bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT332: Biomarker analysis predicts antitumor activity of Ipilimumab therapy in patients with refractory metastatic melanoma
Authors: Chakravarti Nitin , Glitza Isabella C. , Trinh Van A. , Bassett Roland L. , Hwu Wen-Jen , Prieto Victor G. 
Published: May 2015

Abstract
Background: Ipilimumab (Ipi) improves survival of patients (pts) with advanced melanoma. It is unknown which biomarkers predict antitumor activity.
Methods: 81 pts with advanced melanoma who had failed to at least one prior systemic treatment were included in the Ipi Expanded Access Program (EAP) (Table 1). All pts received induction therapy with Ipi 10 mg/kg i.v. q 3 weeks x4 doses. At week 24, pts without progressive disease or toxicity received maintenance therapy with Ipi q 12 weeks. Pertinent biomarkers (CTLA-4, PD-1, PD-L1, pAKT, pS6, fas-l, Ki67, and BRAF V600E) were analyzed by immunohistochemistry on pre-treatment tumor specimens and results were correlated with clinical outcomes.
Results: Median progression free survival (PFS) and overall survival (OS) were 3.7 and 10.6 mos. Higher stages, ECOG (1 and 2), elevated LDH, and low absolute lymphocyte count (ALC) at baseline were associated with poor survival. Of the 71 pts with progression, 32 received alternative treatment and 39 did not; the OS from the time of disease progression was 17 and 2.6 mos, respectively. Increased CTLA-4 in tumor (p=0.003) and TILs (p=0.02) correlated with poor OS. pS6 expression in TILs (p=0.04), high pAkt in tumor (p=0.03) correlated with poor PFS. Low CTLA-4 (p=0.05) and pAkt (p=0.04) expression in tumor cells correlated with better outcome. High CTLA-4 expression in TILs associated with poor OS (p=0.003) in pts who received alternative treatment post-ipi.
Conclusions: High CTLA-4 expression in tumor & TILs as well as activated Akt pathway in tumor cells correlated with poor clinical outcome. High CTLA-4 expression in TILs correlated with poor survival in pts received alternative therapy after Ipi. Analyses of biomarkers predict antitumor activity of Ipi.
Table 1.Patient characteristicsVariableLevelNPercentSexMale4960%Female3240%StageIIIc22%M1a67%M1b1114%M1c6277%ECOG04353%12835%21012%Primary Melanoma SiteAcral Lentiginous45%Cutaneous6175%Mucosal79%Uveal22%Unknown primary79%Brain MetastasesNo4454%Before Treatment2328%During Treatment1012%After Treatment45%ResponseCR1114%PR22%SD22%PD6681%Post-Ipi RadiationNo1235%Yes2065%Post-Ipi SurgeryNo1547%Yes1753%Post-Ipi ImmunotherapyNo2991%Yes39%Post-Ipi Targeted TherapyNo1856%Yes1444%Post-Ipi ChemotherapyNo516%Yes2784%
Citation Format: Nitin Chakravarti, Isabella C. Glitza, Van A. Trinh, Roland L. Bassett, Wen-Jen Hwu, Victor G. Prieto. Biomarker analysis predicts antitumor activity of Ipilimumab therapy in patients with refractory metastatic melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT332. doi:10.1158/1538-7445.AM2014-CT332
Abstract CT404: Phase I/II study of VAL-083 in patients with recurrent glioblastoma multiforme
Authors: Shih Kent C. , Patel Manish R. , Bacha Jeffrey , Brown Dennis M. , Garner William J. , Steino Anne , Schwartz Richard S. , Kanekal Sarath , Li Mike , Lopez Lorena M. , Burris Howard A. 
