bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4769: Gene expression profiling of response to short- and long-term treatment of LSZ102 in MCF7 cells
Authors: Yip Choi Lai Tiong , Korn Joshua , Ruddy David , Rakiec Daniel , Stuart Darrin , Gaither Alex 
Published: August 2019

Abstract
Breast cancer is the most common cancer in women worldwide, and the second most common cause of cancer death in woman in the US. Close to 80% of breast cancer are estrogen receptor (ER) positive and can benefit from antiestrogen treatment. LSZ102 is a novel oral selective estrogen receptor degrader (SERD) in clinical development, which exhibits potent activity in inducing ER degradation, modulating ER-target genes transcription and inhibits the proliferation of breast cancer cells both in-vitro and in-vivo. In this study, we have investigated the effects of short term and prolonged LSZ102 treatment on global gene expression in ER positive MCF-7 breast cancer cells. MCF-7 cells were treated with LSZ102 for 24 hours, 8 weeks and 14 weeks, followed by transcriptome profiling by RNA sequencing. Our findings show LSZ102 effectively inhibited ER transcriptional activity and lead to a sustained suppression of estrogen responsive genes expression in LSZ102-treated cells of all time points. We also observed a cumulative up-regulation of EPAS1, a hypoxia-inducible transcription factor. In addition, we found up-regulation of EGFR and ERBB2 genes and regulated genes in cells with prolonged treatment of LSZ102. In summary, our results suggest a possible role of EPAS1 in eliciting a compensatory growth promoting signals in breast cancer cells adapted to ER inhibition.
Citation Format: Choi Lai Tiong Yip, Joshua Korn, David Ruddy, Daniel Rakiec, Darrin Stuart, Alex Gaither. Gene expression profiling of response to short- and long-term treatment of LSZ102 in MCF7 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4769.
Abstract 4771: The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose
Authors: Rodriguez-Aguirre Maria E. , Viaud Sophie , Mendoza Daniel , Montellano Tiffany , Ostertag Derek G. , Gruber Harry , Jolly Douglas , Bentley Cornelia 
Published: August 2019

Abstract
Background: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU). The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently being evaluated in a randomized phase III clinical trial for recurrent high grade glioma (glioblastoma (GBM) and anaplastic astrocytoma) (NCT02414165, Toca 5). Temozolomide (TMZ), in combination with radiation therapy, is the standard of care used for first-line chemotherapy treatment of patients with GBM, the most common and aggressive form of primary brain cancer. Previously, we have shown that: (1) Toca 511/5-FC treatment provides durable response in a syngeneic murine glioma model and supports anti-tumor immune memory; (2) The combination of TMZ and Toca 511/5-FC had synergistic efficacy in a TMZ-sensitive human glioma nude mouse model; (3) TMZ did not inhibit the efficacy of Toca 511/5-FC in a TMZ resistant murine glioma syngeneic model; (4) Toca 511/5-FC caused significant radiosensitization in a radioresistant murine glioma model.
Results: To assess the interaction of TMZ with escalating doses of Toca 511 (as defined by percent of tumor transduction by RRV), an orthotopic TMZ-resistant murine glioma model, Tu-2449, was utilized. These results show that moderate levels of tumor transduction of Toca 511 (30% - 50%) with 5-FC treatment prolongs survival in the presence of TMZ compared with lower transduction rates (10%). Additionally, mice treated with Toca 511/5-FC and TMZ are being tested for the establishment of anti-tumor immune memory.
Conclusion: These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006).
Citation Format: Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, Cornelia Bentley. The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4771.
Abstract 4778: Identification of promoters for targeted gene expression in tumors
Authors: Sajib Abdul Mohin , Sandey Maninder , Morici Samantha , Schuler Bradley , Agarwal Payal , Smith Bruce 
Published: August 2019

