bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4227: PARP inhibitors sensitize glioblastoma stem cells to oncolytic herpes simplex virus therapy
Authors: Ning Jianfang , Wakimoto Hiroaki , Martuza Robert , Rabkin Samuel 
Published: August 2015

Abstract
Glioblastoma (GBM) is an invariably fatal brain tumor in adults and remains a great challenge for preclinical and clinical research. PARP inhibitors (PARPi) have been used alone or in combination with genotoxic agents for the treatment of cancers with homologous recombination (HR) repair deficiencies. Oncolytic herpes simplex viruses (oHSVs) are genetically-engineered to selectively replicate in cancer cells, and previous studies have shown that oHSV infection of glioblastoma stem cells (GSC) induces DNA damage and compromises HR DNA repair. Therefore, we hypothesized that PARPi and oHSV would synergistically kill GSCs through inducing lethal DNA damage.
Here, we show that PARPi consistently inhibited PARylation in a panel of patient-derived GSC lines. Surprisingly, half of GSCs (4 of 8) were sensitive to PARPi killing, with the other half being resistant. When combined with 2 different oHSVs, MG18L and G47Δ, PARPi olaparib and oHSV synergistically killed olaparib-sensitive GSCs in vitro. Moreover, olaparib sensitized PARPi-resistant GSCs to the cytotoxic effects of MG18L or G47Δ, leading to increased DNA damage and cell death. While monotherapy with systemic olaparib or intratumoral injection of MG18L increased survival in an orthotopic xenograft model generated with olaparib-sensitive GSCs, combination treatment greatly extended survival over either monotherapy alone, with concomitant induction of robust DNA damage and apoptosis in the tumors. Furthermore, in an orthotopic model with olaparib-resistant GSCs, in which olaparib monotherapy was not effective, combinatorial therapy of olaparib and MG18L was significantly more efficacious than MG18L alone in prolonging lifespan. Our studies demonstrate that PARPi have anti-GSC activity in about half of GBMs tested, and combining PARPi with oHSV targets DNA damage responses and induces a synthetic lethal effect in vitro and in vivo against both PARPi-sensitive and -resistant GSCs. This report describes a new therapeutic strategy for GBM and supports investigations of this combination in the clinic.
Citation Format: Jianfang Ning, Hiroaki Wakimoto, Robert Martuza, Samuel Rabkin. PARP inhibitors sensitize glioblastoma stem cells to oncolytic herpes simplex virus therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4227. doi:10.1158/1538-7445.AM2015-4227
Abstract 4244: Comparison of different ALK tests in non-small cell lung cancer (NSCLC) patients treated with crizotinib and their clinical outcome
Authors: van der Wekken Anthonie J. , Hiltermann Thijo JN , Timens Wim , Schuuring Ed , Groen Harry JM 
Published: August 2015

Abstract
Background:
The screening algorithm for detection of ALK-rearranged NSCLC is still under investigation. The Break-Apart ALK FISH is the standard diagnostic test for the treatment with crizotinib. However, immunohistochemistry (IHC) with different antibodies shows excellent results when compared to ALK FISH. The efficacy of crizotinib is studied in relation to ALK FISH. We compared IHC outcome and the number of ALK breaks estimated with FISH with clinical outcome.
Methods:
Patients treated with crizotinib who had biopsies with sufficient tumor tissue were selected. Tumour response was assessed by CT using RECIST. Fluorescence in situ hybridization (FISH) was performed with Vysis LSI ALK Break Apart FISH Probe KIT (Abbott Molecular) and immunohistochemistry with Ventana ALK IHC Kit using D5F3 antibody.
Results:
Twenty one patients with NSCLC were selected, median (range) age 54 yrs (21-75); 19 had adenocarcinoma, 2 had large-cell carcinoma. We confirmed the presence of EML4-ALK fusions in all samples either by FISH or IHC. Median percentage of ALK breaks was 47% (6-76). Tumour response occurred in 12 pts having a median of 51 (6-76) breaks and 9 non-responders having a median of 27 (15-64) breaks. Of the 12 responders, 8 pts had positive IHC (67%), 3 were negative and 1 was not done; the FISH negative, IHC positive patient was one of the responders. Of the 9 non-responders 2 had positive IHC (22%), 3 negative (33%), and 1 was equivocal and 3 not done. Median PFS for positive IHC is 7.9 mo (95% CI., 5.5 - 10.3) and for negative IHC 1.6 mo (1.3 - 1.8), n = 17, p&lt;0.0001. OS survival data are 6.5 mo (95% CI., 0 - 17.8) and 18.3 mo (95% CI., 11.1 - 25.6) respectively, n = 17 p = 0.052.
PFS above 30% number of breaks was 7.0 mo (95% CI., 1.8 - 12.2) versus PFS below is 1.8 mo (95% CI., 0.7 - 2.9), n = 21, p = 0.05. OS survival data are 4.1 mo (95% CI., 0 - 9.3) and 16.1 mo (95% CI., 9.0 - 23.2) respectively, n = 21 p = 0.003. Therefore PFS and OS is more prolonged in those tumors who have ALK breaks above 30%. IHC difference are only significant for PFS.
Conclusions:
Both ALK FISH and IHC identify NSCLC patients who benefit from crizotinib treatment. Patients with ALK breaks above 30% have a better PFS and OS. IHC only differentiates for PFS.
Citation Format: Anthonie J. van der Wekken, Thijo JN Hiltermann, Wim Timens, Ed Schuuring, Harry JM Groen. Comparison of different ALK tests in non-small cell lung cancer (NSCLC) patients treated with crizotinib and their clinical outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4244. doi:10.1158/1538-7445.AM2015-4244
Abstract 4262: PRAME as a biomarker for a new molecular subclass of uveal melanoma
Authors: Field Matthew G. , Decatur Christina L. , Harbour J. William 
Published: August 2015