Published: May 2015

Abstract
Median survival for patients with recurrent glioblastoma multiforme (GBM) is less than 6 months. Front-line systemic therapy is temozolomide, but chemo-resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity has been implicated in poor outcomes. VAL-083 is a structurally unique bi-functional DNA alkylating small molecule drug that crosses the blood-brain barrier and accumulates in brain tumor tissue. Previous human clinical studies by several investigators have suggested that VAL-083 has anti-tumor activity against a broad range of tumor types including GBM. In preclinical in vitro studies, VAL-083 demonstrated activity in a wide range of cancer cell lines, including pediatric and adult GBM cell lines and GBM cancer stem cells. Notably, due to crosslink formation on N7 of guanine, VAL-083 overcomes chemo-resistance to MGMT in vitro. In light of extensive safety data from several clinical trials and promising efficacy signals in CNS tumors, DelMar initiated a new clinical study to determine the safety, tolerability, pharmacokinetics, anti-tumor activity in patients with recurrent GBM. This is an open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 i.v. on days 1, 2, and 3 of a 21 day cycle. GBM patients have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and temozolomide, unless contraindicated. In the ongoing trial, cohorts 1 through 4 (10 mg/m2) have completed the trial successfully with no drug-related serious adverse events (SAEs), and maximum tolerated dose (MTD) was not yet reached. Enrollment for Cohort 5 (20 mg/m2) has been initiated. Pharmacokinetic analyses show dose-dependent increase in exposure with a short 1-2 hour plasma half-life and a Cmax of &lt;200 ng/ml at 10 mg/m2. Historical data suggests a long half-life in the cerebrospinal fluid (CSF) (&gt;20 hours) with preferential accumulation to brain tumor tissue. MGMT status of patients and drug concentration in the CSF are being evaluated when possible. ClinicalTrials.gov Identifier: NCT01478178
Citation Format: Kent C. Shih, Manish R. Patel, Jeffrey Bacha, Dennis M. Brown, William J. Garner, Anne Steino, Richard S. Schwartz, Sarath Kanekal, Mike Li, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT404. doi:10.1158/1538-7445.AM2014-CT404
Abstract CT408: Phase I study of one mixed chelates copper(II) compound, Casiopeína CasIIIia with antitumor activity and its mechanism of action
Authors: Ruiz-Azuara Lena , Bastian Gerard , Bravo-Gómez Maria Elena , Cañas Roberto Carlos , Flores-Alamo Marcos , Fuentes Ines , Mejia Carmen , García-Ramos Juan Carlos , Serrano Alberto 
Published: May 2015

Abstract
Metal complexes have gained a growing interest as pharmaceuticals for their use as diagnostic agents or as chemotherapeutic drugs[1]. In our group some efforts have been done in the development of anticancer agents employing essential metals such as the family of copper (II) compounds known as Casiopeínas®, with a general formula [Cu (N-N) (X-Y) H2O] NO3 where N-N is a diimine (phen or bipy) and X-Y is a bidentate ligand (acac, salal, aminoacidate, peptide, benzimidazol).
These compounds have shown cytostatic, cytotoxic and antineoplastic activity in vitro and in vivo[2]. Also albumin/Casiopeinas interaction is discussed. Among those one have selected that is CasIII-ia as the most adequate to go into clinical trial Phase I.
Although the mechanism of action is still not completely elucidated, experimental evidence suggests the interaction of coordination compounds with DNA (nuclear or mitochondrial) and their components and the generation of reactive oxygen species (ROS) as the main action pathways. Induction of apoptosis has been proved to be the main death tumoral cell pathway. DNA cleavage capacity, compared with the 4, 4´-diimine analogs, then is suggested an intercalation process as the first step for the DNA damage. Also calculations have been done in order to modeling the interaction between Casiopeínas and DNA [3, 4].
The clinical protocol phase I of the dimethyl bpy derivative with acac Cas IIIia is presented and the selection criteria of the drug.
[1] S. H. van Rijt, P. J. Sadler, Drug Discov. Today, 14 (2009) 1089-1097.
[2] L. Ruiz-Azuara, M.E. Bravo-Gómez, Curr. Med. Chem., 17 (2010) 3606-3615.
