bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5938: In vivo targeting of laminin-411-β1 integrin-Notch signaling pathway using nanobioconjugate alters glioma microenvironment for effective treatment
Authors: Ljubimova Julia Y. 
Published: July 2017

Abstract
Introduction: Brain gliomas have been extensively characterized by genomic and molecular marker analysis. These studies have underscored glioblastoma multiforme (GBM) heterogeneity, which may underlie failure of even the newest drugs to improve patient survival. For this reason, we turned to genetic modulation of glioma microenvironment using a novel nanobioconjugate.
Methods/Results: Clinical material from 107 GBM patients was analyzed, and tumors with overexpression of “malignant” tumor vascular basement membrane laminin-411 were found to have higher recurrence rate and shorter patient survival. In 92% of human GBM samples, overexpression of laminin-411 was associated with high expression of cancer stem cell (CSC) markers. To examine the interaction mechanisms between GBM cells and their extracellular matrix microenvironment, blood-brain barrier (BBB) passing nanobioconjugates based on poly(β-L-malic acid) (PMLA) were synthesized that specifically inhibit α4 and β1 chains of trimeric laminin-411. In vitro. Normal brain endothelial cells and astrocytes had higher expression of β1 integrin, Notch-1, and Notch ligands when seeded on “malignant” laminin-411 as compared with “normal” laminin-421. All these markers were downregulated in two GBM cell lines treated with antisense oligonucleotides against laminin α4 and β1 chains, suggesting regulation of Notch pathway by laminin-411 through integrin β1. In vivo. In GBM xenograft mouse models increased expression of laminin-411 correlated with overexpression of integrin β1 and Notch signaling pathway members. In two mouse models with intracranial human LN229 and U87MG GBMs, treatment with PMLA-based nanobioconjugate against tumor microenvironment protein laminin-411 led to significantly increased animal survival, associated with marked suppression of laminin-411- β1 integrin-Dll4-Notch axis and CSC markers CD133, Nestin, and c-Myc.
Conclusion: BBB crossing and brain tumor-targeted nanodrug therapy using laminin-411 suppression provided a unique tool to study mechanistic interactions between tumor microenvironment and signaling pathways, and showed promise for efficient GBM treatment affecting both the bulk of tumor cells and CSC.
Support: NIH grants U01 CA151815, R01 CA136841, R01 CA188743, R01 CA209921
Citation Format: Julia Y. Ljubimova. In vivo targeting of laminin-411-β1 integrin-Notch signaling pathway using nanobioconjugate alters glioma microenvironment for effective treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5938. doi:10.1158/1538-7445.AM2017-5938
Abstract 5939: Dissemination of breast cancer
Authors: Kakkad Samata , Hanna Mikayla , Jacob Desmond , Krishnamachary Balaji , Bhujwalla Zaver M. 
Published: July 2017

