bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 233: Therapeutic efficacy of cancer stem cell-based vaccine in an adjuvant setting.
Authors: Lu Lin , Tao Huimin , Egenti Martin , Wicha Max S. , Chang Alfred E. , Li Qiao 
Published: August 2014

Abstract
So far, the majority of cancer stem cell (CSC) studies have been confined to human tumors inoculated into severely immunosuppressed hosts (e.g. SCID mice), where adaptive immune responses are absent, and such hosts are therefore not suitable for the immunologic evaluation of CSCs. The lack of immunocompetent syngeneic animal tumor models where stem cells can be isolated has been the primary obstacle to evaluating the immunogenicity of CSCs. We recently reported the identification of CSC-enriched populations using ALDEFLUOR/ALDH as a marker in murine melanoma D5 and squamous cell cancer SCC7, and evaluated their immunogenicity in two genetically distinct syngeneic immunocompetent hosts. Enriched CSCs are immunogenic and significantly more effective as an antigen source in inducing protective anti-tumor immunity than unsorted tumor cells or purified non-CSCs. We further found that selective targeting of CSCs by CSC-primed antibodies and T cells represents the mechanisms involved in CSC vaccine-conferred protective immunity. If a CSC vaccine is to be clinically relevant, it needs to be evaluated in a therapeutic model. In this study, we examined two models for this purpose. The first model involves the treatment of micrometastatic disease. We initiated vaccination 24 hrs after s.c. inoculation of D5 tumor cells in the syngeneic immunocompetent host (B6 mice), and repeated the vaccination one week later. Comparison was made among the group with PBS-injected controls; mice vaccinated with dendritic cells (DC) pulsed with the lysate of ALDHhigh D5 cells (CSC-TPDC) vs. ALDHlow D5 cells (ALDHlow -TPDC). We found that CSC-TPDC inhibited the tumor growth more than ALDHlow-TPDC and PBS controls, and significantly prolonged the survival of the tumor-bearing mice. The second model involves the treatment of established tumors using CSC-TPDC vaccine as an additional strategy to radiation therapy (RT). Day 7 D5 sc tumors were treated with localized RT with repeat treatments on D8. Vaccine therapy commenced on D8. This combination therapy was repeated twice with one week apart. CSC-TPDC plus RT mediated D5 tumor regression more than ALDHlow-TPDC + RT, RT alone and PBS controls, and prolonged the survival of the tumor-bearing mice. Importantly, we observed metastasis of the D5 tumors to the lung in all the groups except for the one treated with CSC-TPDC plus RT. The findings may help develop novel approaches for cancer treatment by utilizing an autologous cancer stem cell-based vaccine to selectively and immunologically target cancer stem cells.
Citation Format: Lin Lu, Huimin Tao, Martin Egenti, Max S. Wicha, Alfred E. Chang, Qiao Li. Therapeutic efficacy of cancer stem cell-based vaccine in an adjuvant setting. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 233. doi:10.1158/1538-7445.AM2013-233
Abstract 2332: Oncogenic MYD88 mutants require Toll-like receptors.
Authors: Lim Kian-Huat , Barton Gregory M. , Staudt Louis M. 
Published: August 2014

Abstract
Oncogenic mutations affecting the signaling adapter MyD88 are present in 39% of activated B-cell-like (ABC) diffuse large B cell lymphomas (DLBCLs), with the most recurrent MyD88 mutant, L265P, present in 29% of cases. MYD88 mutations constitutively activate multiple signaling cascades that promote the survival and proliferation of ABC DLBCLs, including the NF-B, type-1 interferon, p38 and JAK/STAT pathways. It is unknown whether MyD88 mutants act autonomously or require a receptor to engage these downstream pathways. Here we show that the MyD88 L265P oncoprotein binds constitutively to two members of the Toll-like receptor family, TLR7 and TLR9, thereby amplifying signals that emanate from these receptors. Knockdown of TLR7 or TLR9 potently suppressed NF-B activity in ABC DLBCL cell lines and promoted apoptosis. Depletion of known proteins essential for TLR7 and TLR9 trafficking and signaling, including UNC93B1, PRAT4A or CD14, was lethal for ABC DLBCL lines. Similarly, pharmacologic inhibition of TLR7 and TLR9 function in lysosomal compartments using the cathepsin inhibitor zFA-fmk or hydroxychloroquine diminished MyD88 signaling and reduced survival of ABC DLBCL lines. TLR7 or TLR9 mutants that are defective in ligand binding failed to promote the survival of ABC DLBCL lines following knockdown of endogenous TLR7 or TLR9 expression in ABC DLBCL lines. Moreover, an inhibitory oligonucleotide capable of suppressing TLR9 responses in normal B cells blocked NF-B signaling and survival of ABC DLBCL lines. These new insights into the oncogenic mechanisms of MyD88 mutants provide a rationale for targeting of TLR7 and TLR9 signaling for the therapy of ABC DLBCL.
Citation Format: Kian-Huat Lim, Gregory M. Barton, Louis M. Staudt. Oncogenic MYD88 mutants require Toll-like receptors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2332. doi:10.1158/1538-7445.AM2013-2332
Abstract 2340: Preferential targeting of KRAS mutant or BRAF mutant tumors using MEK inhibitors with distinct mechanisms of action.
Authors: Hatzivassiliou Georgia , Haling Jacob , Chen Huifen , Song Kyung , Luoh Shiuh-Ming , Price Steve , Heald Robert , Zak Mark , Merchant Mark , Hoeflich Klaus , Friedman Lori , Malek Shiva , Belvin Marcia P. 
Published: August 2014