[3] R. Galindo-Murillo, J. Hernández-Lima, M. González-Rendón, F. Cortés-Guzmán, L. Ruíz-Azuara, R. Moreno-Esparza Phys. Chem. Chem. Phys., 13 (2011) 14511-14516.
[4] R. Galindo-Murillo, L. Ruiz-Azuara, R. Moreno-Esparza, F. Cortés-Guzmán Phys. Chem. Chem. Phys., 14 (2012) 15539-15546.
Citation Format: Lena Ruiz-Azuara, Gerard Bastian, Maria Elena Bravo-Gómez, Roberto Carlos Cañas, Marcos Flores-Alamo, Ines Fuentes, Carmen Mejia, Juan Carlos García-Ramos, Alberto Serrano. Phase I study of one mixed chelates copper(II) compound, Casiopeína CasIIIia with antitumor activity and its mechanism of action. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT408. doi:10.1158/1538-7445.AM2014-CT408
Abstract DDT01-04: SGN-CD19A: A novel Anti-CD19 antibody drug conjugate
Authors: Albertson Tina M. , Sandalic Lali , Zhao Baiteng , Kostic Ana , Law Che-Leung 
Published: May 2015

Abstract
CD19, a member of the immunoglobulin superfamily, is a B-cell specific marker that is found on B cells as early as the pro-B cell stage. CD19 is maintained upon malignant transformation and is expressed in the majority of patients with B-lineage acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL).
SGN CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. In mice bearing B-lineage ALL and lymphoma xenografts, SGN-CD19A induced dose-dependent tumor growth delay and extended survival.
Two first-in-human, phase 1, dose-escalation studies are ongoing to investigate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN CD19A; one trial in adult and pediatric patients with relapsed or refractory (R/R) B cell ALL or highly aggressive B-cell lymphoma (CT.gov NCT01786096) and the second trial in adult patients with R/R B-cell NHL (CT.gov NCT01786135). Both trials employ a modified continual reassessment method (CRM) to estimate the dose-toxicity relationship and to estimate the maximum tolerated dose. Exploratory analyses include correlation of target (CD19) expression, target saturation, and apoptotic cellular markers with clinical response and clearance of leukemic blasts; dose and PK of SGN-CD19A will also be correlated with target saturation and intracellular levels of cys-mcMMAF.
Early PK analyses indicate that plasma SGN-CD19A ADC generally increases with higher doses. Rapid clearance of ADC was observed at low doses in patients with leukemia, suggesting target-mediated drug disposition.
Dose escalation of SGN-CD19A is ongoing in both clinical trials. In preliminary safety analyses, SGN-CD19A was generally tolerable at doses examined to date. Encouraging antitumor activity has been observed, with multiple patients achieving complete remissions in both trials.
Citation Format: Tina M. Albertson, Lali Sandalic, Baiteng Zhao, Ana Kostic, Che-Leung Law. SGN-CD19A: A novel Anti-CD19 antibody drug conjugate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT01-04. doi:10.1158/1538-7445.AM2014-DDT01-04
Abstract LB-150: Local maturation and inhibition of antitumor CD8 T-cell responses in a model of immunoevasive breast cancer
Authors: Boldajipour Bijan A. , Krummel Matthew F. 
Published: May 2015

Abstract
The purpose of this study is to investigate the cell interactions and mechanisms that limit anti-tumor CD8 T cell responses in tumor microenvironments.
We used cutting-edge multiphoton imaging of immunoevasive tumors to determine the behavior and anti-tumor responses of CD8 T cells. This was achieved by adoptively transferring T cells into a modified MMTV-PyMT breast tumor model (mouse mammary tumor virus promoter-driven, polyoma middle T antigen-induced luminal breast cancer). In this model, tumor cells expresses ovalbumin as tumor-antigen and mCherry as a fluorescent markers, thus allowing immunologic assessment and intravital imaging of T cell activity against tumor cells in and ex vivo. Furthermore, we were able to investigate the effect of antigen-presenting immune cells and immunomodulatory treatment regimens on anti-tumor T cell activity in and ex vivo.