Abstract
Breast cancer is the second leading cause of death in US women. Despite advances in early detection, diagnosis and treatment of breast cancer, metastasis and tumor recurrence persist leading to continued morbidity and mortality. Several breast cancer studies have highlighted the role of cyclooxygenase-2 (COX-2) and its interaction with the tumor microenvironment (TME) in breast cancer progression. The TME consists of stromal cells that include fibroblasts, macrophages, the extracellular matrix (ECM), and several secreted factors that contribute to aggressiveness of the cancer and resistance to therapy. Increased density of collagen 1 (Col1) fibers, a major structural component of the ECM in solid tumors, and their alignment in tumors frequently result in increased invasion and metastasis of cancer cells. To understand the role of COX-2 at the lung metastatic site, and its relationship with Col1 fibers, COX-2 overexpressing triple negative SUM-149 human breast cancer cells (SUM-149-COX-2) or empty vector SUM-149 cells (EV) were injected through tail vein in SCID mice to compare Col1 fiber patterns in metastatic lesions. We isolated the lungs, processed the tissue, and imaged for Col1 fiber by second harmonic generation microscopy on H&E stained sections. The number of cancer associated fibroblasts (CAFs) were detected in adjacent sections by immunostaining for α-SMA. COX-2 overexpression did not increase the size of the cancer cell emboli in blood vessels or the size of pulmonary metastasis formed in the lungs. However, COX-2 overexpression did significantly increase the number of pulmonary metastases. Significantly higher Col1 fiber volume was observed in emboli compared to pulmonary metastases independent of COX-2 overexpression. Interestingly, the Col1 fibers were significantly more aligned in the COX-2 overexpressing pulmonary metastases compared to COX-2 overexpressing and EV emboli. The COX-2 overexpressing emboli had significantly higher amounts of CAFs detected by α-SMA expression compared to the EV emboli and the EV and COX-2 overexpressing pulmonary metastases. Pulmonary metastases from COX-2 overexpressing cells were detected further away from the nearest blood vessel compared to the metastases from EV cells suggesting that COX-2 may facilitate the formation of distant metastases. These data provide new insights into the role of COX-2, Col1 fibers, and CAFs in enabling emboli to extravasate to form pulmonary metastatic foci. These insights are important as COX-2 upregulation during treatment may potentiate metastasis. This work was supported by NIH R01 CA82337.
Citation Format: Samata Kakkad, Mikayla Hanna, Desmond Jacob, Balaji Krishnamachary, Zaver M. Bhujwalla. Dissemination of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5939. doi:10.1158/1538-7445.AM2017-5939
Abstract 6: New chk1 inhibitor development & the feasibility of use of chk1 inhibitor with antimetabolite for NSCLC
Authors: Chung Injae 
Published: July 2017

Abstract
DNA damaging anticancer agents activate checkpoints that stop the cell cycle to prevent additional DNA replication & mitosis until damaged region has been repaired. One of the important regulatory proteins activated in DNA damage response pathway is Checkpoint kinase 1 (Chk1). Therefore, Chk1 inhibitors have emerged as promising new therapeutics for cancer. In order to find novel Chk1 inhibitor, we have conducted a structure based virtual screening. Several small molecules have shown 75 - 100 % inhibition of Chk1 in the binding affinity assay. Combined with the results of kinase assay with ATP & mechanism based cell assay, hit candidates has been led. Lung cancer is the leading cause of cancer related deaths in Korea. About 85 % of lung cancer is non-small cell lung carcinoma (NSCLC) worldwide. Chemotherapy for NSCLC is often regarded ineffective. To test the feasibility of Chk1 inhibitor to sensitize antimetabolite in NSCLC, growth inhibition induced by gemcitabine plus MK8776 was assessed in A549 & H1129 cells. These cells are insensitive to the MK8776 when treated as a single agent (IC50 &gt;10 μM). In contrast, MK8776 reduced the concentration of gemcitabine required to inhibit H1299 or A540 cell growth by almost 3-30 fold or 6-15 fold, respectively, depending on the concentration used. These results would imply the potential clinical utility of Chk1 inhibitor as an adjuvant for antimetabolite such as gemcitabine for NSCLC. Further studies to evaluate the effectiveness of Chk1 inhibitor including new molecules would be warranted in additional preclinical and clinical settings. [The chemical library used in this study was kindly provided by Korea Chemical Bank & KIST. This study was supported by a grant (2015R1D1A1A01057014) from the National Research Foundation of Korea.]
Citation Format: Injae Chung. New chk1 inhibitor development & the feasibility of use of chk1 inhibitor with antimetabolite for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 6. doi:10.1158/1538-7445.AM2017-6
Abstract 60: Reducing toxicity of antibody-drug conjugates through modulation of pharmacokinetics
Authors: Simmons Jessica , Zapata Francisco , Neff-Laford Haley , Hunter Joshua , Cochran Julia , Burke Patrick , Lyon Robert P. 
Published: July 2017

