells, with increased levels observed on chronic lymphocytic leukemia (CLL) cells. Soluble CD23 is produced by the cleavage of mCD23 by endogenous proteases into various fragments, with the 25 kD fragment found in normal human serum at concentrations around 2 ng/ml. Increased levels of sCD23 are found in the serum of patients with several disease states including CLL. Data from a Phase 1 lumiliximab monotherapy trial in relapsed CLL showed that levels of sCD23 rapidly increased in the serum of some patients after dosing with lumiliximab. To confirm this phenomenon, serum sCD23 levels and their relationship with treatment response were evaluated in a Phase 1/2 study of lumiliximab in combination with fludarabine, cyclophosphamide, rituximab (FCR) in patients with relapsed CLL. The pharmacokinetic (PK) profiles of both lumiliximab and rituximab were also compared to sCD23 profiles.
Methods: Thirty-one patients with relapsed CLL were enrolled to receive up to 6 cycles treatment with lumiliximab plus FCR. Lumiliximab PK, Rituxan PK and sCD23 levels were each measured in 31 patients using validated enzyme-linked immunosorbant assays. PK data was analyzed with WinNonlin.
Results and Conclusions: Our analysis shows that sCD23 increases from the ng/ml range to the ug/ml range immediately after each dosing with lumiliximab/FCR, then declines throughout the remainder of the treatment cycle. The levels of sCD23 increase again with subsequent lumiliximab/FCR doses, until the there are little to no B-CLL cells remaining in the circulation. The pattern of increase parallels the PK profile of lumiliximab. The intensity of sCD23 increase varied from patient to patient, and did not appear to correlate with treatment outcome. These data demonstrate that although lumiliximab/FCR dosing increases serum levels of sCD23, there is no apparent impact on patient response. This will be evaluated further in upcoming clinical trials. The mechanism of sCD23 release is also currently being investigated.