Abstract
A variety of novel therapeutic approaches to cancer have been proposed in the past several decades. One of the most compelling is the use of gene therapy to treat tumors. Restricting the expression of these genes to tumor avoids toxicity in normal cells and the concurrent side effects that this activity engenders. Promoter sequences can be used as a tool for transcriptional targeting, by restricting the expression of the therapeutic genes, or, in the case of oncolytic virotherapy, the replication of the viral agent. Several tumor-upregulated promoters have been identified in a wide variety of human tumors. Given the recognition of the validity of canine tumors as comparative models of human disease, it is critical to determine the activities of these promoters in the canine system. To achieve this goal, endogenous cSurvivin, cTERT, and cCXCR4 promoter activity was evaluated in a panel of canine normal and tumor cell lines/tissues and primary tumors by RT-Q-PCR. These three promoters, along with an E2F modified Canine Adenovirus 2 E1a promoter (E2F-E1a), were also assessed for their activity when supplied exogenously to tumor cells in an in vitro GFP reporter transfection assay. Endogenous expression of cTERT showed negligible differences between normal canine cells/tissues and tumor cell/tissues. cSurvivin showed elevated endogenous activity in non-hematopoietic tumor cells and moderately elevated activity in some normal tissues and hematopoietic tumors. cCXCR4 activity was elevated exclusively in a T-lymphoma cell line and a primary T-cell lymphoma. Exogenous expression in most cancer cell lines showed enhanced activity with most of the promoters tested. The percentage of cells expressing GFP was elevated in tumor compared to normal with all four tested promoters, when normalized to CMV-GFP expression. However, the relative fluorescence intensity varied significantly between cell lines, while the fluorescence intensity varied less between promoters within a specific cell line. Exogenous expression results did not correlate well with endogenous expression in tumor cells, but they did correlate well in normal cells. This disparity implies that promoter selection for transcriptional targeting of tumors should account for both endogenous and exogenous expression patterns. Additionally, these findings indicate that identification of a pan-cancer promoter is complex and that expression targeting may need to rely on selecting patient-specific promoters to drive the activity of therapeutic genes.
Citation Format: Abdul Mohin Sajib, Maninder Sandey, Samantha Morici, Bradley Schuler, Payal Agarwal, Bruce Smith. Identification of promoters for targeted gene expression in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4778.
Abstract 4779: Coxsackievirus A11 as a novel oncolytic viral therapy for human colorectal cancer
Authors: Ogata Hisanobu , Wang Beibei , Miyamoto Shoei , Takishima Yuto , Sagara Miyako , Murahashi Mutsunori , Onishi Hideya , Tani Kenzaburo 
Published: August 2019

Abstract
Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. It is the third most common cancer worldwide and the fourth most common cause of death. FOLFOX is known as the effective chemotherapy for stage III and stage IV CRC. Oxaliplatin (L-OHP) is a third-generation platinum agent used among FOLFOX in CRC treatment. Patients with L-OHP-resistant CRC has a worse prognosis. Coxsackievirus is a virus that belongs to a family of nonenveloped, linear, positive-sense ssRNA viruses, Picornaviridae and the genus Enterovirus. Enteroviruses are among the most common and important human pathogens, and ordinarily its members are transmitted by the fecal-oral route. Coxsackieviruses share many characteristics with poliovirus. Coxsackieviruses are among the leading causes of aseptic meningitis. Recently, coxsackievirus A21, which is also called Cavatak, has already been reported to have the oncolytic activity. In this study, we tested whether coxsackievirus A11 (CVA11) has an oncolytic activity or not in CRC. Through our first screening assay, we found that CVA11 displayed the potent oncolytic activities in 4 of 5 various human CRC cell lines including two L-OHP-resistant CRC cells. Mechanistically, the CVA11-mediated cytotoxicity was significantly impaired when PI3K or Wnt inhibitor was added to the CVA11 infection. CVA11 had little effect on the L-OHP-resistant CRC. The pretreatment with L-OHP in L-OHP-resistant CRC cells displayed enhanced oncolytic activity of CVA11 in L-OHP-resistant CRC cells, whereas either L-OHP or CVA11 treatment alone caused slight oncolytic activity. These results suggest that L-OHP pretreatment could sensitize the susceptibility of CRC cells to CVA11 infection. Furthermore, our results of in vivo mouse study showed that intratumoral CVA11 administrations with pretreatment of L-OHP significantly suppressed the outgrowth of L-OHP-resistant xenografts. This combination therapy was more effective than the treatment with only CVA11. Altogether, our findings showed that the combination therapy with L-OHP and CVA11 displayed a remarkable oncolytic activity against L-OHP-resistant human CRC both in vitro and in vivo. Our study also provides the therapeutic potential for L-OHP-resistant CRC by Coxsackieviruse.
Note: This abstract was not presented at the meeting.
Citation Format: Hisanobu Ogata, Beibei Wang, Shoei Miyamoto, Yuto Takishima, Miyako Sagara, Mutsunori Murahashi, Hideya Onishi, Kenzaburo Tani. Coxsackievirus A11 as a novel oncolytic viral therapy for human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4779.
Abstract 4783: Highly efficient, non-viral precision genome engineering for the generation of personalized neoepitope-specific adoptive T cell therapies
Authors: Jacoby Kyle , Moot Robert , Lu William , Nguyen Diana , Sennino Barbara , Conroy Andrew , Purandare Bhamini , Litterman Adam J. , Urbinati Fabrizia , Foy Susan P. , Hunter Theresa , Tai Albert , Bethune Michael T. , Peng Songming , Dalmas Olivier , Franzusoff Alex , Mandl Stefanie J. 
Published: August 2019