Abstract
Antibody-drug conjugates (ADCs) continue to emerge as effective therapeutics in a variety of oncology indications. Research on ADCs has revealed that the physicochemical properties of the drug-linker component can exert a significant impact on the disposition of the ADCs, particularly at higher levels of drug loading. We have recently reported (Nature Biotechnology 33, 733-735 (2015); Molecular Cancer Therapeutics, manuscript accepted) that these properties can be modulated through the judicious incorporation of small, discrete PEG chains of varying lengths into a monomethyl auristatin E (MMAE) drug-linker. Homogeneous DAR 8 ADCs prepared with these drug-linkers using native cysteine conjugation display a continuum of pharmacokinetic behaviors that mirror the length of the incorporated PEG chain. We selected four of these drug-linkers that span the range of observed pharmacokinetics and used them as model compounds to evaluate the impact of ADC clearance on the concentration profile of released MMAE in normal tissues and consequent toxicology in the Sprague-Dawley rat. Faster clearing ADCs (prepared with drug-linkers containing very short or no PEG modifier) produced higher tissue MMAE Cmax values at early post-dose time points relative to slower clearing ADCs that incorporate longer PEG chains. This finding indicates that MMAE concentrations in tissues are proportional to the rate at which the ADC is catabolized, a process which converts the conjugated payload into free drug. Faster clearing ADCs also exhibited diminished tolerability, with greater histologic depletion of bone marrow and more dramatic decreases and/or delayed recovery in select peripheral hematology parameters. These results provide a strategy for reducing the non-antigen-mediated toxicity of ADCs through modulation of pharmacokinetics.
Citation Format: Jessica Simmons, Francisco Zapata, Haley Neff-Laford, Joshua Hunter, Julia Cochran, Patrick Burke, Robert P. Lyon. Reducing toxicity of antibody-drug conjugates through modulation of pharmacokinetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 60. doi:10.1158/1538-7445.AM2017-60
Abstract 603: Evaluation of CD19 targeted T cells in relapsed or refractory ALL patients unable to afford allogenic bone marrow transplant in India
Authors: Dwivedi Alka , Kumar Sushant , Fry Terry , Narula Gaurav , Purwar Rahul 
Published: July 2017

Abstract
CAR-T cell therapy has demonstrated remarkable success in long-term remission of relapsed or refractory B-ALL. Unlike western countries, most of the relapsed/refractory B-ALL patients in India are unable to afford allogeneic stem cell transplant (allo-SCT), and simply choose palliation. To assess the potential use of CAR-T cells as a first line therapy, it is critical to evaluate CAR-T cell efficacy in patients unable to undergo allo-SCT. As a first step, a novel anti-CD19 CAR was designed and CD19-vector was produced using lentiviral mediated gene delivery system. To generate CD19+CAR T cells, T cells from healthy subjects were transduced and expanded either with rIL-2 or rIL-15. Almost 20-50% transduced T cells express CD19-CAR on their surface as analysed by flow cytometry. Next, efficacy of CD19-CAR-T cells was examined by cytotoxicity assay using CD19+ malignant B cell lines (Raji cells) and autologous B cells. CAR-T cells were able to kill majority of CD19+B cells effectively (100% killing). In addition, CAR-T cells secreted high levels of IFNΓ and IL-2. The CAR-T cells expanded in presence of rIL-15 showed fewer Treg compared to CAR-T cells expanded using rIL-2, however, there were no differences in numbers of T stem cells (TSC) and central memory T cells (TCM). In addition to data on healthy volunteers reflected above, results of above tests in relapsed/ refractory B-ALL patients is ongoing and being collated for inclusion in the final analysis. In conclusion, our data demonstrate the successful development of an indigenous CAR-T cell platform for subsequent use in clinical trials of CD19+B cell malignancies.
Citation Format: Alka Dwivedi, Sushant Kumar, Terry Fry, Gaurav Narula, Rahul Purwar. Evaluation of CD19 targeted T cells in relapsed or refractory ALL patients unable to afford allogenic bone marrow transplant in India [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 603. doi:10.1158/1538-7445.AM2017-603
Abstract 611: Reversion of mesenchymal features in NSCLC cells using M7824, a first-in-class bi-functional immunotherapeutic agent targeting PD-L1 and TGFβ1 (TGFβ TRAP)
Authors: David Justin M. , Schlom Jeffrey , Lan Yan , Palena Claudia 
Published: July 2017