In this work we found that newly arriving tumor-specific T cells undergo defined phases of maturation within the tumor microenvironment. First, after arriving to the tumor site, T cells engage in close interactions with antigen-presenting cells and exhibit reduced motility and rounded morphology. After this initial phase, T cells dramatically increase motility and survey the tumor microenvironment, however they do not form stable interactions with other cell types and further do not engage tumor cells. In contrary to other publications, swarming T cells do not express surface markers associated with exhaustion or anergy, and exhibit extensive in situ proliferation and ex vivo CTL activity. The capability of tumor CD8 T cells to kill targets ex vivo conflicts with the absence of tumor cell death in vivo. Additionally, individual immune cell populations isolated from tumors or tumor culture supernatants do not exhibit T cell suppressive capability when added as supplements to killing assays.
Our results define sequential fates for T cells entering tumor microenvironments, suggesting that tumor-infiltrating lymphocytes exist in distinct ‘states’ depending on the extent to which tumor antigen-presenting cells have matured them. Further, T cell suppression appears to be a local phenomenon and cannot be achieved by soluble factors or a specific cell type alone. This may suggest that combinations of therapies that individually target the different maturation states are required to achieve therapeutic effects.
Citation Format: Bijan A. Boldajipour, Matthew F. Krummel. Local maturation and inhibition of antitumor CD8 T-cell responses in a model of immunoevasive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-150. doi:10.1158/1538-7445.AM2014-LB-150
Abstract LB-206: Role of Olig2 phosphorylation in pediatric glioma formation
Authors: GRIVEAU Amelie , TIEN An-Chi , Rowitch David H. 
Published: May 2015

Abstract
Malignant gliomas are a leading cause of tumor-related mortality in children. Current therapies often have significant adverse effects on brain development and are largely ineffective against aggressive gliomas. The development of rational therapies has been limited by poor information regarding the cell of origin for pediatric glioma and the relevant underlying genetic alterations. Recent findings now reveal that mutations existing in pediatric glioma are different than those seen in adult gliomas. For example, BRAFV600E activating mutations are associated with deletion of the tumor suppressor gene, p16 (Ink4a-Arf), in about 15% of pediatric gliomas. We have generated a faithful genetic mouse model in which there is concomitant activation of BRAFV600E and deletion of Ink4a-Arf in oligodendrocyte progenitor cells (OPCs) leading to the generation of pediatric high-grade glioma. OPCs have been shown to be a potential cell of origin for glioma and expression of Olig2 is found in 100 percent of human pediatric and adult high-grade gliomas. Given that Olig2 is also required for normal myelin development, targeting all Olig2-expressing cells with small molecule inhibitors would likely have detrimental effects. We have recently found that Olig2 protein is present in a phosphorylated form that promotes proliferation of adult glioma cells. In this study, we demonstrate that phospho-Olig2 is expressed in tumorigenic oligodendrocyte progenitor cells and is required for pediatric glioma generation. In addition, we found that phospho-Olig2 and Olig2 interact with different proteins, some of which are feasible drug targets. This study gives insights into new therapies by understanding key protein interactions in normal oligodendrocyte development as well as in tumorigenic oligodendrocyte progenitor cells.
Citation Format: Amelie GRIVEAU, An-Chi TIEN, David H. Rowitch. Role of Olig2 phosphorylation in pediatric glioma formation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-206. doi:10.1158/1538-7445.AM2014-LB-206
Abstract LB-261: Atopic allergic conditions and colorectal cancer risk in the Multiethnic Cohort
Authors: Tambe Neal A. , Stram Dan O. , Wilkens Lynne R. , Wan Peggy , Gilliland Frank D. , Henderson Brian E. , Marchand Loic L. , Haiman Christopher A. 