Abstract
Methods used to engineer cells for adoptive cell therapies (ACT) utilizing receptors that are constant across many patients (CAR or shared Ag TCRs) typically rely on Lenti-, retro-, or adeno-associated virus to deliver specificity-altering sequences to T cells. However, for personalized therapies such as the generation of neoepitope-specific TCR T cell therapies, use of viral vectors is not feasible due to long manufacturing timelines and prohibitive per-patient costs. PACT Pharma has developed a highly efficient, DNA-mediated (non-viral) proprietary precision genome engineering approach to engineer neoepitope-specific primary human T cells. This method can be widely utilized to generate T cells at research scale, as well as for ex vivo manufacturing.
Briefly, genomes of individual primary human CD8 and CD4 T cells are engineered with site-specific nucleases in a single-step transfection process to yield efficient, targeted replacement of the endogenous TCR with the therapeutic neoTCR sequences. In this way, the expression of the endogenous TCR is abolished ensuring natural expression and regulation of the inserted neoTCR. The precision of neoTCR-T cell genome engineering was evaluated by Targeted Locus Amplification (TLA) for off-target integration hot spots or translocations, and by next generation sequencing based off-target cleavage assays and found to lack evidence of unintended outcomes.
Engineered neoepitope-specific T cells are highly functional as demonstrated by antigen-specific proliferation, killing and cytokine production. Phenotype and detailed functional characterization of PACTs neoTCR-P1 T cells were performed and are described in a separate abstract.
PACT’s precision genome engineering approach enables highly efficient generation of bespoke NeoTCR T cells for personalized adoptive cell therapy for patients with solid tumors. Furthermore, PACT precision genome engineering method is not restricted to the use in T cells and has also been applied successfully to other primary cell types, including natural killer and hematopoietic stem cells.
Citation Format: Kyle Jacoby, Robert Moot, William Lu, Diana Nguyen, Barbara Sennino, Andrew Conroy, Bhamini Purandare, Adam J. Litterman, Fabrizia Urbinati, Susan P. Foy, Theresa Hunter, Albert Tai, Michael T. Bethune, Songming Peng, Olivier Dalmas, Alex Franzusoff, Stefanie J. Mandl. Highly efficient, non-viral precision genome engineering for the generation of personalized neoepitope-specific adoptive T cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4783.
Abstract 4788: Novel hybrid benzothiazole screening in U87-MG glioblastoma cell line
Authors: Kyi Priscilla , Murray Desmond H. , Smith Denise L. 
Published: August 2019