Abstract
Introduction: Uveal melanoma is the most common primary intraocular tumor of the eye and has a propensity for fatal hematogenous metastasis. Gene expression profiling is routinely used in clinic to classify uveal melanoma into prognostic subgroups: Class 1 (low metastatic risk) and Class 2 (high metastatic risk). Approximately 40% of Class 2 patients metastasize, which accounts for 85% of metastasis. The remaining 15% of patients that metastasize are Class 1 based on gene expression profiling, however this study demonstrates that the Class 1 patients that metastasize (Class1met+) can be defined as a new molecular subclass, distinct from Class 1 patients that do not metastasize (Class1met-) and Class 2 patients.
Methods: Tumor samples from Class1met+ and Class1met- patients with at least 1 year of follow-up underwent histopathologic, cytogenetic and transcriptomic analyses.
Results: In a comparison of Class1met+ and Class1met- tumors, the only significant difference was a larger mean basal tumor diameter in Class1met+ tumors. Cytogenetic analyses revealed more extensive copy number gains and losses in Class1met+ tumors. The most significant differentiating features in Class1met+ tumors included 1q gain, 6p gain, 6q loss, and 8q gain. Using principal component analysis, the Class1met+ tumors clustered separately from the Class1met- tumors, indicating the existence of significant transcriptomic differences between the two subgroups. Strikingly, the most highly differentially expressed gene in Class1met+ tumors was preferentially expressed antigen in melanoma (PRAME); mean mRNA expression of PRAME in Class1met+ tumors was 61-fold higher than in Class1met- tumors.
Discussion: We define a new subtype of uveal melanoma and demonstrate that gene expression of PRAME can distinguish between Class1met+ patients and Class1met- patients.
Citation Format: Matthew G. Field, Christina L. Decatur, J. William Harbour. PRAME as a biomarker for a new molecular subclass of uveal melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4262. doi:10.1158/1538-7445.AM2015-4262
Abstract 4263: Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials
Authors: Subbiah Ishwaria M. , Janku Filip , Tsimberidou Apostolia M. , Naing Aung , Subbiah Vivek , Wheler Jennifer J. , Zinner Ralph , Eng Cathy , Overman Michael J. , Kopetz Scott , Hong David S. 
Published: August 2015

Abstract
Background: Relapsed refractory colorectal adenocarcinoma (CRC) is evolving as a disease with distinct molecular subsets rather than a singular histology. Given the varied outcomes of CRC patients treated on clinical trials particularly with targeted therapies, we aimed to identify a molecular phenotype for future therapeutic targeting.
Methods: We identified CRC patients referred to our Phase I clinic with adequate tissue for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions.
Results: Overall, 60 relapsed CRC patients (31 male, 29 female; median age 55 years; 56 colon primary, 4 rectum primary). 48 (80%) patients had a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 43 pts, 90%). Of these 48 patients, over half (n = 26, 54%) demonstrated a concurrent mutation affecting the PI3K cascade (PIK3CA in 12 patients [4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K, 1 R38C]). Of these 26 pts with concurrent aberrant Wnt and PI3K pathways, 22 also demonstrated a concomitant MAPK pathway mutation (17 KRAS and 3 BRAF). Of the 60 CRC pts overall, 22 (37%) patients had coexisting aberrations linked to in all three (Wnt, PI3K, and MAPK) cascades.
Conclusions: Concomitant mutations in three pathways (Wnt, MAPK, PI3K) implicated in cancer occur frequently in patients with advanced CRC, emphasizing the need for a combinatorial therapeutic strategy ideally targeting all three cascades.
Note: This abstract was not presented at the meeting.
Citation Format: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong. Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2015-4263
Abstract 427: Host and tumoral CXCR2 signaling contributes to tumor growth
Authors: Carroll Danielle , Harper James , McDaid Karen , Franks Ruth , Eberline Catherine , Kendrew Jane , Sainson Richard , Anderton Judith , Rossant Chris , Coffman Karen , Leow Ching Ching , Inigo Ivan , Reville Mitchell , Shenton Jacintha , Young Lesley , Barry Simon 
Published: August 2015