Abstract
Background: Evasion of antitumor immunity is widely regarded as a hallmark of cancer. Tumor cells can avoid immune destruction by upregulating the immune checkpoint molecule PD-L1, and antibodies targeting the PD-1/PD-L1 axis have demonstrated clinical efficacy in several tumor types. Antitumor immunity can also be suppressed by TGFβ, a pleiotropic cytokine that reduces innate and adaptive antitumor immune responses. Additionally, TGFβ impacts tumor cells by activating a differentiation program called epithelial-mesenchymal transition (EMT), in which tumor cells lose epithelial features and gain mesenchymal characteristics. The gain of mesenchymal traits is associated with metastasis, stemness, and resistance to multiple therapeutic modalities, including chemotherapy and radiation. The objective of this work is to investigate the therapeutic potential of M7824 in non-small cell lung cancer (NSCLC). M7824 is a first-in-class bi-functional immunotherapeutic agent designed to target two negative regulatory pathways in immunosuppression. It is a novel fusion protein comprised of the extracellular domain of human TGFβRII covalently linked to the C-terminus of the Fc domain of the fully human anti-PD-L1 IgG1 antibody avelumab.
Methodology: In vitro assays were conducted using NSCLC cell lines treated with TGFβ1 alone or in combination with avelumab or M7824 to assess the ability of M7824 to revert features of tumor cell EMT, including molecular marker expression, cell proliferation, and response to various chemotherapies. The ability of M7824 to mediate antibody-directed cellular cytotoxicity (ADCC) of TGFβ1-treated cells in vitro was also assessed.
Results: Treatment with TGFβ1 induced mesenchymal marker expression, reduced cell proliferation, and enhanced resistance to docetaxel, paclitaxel, and gemcitabine. Treatment with M7824, but not avelumab, was able to both prevent and revert these effects of TGFβ1. M7824 also exhibited the ability to mediate ADCC of TGFβ1-treated cells in vitro.
Conclusions: M7824 effectively antagonizes TGFβ1-mediated tumor cell mesenchymalization, including resistance to chemotherapy. These results suggest that M7824 has the potential to relieve immunosuppression and block treatment-resistance induced by TGFβ1 in patients with NSCLC.
Citation Format: Justin M. David, Jeffrey Schlom, Yan Lan, Claudia Palena. Reversion of mesenchymal features in NSCLC cells using M7824, a first-in-class bi-functional immunotherapeutic agent targeting PD-L1 and TGF&#9461 (TGFβ&#946 TRAP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 611. doi:10.1158/1538-7445.AM2017-611
Abstract 618: Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells
Authors: Li Peng , Du Xin , Xin Yun , Weng Jianyu , Lai Peilong 
Published: July 2017

Abstract
Chimeric antigen receptor (CAR) T cell immunotherapies have shown unprecedented success in treating leukemia but lack efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor (TIR) domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed enhanced effector function, expansion and persistency against CD19+ leukemic or mesothelin+ lung cancer cells in vitro and in vivo. In a patient with relapsed B cell acute lymphoblastic leukemia, a single dose of 5×104/kg 1928zT2 T cells resulted in robust expansion and leukemia eradication and led to complete remission. Hence, our results demonstrate that TLR2 signaling is a contributing component to CAR T cells for both leukemia and solid tumors and is capable of increasing the efficacy of CAR T cells and facilitating low dose clinical usage.
Citation Format: Peng Li, Xin Du, Yun Xin, Jianyu Weng, Peilong Lai. Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 618. doi:10.1158/1538-7445.AM2017-618
Abstract 636: Comprehensive analysis of T cells responsive to neoantigens derived from tumor-specific genetic mutations
Authors: Sasada Tetsuro , Ohtake Junya , Wada Satoshi , Yada Erika , Yoshida Shintaro 
Published: July 2017