Abstract
KRAS and BRAF mutant cancers represent an area of high unmet medical need in oncology. Multiple allosteric MEK inhibitors are being tested in clinical trials in BRAF mutant and KRAS mutant cancers, where to date they have demonstrated impressive single agent activity in BRAF mutant melanoma, but not in KRAS mutant disease. Active, phosphorylated MEK is elevated in BRAFV600E mutant melanoma tumor models compared to KRAS mutant tumor models, in line with evidence that MAPK pathway regulation differs depending on the upstream oncogenic lesion. However, the precise differences in MEK activation by mutant KRAS or BRAF and how to create MEK inhibitors to block that activation are not known. In this study we describe two clinical, allosteric MEK inhibitors, GDC-0973 and GDC-0623, that have complementary efficacy profiles, with one showing superior efficacy in BRAF mutant models and the other showing superior efficacy in KRAS mutant models. Using structural information and targeted mutagenesis, we demonstrate that although both inhibitors effectively block MEK kinase activity and downstream ERK activation, their unique binding modes result in differential effects on active versus inactive MEK and MEK interaction with RAF that translates into unique efficacy profiles in BRAFV600E versus KRAS mutant tumors. GDC-0973 has already shown promising efficacy as a single agent in BRAFV600E mutant melanoma, and both inhibitors are currently being tested in KRAS mutant tumors in the clinic. Our study highlights that subtle differences in the binding mode of kinase inhibitors can have a large impact on inhibitor/target interactions and efficacy through allosteric mechanisms. These differences may impact the therapeutic index of MEK inhibitors in either BRAF mutant or KRAS mutant cancers.
Citation Format: Georgia Hatzivassiliou, Jacob Haling, Huifen Chen, Kyung Song, Shiuh-Ming Luoh, Steve Price, Robert Heald, Mark Zak, Mark Merchant, Klaus Hoeflich, Lori Friedman, Shiva Malek, Marcia P. Belvin. Preferential targeting of KRAS mutant or BRAF mutant tumors using MEK inhibitors with distinct mechanisms of action. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2340. doi:10.1158/1538-7445.AM2013-2340
Abstract 2345: Combined inhibition of protein kinase C and MEK is a rational therapeutic approach for melanomas with GNAQ or GNA11 mutations.
Authors: Chen Xu , Wu Qiuxia , Bastian Boris C. 
Published: August 2014