Abstract
Benzothiazole is a heteroaromatic compound known for its wide range of bioactivities including anticancer, antiviral, antimicrobial, anti-inflammatory, anticonvulsant, antidiabetic, antihelminthic, and antitubercular activities. Research has shown that derivatives of benzothiazole exhibit inhibition of proliferation via apoptosis in various human cancer cell lines, such as liver cancer (Wang, et. al., 2010). In this study, a series of novel hybrid benzothiazole α-cyanostilbene derivatives and styrylbenzothiazole derivatives containing boronic acid and non-boronic acid pharmacophores were synthesized and their anti-cancer properties on U87-MG glioblastoma cells were investigated in vitro. U87-MG cells were incubated with synthesized novel hybrid compounds at varying concentration to determine the inhibitory concentration 50 (IC50) of the compounds. Most hybrid compounds displayed inhibitory effects on cell growth and the IC50 of the compounds varied depending on the nature of the pharmacophores. Moreover, boronic acid-containing compounds exhibit lower IC50 than nonboronic acid-containing compounds. Cell mobility has been investigated and we have found that treated cells were less mobile than untreated cells. In the future, we will be further screening for mobility, invasiveness, and mode of death of these novel hybrid benzothiazole treated glioblastoma cells.
Citation Format: Priscilla Kyi, Desmond H. Murray, Denise L. Smith. Novel hybrid benzothiazole screening in U87-MG glioblastoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4788.
Abstract 4792: Azetidine functionalized small-molecules potently inhibit STAT3 signaling and block tumor growth in human breast cancer xenografts
Authors: Yue Peibin , Lopez-Tapia Francisco , Fu Wenzhen , Brotherton-Pleiss Christine , Tius Marcus , Turkson James 
Published: August 2019

Abstract
The development of inhibitors of Signal transducer and activator of transcription (STAT) 3 for clinical application has faced significant challenges and to date there are no suitable STAT3 small molecule inhibitors in the clinic. We report a novel class of azetidine-based small molecules that potently and preferentially inhibit STAT3 DNA-binding activity in vitro, with IC50 of 300-800 nM, compared to IC50 of 17 μM or higher against STAT1 DNA-binding activity. In the human breast cancer MDA-MB-231 and MDA-MB-468 cells treated with the azetidine compounds, including H182, constitutive STAT3 DNA-binding activity and tyrosine phosphorylation were strongly inhibited in both time- and dose-dependent manner. By contrast, the azetidine compounds showed little effects on EGF-induced STAT1 activity, Ras-Raf-MEK-ERK or other STAT3-independent signaling pathways, or on other SH2 domain-containing proteins. Furthermore, H182 and other azetidine compounds strongly inhibited viability, anchorage-dependent and -independent growth, and colony survival of the human breast cancer cells, with IC50 of 1.0 - 1.9 μM, compared to the IC50 of 3.8 - 8.1 μM against the viability and growth of the immortalized breast epithelial MCF-10A cells. The migration of breast cancer cells in vitrowere similarly inhibited by treatment with low concentrations of H182 for 18 h, without changes in viable cell number. Analysis of STAT3 downstream genes show that the expression of VEGF and survivin were significantly suppressed in breast cancer cells treated with the azetidine compounds. In vivo evaluation of antitumor efficacy shows H182 inhibited growth of human breast tumor xenografts. Studies together identify the azetidine-functionalized small molecules as potential candidate compounds for clinical development as novel therapeutic agents for human breast and other cancers that harbor aberrantly-active STAT3.
Citation Format: Peibin Yue, Francisco Lopez-Tapia, Wenzhen Fu, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Azetidine functionalized small-molecules potently inhibit STAT3 signaling and block tumor growth in human breast cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4792.
Abstract 4801: 2’-Hydroxyflavanone, a diet-derived citrus bioflavonoid, inhibits in vitro and in vivo growth of breast cancer cells by targeting RLIP
Authors: Singhal Sharad S. , Chikara Shireen , Singhal Jyotsana , Horne David , Salgia Ravi , Awasthi Sanjay 
Published: August 2019