Abstract
Chemokines are essential mediators of leukocyte migration and inflammation. Additionally they play an important role in tumour growth. The G-protein coupled receptor, CXCR2, and its ligands (CXCL 1,2,3,5,6,7 and IL8) have been shown to promote tumour initiation and growth, chemo-resistance, angiogenesis and immune cell infiltration (neutrophil, myeloid derived suppressor cells (MDSCs) and macrophages) into the tumour microenvironment. However the contribution of host and tumour CXCR2 has not been elucidated.
We have developed both murine and human specific anti-CXCR2 antibodies alongside a humanised CXCR2 transgenic mouse to address the contribution of host and tumour CXCR2 signalling to tumour growth and maintenance. In pre-clinical tumours, granulocytic cells (neutrophils and MDSCs) within the tumour increase with size, in parallel with alteration in cell numbers observed within the spleen, peripheral blood and bone marrow.
Inhibition of host CXCR2 has a dramatic impact on peripheral neutrophil levels, as well as their ability to become activated.
In pre-clinical tumour models, inhibition of CXCR2 results in tumour growth inhibition. Contribution of host or tumour cells to the effect of CXCR2 blockade was model dependent. In the EL4 murine lymphoma model, only inhibition of host/peripheral CXCR2 was able to impact tumour growth. Whereas, in other murine syngeneic models (CT26 and B16), both host and tumour CXCR2 play a role in tumour growth. This was further demonstrated in an NSCLC patient derived xenograft, where the contribution of tumour CXCR2 was stronger than the host.
Collectively our data show that CXCR2 inhibition (alone or in combination) has potential to influence growth of a number of tumour types. Future work is focused on understanding the mechanisms underlying the effects of CXCR2 inhibition, which remain key to developing it as an effective anti-cancer therapeutic.
Citation Format: Danielle Carroll, James Harper, Karen McDaid, Ruth Franks, Catherine Eberline, Jane Kendrew, Richard Sainson, Judith Anderton, Chris Rossant, Karen Coffman, Ching Ching Leow, Ivan Inigo, Mitchell Reville, Jacintha Shenton, Lesley Young, Simon Barry. Host and tumoral CXCR2 signaling contributes to tumor growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 427. doi:10.1158/1538-7445.AM2015-427
Abstract 4283: Anticancer effects obtained against A20 lymphomas following treatment with LTX-315 (Oncopore®) in combination with low-dose cyclophosphamide
Authors: Camilio Ketil André , Eike Liv-Marie , Rekdal Øystein , Sveinbjornsson Baldur 
Published: August 2015

Abstract
Background: Host defense peptides (HDPs) are naturally occurring molecules found in most eukaryotic species, where they play a significant role in the first line of defense against pathogens. Several HDPs have been shown to possess anticancer activity. Structure-activity relationship studies on the HDP bovine lactoferricin has resulted in the design of LTX-315, a short chemically modified peptide that induces immunogenic dell death. Previous animal studies have demonstrated that intratumoral (i.t.) treatment of syngeneic murine A20 B-cell lymphomas, CT26WT colon carcinomas and B16F1 melanomas with LTX-315 resulted in complete tumor regression and tumor specific immune responses. In the present study, we investigated the antitumor effects of LTX-315 in combination with low-dose cyclophosphamide (CY) against A20 lymphomas. Methods: A20 lymphoma cells (5 × 106) were intradermally inoculated into the abdomen of syngeneic Balb/c mice. Established tumors were treated i.t. with LTX-315 in combination with low-dose CY. Results: Intratumoral (i.t.) administration of LTX-315 in a suboptimal setting resulted in a synergistic antitumor effect when combined with low-dose CY, compared to CY and LTX-315 alone. In the combination therapy group the treatment induced a complete regression of the tumor in the majority of the animals (6 out of 9 animals), compared to LTX-315 alone (1 out of 8 animals) and no regression in the two control groups (CY alone and vehicle). Conclusions: Our results demonstrate that treatment with LTX-315 in combination with low-dose CY results in a synergistic antitumor effect in vivo. Thus, local treatment with the immunogenic cell death inducer LTX-315 combined with systemic chemotherapy may represent a promising combination strategy in future cancer therapy.
Citation Format: Ketil André Camilio, Liv-Marie Eike, Øystein Rekdal, Baldur Sveinbjornsson. Anticancer effects obtained against A20 lymphomas following treatment with LTX-315 (Oncopore®) in combination with low-dose cyclophosphamide. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4283. doi:10.1158/1538-7445.AM2015-4283
Abstract 4285: Immunomodulatory activity of aza-podophyllotoxin derivatives
Authors: Kumar Ajay , Valentin Eric Miranda , Otero Miguel 
Published: August 2015