Abstract
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults. There currently is no effective treatment for metastatic UM. UM differs from cutaneous melanoma in that it lacks BRAF, NRAS, or KIT mutations but instead harbors mutations in the Gαq family members GNAQ and GNA11 in over 80 to 90% of cases. Understanding the downstream effector pathways of these oncoproteins is of considerable interest to identify opportunities for targeted therapy. Using 293T cells, immortalized mouse and human melanocytes, we find that GNAQQ209L or GNA11Q209L induce activation of the protein kinase C (PKC) and MAPK pathways. ShRNA mediated knock-down of mutant GNAQ abrogates both PKC and MAPK activation in human melanoma cell lines or model systems. Using two different PKC inhibitors we found selective extinction of PKC and MAPK signalling and induction of G1 arrest in panels of melanoma cell lines carrying GNAQ or GNA11 mutations, whereas no such effect was observed in melanoma cell lines with other mutations. MAPK activation occurred downstream of activated PKC in cells with GNAQ or GNA11 mutations. In contrast to PKC inhibitors, which selectively inhibited the growth of melanoma cell lines with GNAQ or GNA11 mutations, the MEK inhibitor PD0325901 inhibited melanoma cell lines irrespective of their GNAQ/11 mutation status. In vivo the PKC inhibitor AEB071 slowed the growth of tumors in an allograft model of GNAQQ209L transduced melanocytes, but did not induce tumor shrinkage. Analysis of tumor lysates identified suppression of PKC signaling but not of MAP-kinase pathway signaling under chronic PKC inhibition. The rebound of MAP-kinase activation could be overcome using a combination of AEB071 with the MEK inhibitor PD0325901, which showed strong synergy in halting proliferation and in inducing apoptosis. Our data suggest that PKC is a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and indicate that a combination therapy with MEK inhibitor is superior to treatment with either approach alone.
Citation Format: Xu Chen, Qiuxia Wu, Boris C. Bastian. Combined inhibition of protein kinase C and MEK is a rational therapeutic approach for melanomas with GNAQ or GNA11 mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2345. doi:10.1158/1538-7445.AM2013-2345
Abstract 2350: Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design.
Authors: Lee Taekyu , Friberg Anders , Vigil Dominico , Zhao Bin , Daniels R. Nathan , Burke Jason P. , Garcia-Barrantes Pedro M. , Camper DeMarco , Chauder Brian A. , Olejniczak Edward T. , Fesik Stephen W. 
Published: August 2014

Abstract
Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Overexpression of Mcl-1 is also a resistance mechanism that prevents tumor cells from being effectively treated by existing chemotherapies. Thus, inhibition of Mcl-1 is a promising therapeutic strategy for the treatment of cancer. However, Mcl-1 exerts its effects through protein-protein interactions and is thought to be very challenging to target with small molecules. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. From an NMR-based screen of a large fragment library, over 130 hits were identified. Two distinct chemical hit series were found that bind to two different sites on Mcl-1 as revealed by NMR-derived model structures. Members of the two fragment classes were merged together to produce compounds that bind to Mcl-1 with greater than two orders of magnitude improved binding affinity. Structures of these compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition involved in small-molecule binding to Mcl-1. Lead compounds exhibited a dissociation constant of &lt;100 nM, with selectivity for Mcl-1 over Bcl-xL and Bcl-2. These compounds represent useful starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.
Citation Format: Taekyu Lee, Anders Friberg, Dominico Vigil, Bin Zhao, R. Nathan Daniels, Jason P. Burke, Pedro M. Garcia-Barrantes, DeMarco Camper, Brian A. Chauder, Edward T. Olejniczak, Stephen W. Fesik. Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2350. doi:10.1158/1538-7445.AM2013-2350
Abstract 2355: Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer .
Authors: Song Ji Woong , Jeon Hyo-Sung , Lee Eung Bae , Lee Shin Yup , Park Jae Yong 
Published: August 2014

Abstract
Telomere shortening leads to genomic instability that drives oncogenesis through the activation of telomerase and the generation of other mutations necessary for tumor progression. This study was conducted to determine the impact of telomere shortening on the survival of patients with early stage non-small cell lung cancer (NSCLC).
Relative telomere length in tumor tissues was measured by quantitative polymerase chain reaction in 164 patients with surgically-resected NSCLC. The association between telomere length and overall survival (OS) and disease-free survival (DFS) was analyzed.
When the patients were categorized into quartiles based on telomere length, those patients with the 1st quartile (shortest) of telomere length had a significantly worse OS and DFS compared to patients with the 2nd to the 4th quartiles of telomere length (adjusted hazard ratio for OS =
2.67, 95% confidence interval = 1.50-4.75, P = 0.001; and adjusted hazard ratio for
DFS = 1.92, 95% confidence interval = 1.17-3.14, P = 0.01). An association between telomere length and survival outcome was more pronounced in squamous cell carcinomas than adenocarcinomas (P-value of test for homogeneity for OS and DFS = 0.05 and 0.02, respectively).
Telomere length of tumor tissues is an independent prognostic factor in patients with surgically resected early stage NSCLC.
Citation Format: Ji Woong Song, Hyo-Sung Jeon, Eung Bae Lee, Shin Yup Lee, Jae Yong Park. Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2355. doi:10.1158/1538-7445.AM2013-2355
Abstract 2359: Characterization of a lung cancer growth factor, LASEP3, as a serological and prognostic biomarker and a therapeutic target.
Authors: Takano Atsushi , Nakamura Yusuke , Daigo Yataro 
Published: August 2014