Published: May 2015

Abstract
Previous studies have provided suggestive evidence of an inverse association between atopic allergic conditions (AAC) and colorectal cancer (CRC) incidence and mortality in predominantly White populations. Here we examined the association between AAC and CRC among White, African American, Native Hawaiian, Japanese American, and Latino men and women in the Multiethnic Cohort (MEC). AAC exposure status was ascertained via self-reported physician diagnosis using a baseline 26-page validated questionnaire. The analysis included 4259 incident CRC cases and 1221 CRC-related deaths ascertained between 1993 and 2010. We also examined associations by ethnic group, location, and stage of cancer as well as potential effect modification by CRC risk factors. AAC was associated with a reduced risk of colorectal cancer incidence among both men and women (RR = 0.85, 95% CI 0.79, 0.91, p &lt; 0.0001). The reduction in risk was noted in each population and was significant in Whites (RR = 0.84, 95% CI 0.71, 0.98, p = 0.03), African Americans (RR = 0.81, 95% CI 0.69, 0.95, p = 0.01), and Japanese Americans (RR = 0.85, 95% CI 0.75, 0.97, p = 0.01). Suggestive evidence of effect modification was noted by smoking (p = 0.07) and aspirin use (p = 0.08), with a greater protective effect observed among current smokers (RR = 0.72, 95% CI 0.58, 0.89, p = 0.002) and never users of aspirin (RR = 0.81, 95% CI 0.73, 0.89, p &lt; 0.0001). Individuals with AAC also had a 19% reduction in CRC-related mortality (P = 0.004). Colonoscopy screening is unlikely to explain these inverse associations, as individuals with AAC were more likely to be screened than those without AAC (p &lt; 0.003 for all ethnic groups). These findings provide support for an association between immune pathology and colorectal cancer, potentially through modulation of the immune system's IgE-mediated pathways systemically and within the gut.
Citation Format: Neal A. Tambe, Dan O. Stram, Lynne R. Wilkens, Peggy Wan, Frank D. Gilliland, Brian E. Henderson, Loic Le Marchand, Christopher A. Haiman. Atopic allergic conditions and colorectal cancer risk in the Multiethnic Cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-261. doi:10.1158/1538-7445.AM2014-LB-261
Abstract LB-282: Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A
Authors: Wang Hansong , Burnett Terrilea , Kono Suminori , Haiman Christopher , Iwasaki Motoki , Wilkens Lynne , Loo Lenora , Berg David Van Den , Kolonel Laurence , Henderson Brian , Keku Temitope , Sandler Robert , Signorello Lisa , Blot William , Newcomb Polly , Pande Mala , Amos Christopher , West Dee , Bézieau Stéphane , Berndt Sonja , Zanke Brent , Hsu Li , Lindor Noralane , Haile Robert , Hopper John , Jenkins Mark , Gallinger Steven , Casey Graham , Stenzel Stephanie , Schumacher Fredrick , Peters Ulrike , Gruber Stephen , Tsugane Shoichiro , Stram Dan , Marchand Loic L. 
Published: May 2015

Abstract
To identify genetic variants that contribute to colorectal cancer (CRC) susceptibility, we performed a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, followed by a replication of genome-wide statistically significant associations (P &lt; 5E-8) in 16,823 cases and 18,211 controls of European ancestry. This study revealed a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.5E-9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations.
Citation Format: Hansong Wang, Terrilea Burnett, Suminori Kono, Christopher Haiman, Motoki Iwasaki, Lynne Wilkens, Lenora Loo, David Van Den Berg, Laurence Kolonel, Brian Henderson, Temitope Keku, Robert Sandler, Lisa Signorello, William Blot, Polly Newcomb, Mala Pande, Christopher Amos, Dee West, Stéphane Bézieau, Sonja Berndt, Brent Zanke, Li Hsu, Noralane Lindor, Robert Haile, John Hopper, Mark Jenkins, Steven Gallinger, Graham Casey, Stephanie Stenzel, Fredrick Schumacher, Ulrike Peters, Stephen Gruber, Shoichiro Tsugane, Dan Stram, Loic Le Marchand. Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2014-LB-282