Abstract
Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. Due to structural complexity of podophyllotoxin, commercial synthesis, further derivative synthesis and structural modifications of podophyllotoxin are limited. We have developed some heterocyclic analogues of podophyllotoxin i.e. N-hydroxyethyl-4-aza-podophyllotoxin derivatives (AZPs). Advantage of these compounds is their easy and fast synthesis as compared to the parent natural lignin i.e. podophyllotoxin. Owing to their promising activity against 60 cell lines at NCI, we further expanded the library of AZPs substituted at ring A and E. This was followed by a screen of in vivo activity using a panel of tumor hollow-grafts implanted in mice consisting of breast (MDA-MB-231), non-small lung (NCI-H23 and NCI-H522), colon (SW-620 and COLO 205), melanoma (UACC-62, MDA-MB-435 and LOXIMVI), ovarian (OVCAR-5 and OVCAR-3) and CNS (U251 and SF-295) cell lines. These new compounds shows comparatively excellent activity against several human cancer cell lines at NCI. We recently reported activity of AZPs in MTA resistant Cancer Cells.
We are now reporting immunomodulatory effect of our AZPs for the first time, assessed by in-vitro stimulation of mouse lymphocytes for five days. Specifically, our preliminary data shows AP-102, AP-103, AP-104, and AP-205 to induce 2208, 2575, 2071, and 7166 pg/mL of G-CSF, respectively, and the AP-311, AP-312, AP-102, AP-103, AP-104, and AP-205 induced 551, 810, 772, 1125, 782, and 4351 pg/mL of IL-6, respectively. These data demonstrate the immunostimulatory ability of our AP compounds. Further experiments need to be performed to study the impact of these compounds in the modulation of the immune system.
Citation Format: Ajay Kumar, Eric Miranda Valentin, Miguel Otero. Immunomodulatory activity of aza-podophyllotoxin derivatives. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4285. doi:10.1158/1538-7445.AM2015-4285
Abstract 4287: Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity
Authors: Piasecki Julia , Rottman Jim , Le Tiep , Ponce Rafael , Beers Courtney 
Published: August 2015

Abstract
Talimogene laherparepvec is an investigational oncolytic immunotherapy based on a modified herpes simplex virus type-1 (HSV-1) immunotherapy designed to selectively replicate in tumors and to initiate an anti-tumor immune response. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors. Iterative replication of virus within permissive tumor tissue results in lytic cell destruction and local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally such that it can recruit and stimulate antigen presenting cells which, in addition to relevant tumor-derived antigens, are required for the initiation of a systemic antitumor immune response.
The talimogene laherparepvec-induced immune mediated mechanism of action in both the virus-injected and distant tumors have yet to be fully understood therefore, we evaluated viral replication, tumor cell lysis, and the changes in immune cell populations in both the injected and distant tumors using syngeneic contralateral tumor models. Animals received a single intratumoral dose of the murine surrogate of talimogene laherparepvec (OncoVEXmuGM-CSF), which induced regression in the majority of virus-injected tumors and tumor growth inhibition/regression in the contralateral (uninjected) tumors. HSV-1 antigen was only detected by IHC in the virus-injected tumor and not the contralateral tumor (and no other tissues). Virally-mediated tumor destruction (oncolysis) was also localized to only the virus-injected tumor. In preliminary experiments, morphometric analysis of the tumor tissue revealed that the percent area of CD3+ and CD8+ lymphocytes were significantly increased in both the virus-injected and contralateral tumors compared to the formulation control mice. In addition, the percent area occupied by CD103+ cells (a marker found on potent cytotoxic T cell stimulating dendritic cells) was increased in the virus-injected tumor compared to the contralateral tumor and the tumors in the control animals. Although cellular infiltration was increased in both virus-injected and contralateral tumors and was inversely correlated with tumor volume, the decreased volume of injected tumors was attributed to viral oncolysis. Taken together these data supports that talimogene laheparepvec activates a systemic T cell mediated anti-tumor immune response.
Citation Format: Julia Piasecki, Jim Rottman, Tiep Le, Rafael Ponce, Courtney Beers. Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4287. doi:10.1158/1538-7445.AM2015-4287