Abstract
To identify novel biomarkers or therapeutic targets for lung cancers, we have been screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers, using cDNA microarrays. During this process, we identified a secreted protein, LASEP3 (lung cancer-associated serum protein 3) as a candidate.
Immunohistochemical analysis showed that strong positive staining of LASEP3 was observed in 198 (54.8%) of 361 NSCLCs (non-small cell lung cancer).
High level of LASEP3 expression was associated with poor prognosis of NSCLC patients. (P=0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs, while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Moreover serum LASEP3 levels were significantly higher in breast and colon cancer patients than in healthy volunteers.
A combined assay using both LASEP3 and CEA increased sensitivity because 79.5% of the NSCLC patients were then diagnosed as positive, whereas only 7.3% of 109 healthy volunteers were falsely diagnosed as positive. In addition, the use of both LASEP3 and proGRP increased sensitivity because 78.3% of the lung SCLC patients were diagnosed as positive, whereas only 6.6% of 121 healthy volunteers were falsely diagnosed. LASEP3 protein was overexpressed in breast, cervical and colon cancer tissues. Furthermore, treatment of lung cancer cells with
LASEP3-siRNAs suppressed its expression and suppressed cell growth and invasion.
To clarify the mechanism of tumor suppression by siRNAs against LASEP3, we performed flow cytometric analysis of the tumor cells transfected with these siRNAs. We found a significant increase of the cells at the G0/G1 phase. These data suggest that LASEP3 is a diagnostic and prognostic biomarker and therapeutic target for lung and various type of human cancer.
Citation Format: Atsushi Takano, Yusuke Nakamura, Yataro Daigo. Characterization of a lung cancer growth factor, LASEP3, as a serological and prognostic biomarker and a therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2359. doi:10.1158/1538-7445.AM2013-2359
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2364: Long non-coding RNA HOTAIR is expressed in small cell lung cancer and relevant to cellular proliferation, invasiveness and clinical relapse - analyses based on tumor tissues and cell lines.
Authors: Ono Hiroshi , Miyauchi Eisaku , Motoi Noriko , Ushijima Masaru , Matsuura Masaaki , Okumura Sakae , Nishio Makoto , Hirose Tetsuro , Itou Satoru , Fujiwara Mutsunori , Inase Naohiko , Ishikawa Yuichi 
Published: August 2014

Abstract
Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis, showing early relapse after initial fair response to chemotherapy. A long non-coding RNA, Hox transcript antisense intergenic RNA (HOTAIR) has been reported to be involved in breast and colon cancer metastasis. Here we revealed, using 35 surgical SCLC cases, that HOTAIR was expressed highly in pure, rather than combined, SCLC (p=0.012) and that a subset of SCLC with its higher expression tended to relapse earlier (p=0.086). Also, knock down of HOTAIR by siRNA transfection in an SCLC cell line, SBC-3, led to the reduced proliferation activity and invasiveness, due to changes of expression of cell adhesion-related genes. These findings suggest that the HOTAIR expression changes gene expression in relation to cell adhesion and subsequently alters proliferation activity and invasiveness of tumor cells, resulting in early relapse of SCLC. Our results imply that HOTAIR could be a prognostic biomarker and a therapeutic target of SCLC.
Citation Format: Hiroshi Ono, Eisaku Miyauchi, Noriko Motoi, Masaru Ushijima, Masaaki Matsuura, Sakae Okumura, Makoto Nishio, Tetsuro Hirose, Satoru Itou, Mutsunori Fujiwara, Naohiko Inase, Yuichi Ishikawa. Long non-coding RNA HOTAIR is expressed in small cell lung cancer and relevant to cellular proliferation, invasiveness and clinical relapse - analyses based on tumor tissues and cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2364. doi:10.1158/1538-7445.AM2013-2364
Abstract 2369: Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung.
Authors: Jung Minkyu , Lee Chul Ho , Park Hyung Soon , Lee Ji Hyun , Kim Dae Joon , Lim Sun Min , Kim Joo Hang , Cho Byoung Chul 
Published: August 2014

Abstract
Purpose: The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed. Materials and Methods: We assessed polymorphisms at 8 sites in 4 genes (thymidylate synthase (TS), dihydrofolate reductase (DHFR) [1610, 680, 317, intron 1], methylenetetrahydrofolate reductase (MTHFR) [677, 1298], glycinamide ribonucleotide formyl transferase (GARFT) [2255]) associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung. Results: Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes with of pemetrexed. Conclusions: The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung.
Citation Format: Minkyu Jung, Chul Ho Lee, Hyung Soon Park, Ji Hyun Lee, Dae Joon Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho. Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2369. doi:10.1158/1538-7445.AM2013-2369
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.