Abstract
Neoantigens derived from tumor-specific genetic mutations can be recognized as foreign by the host immune system, and might be suitable as target for cancer immunotherapy possibly due to their higher immunogenicity. In this study, to really know the immunogenicity of tumor-specific neoantigens, we comprehensively investigated T cell responses against neoantigens derived from genetic mutations in gastric cancer. Using next-generation sequencing, 156 missense mutations were identified in tumor cells from two gastric cancer patients. From them, we selected 30 potentially immunogenic amino acid sequences, which were derived from the mutations and predicted to potentially bind to HLA-class I (A*0201, A*0206, or A*2402) by an epitope prediction server, IEBD. We synthesized 30 kinds of 27mer long peptides, in which the mutated sequences were located in the center, and then cultured peripheral blood mononuclear cells (PBMC) from healthy donors in the presence of the synthetic peptides to evaluate whether they could really induce antigen-specific T cell responses. In the analysis with PBMC from 18 healthy donors, 27/30 (90%) synthetic peptides showed an ability to induce antigen-specific T cell responses in at least one donor, assessed by cytokine production assay. Among them, 15 peptides were immunogenic in more than one donor. The antigen-specific T cell responses were detected more frequently in CD4+ T cells (70%) than in CD8+ T cells (43%). The specificity of T cell responses to mutated sequences, but not to the corresponding wild type sequences, were confirmed in 5 of 8 (63%) peptides examined. In addition, antigen-specific T cell responses induced by mutated peptides were shown to be much higher than those induced by the corresponding wild type peptides. These findings clearly demonstrated high immunogenicity and specificity of neoantigens derived from tumor-specific genetic mutations. Further studies would be recommended to develop a novel immunotherapeutic approach, “personalized cancer vaccination”, targeting mutation-derived neoantigens.
Citation Format: Tetsuro Sasada, Junya Ohtake, Satoshi Wada, Erika Yada, Shintaro Yoshida. Comprehensive analysis of T cells responsive to neoantigens derived from tumor-specific genetic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 636. doi:10.1158/1538-7445.AM2017-636
Abstract 642: Detection of circulating antibodies against KRAS in patients with advanced cancers
Authors: Kheder Ed , Huang Helen J. , Wu Alice , Hong David S. , Piha-Paul Sarina A. , Karp Daniel D. , Fu Siqing , Subbiah Vivek , Tsimberidou Apostolia M. , Naing Aung , Diab Adi , Javle Milind , Kopetz Scott , Sood Anil K. , Kurie Jonathan M. , Meric-Bernstam Funda , Gleeson Martin , Janku Filip 
Published: July 2017

Abstract
Introduction: KRAS gene plays a major role in tumorigenesis, cell proliferation and survival. Yet, there has been no effective targeted therapy against KRAS mutation-mediated tumors. We hypothesized that KRAS can induce humoral-mediated immune response.
Methods: Plasma or serum samples from patients with progressing advanced cancers with or without KRAS mutations were tested for the presence of circulating KRAS antibodies. We used the Maverick Detection System (Genalyte, San Diego, CA), which can perform real-time detection of macromolecules in crude samples using biologically functionalized silicon photonic biosensors lithographically printed on disposable silicon chips.
Results: We collected serum or plasma samples from 213 patients with advanced cancers (KRAS-mutant, N=100; KRAS wild-type, N=113) and 50 (23%) were found to have circulating KRAS antibodies. There was no association between KRAS antibodies and tumor KRAS mutation status (21/100, 21% for KRAS-mutant vs. 29/113, 26% for KRAS wild-type; P=0.52). In addition, there was no difference in detection of KRAS antibodies in colorectal cancer (21/89, 24%) compared to other cancers (29/124, 23%; P=1.00). There was no difference in the median survival in patients with KRAS antibodies compared to patients without KRAS antibodies (9.0 months vs. 10.1 months; P= 0.825). Similarly, there was no difference in the median survival according to the presence of circulating KRAS antibodies in subgroups of patients with tumor KRAS mutations (P= 0.96) and without tumor KRAS mutations (P=0.63). On the contrary, the median survival of patients with tumor KRAS mutation was shorter compared to patients with KRAS wild-type (7.2 months vs. 11.5 months; P&lt;0.001).
Conclusion: Circulating KRAS antibodies can be detected in 23% of patients with advanced cancers. Biological implications of circulating KRAS antibodies remain to be understood.
Citation Format: Ed Kheder, Helen J. Huang, Alice Wu, David S. Hong, Sarina A. Piha-Paul, Daniel D. Karp, Siqing Fu, Vivek Subbiah, Apostolia M. Tsimberidou, Aung Naing, Adi Diab, Milind Javle, Scott Kopetz, Anil K. Sood, Jonathan M. Kurie, Funda Meric-Bernstam, Martin Gleeson, Filip Janku. Detection of circulating antibodies against KRAS in patients with advanced cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 642. doi:10.1158/1538-7445.AM2017-642