Abstract
Breast cancer remains one of the major causes of cancer deaths in women. Consumption of citrus-fruits is associated with reduced incidence of breast cancer, the most common cancer diagnosed in women across the globe. In this study, we investigated the anticancer potential of 2-Hydroxyflavanone (2HF) in breast cancer. 2HF, a citrus-bioflavonoid, has demonstrated anticancer properties in various cancers, but its anticancer role in breast cancer has not been well studied. We investigated the in-vitro and in-vivo growth inhibitory effects of 2HF in an array of BC lines and in xenograft mouse models of ER-positive and HER2-positive breast cancer cells. Compared to control, 2HF treatment reduced cell viability of breast cancer cells, while, no growth inhibitory effects were observed in non-tumorigenic breast epithelial cells. Further, 2HF inhibited the expression of RLIP, a stress-defensive and anti-apoptotic protein, which is over-expressed in breast cancer cells and simultaneously reduced proliferation of breast cancer cells. Nude mice bearing MCF7 or SKBR3 breast cancer cells xenografts treated with either 2HF or targeting RLIP by RLIP-antisense or RLIP-antibody treatment had significantly lower tumor-weight as compared to corresponding controls. In addition, Western-blotting and immunohistochemical analysis of tumor tissue from control and treatment group mice showed that 2HF decreased protein expression levels of RLIP, and the decrease was similar to those seen following RLIP-antisense treatment. Furthermore, 2HF decreased expression of Ki67, CD31, vimentin, inhibited phosphorylation of AKT and expression of survivin and Bcl2, and increased levels of Bax, E-cadherin, and cleaved-PARP. Therefore, our results indicate that 2HF may suppress breast cancer growth in-vitro and in-vivo by targeting RLIP, and may serve as a potential adjuvant treatment in breast cancer patients. (This work was supported in part by the Department of Defense grant W81XWH-16-1-0641. Funding from the Beckman Research Institute of City of Hope is also acknowledged).
Citation Format: Sharad S. Singhal, Shireen Chikara, Jyotsana Singhal, David Horne, Ravi Salgia, Sanjay Awasthi. 2’-Hydroxyflavanone, a diet-derived citrus bioflavonoid, inhibits in vitro and in vivo growth of breast cancer cells by targeting RLIP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4801.
Abstract 4808: Preclinical studies of the combination of ONC201, radiotherapy and Temozolomide against GBM, DIPG and ATRT cell lines
Authors: Zhou Lanlan , El-Deiry Wafik S. 
Published: August 2019

Abstract
The American Cancer Society predicts, in 2018, there will be ~23,880 new cases and 16,830 deaths caused by primary cancer of the brain and spinal cord, in the US. CNS tumors are the most common cause of cancer-related deaths in adolescents and young adults. First-in-class small-molecule imipridone ONC201 can act as a dual inhibitor of ERK/AKT and can induce an integrated stress response (ISR), pro-apoptotic TRAIL receptor DR5 activation, cancer stem cell depletion, and growth arrest. ONC201 crosses the blood brain barrier and has demonstrated clinical benefits in glioblastoma patients. Radiation therapy is used alone or in combination with surgery and/or chemotherapy such as Temozolomide in the treatment of primary or metastatic brain tumors. We hypothesized that ONC201 may synergize with radiotherapy and Temozolomide in brain tumor treatment. Glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG) and atypical teratoid rhabdoid tumor (ATRT) cell lines were tested in this study. Cell viability and colony formation assays were performed with ONC201 alone up to 20 μM or in combination with radiotherapy up to 8 Gy and Temozolomide up to 100 μM. Western blots were used to document apoptosis of treated cells. We observed synergy between ONC201 and radiation and between ONC201 and Temozolomide with the best combination indices of 0.51 and 0.21 respectively. Further studies are evaluating the role of dopamine receptors engaged by ONC201, the ISR and TRAIL pathway in the synergistic effect that would support further development of the triple combination therapy in brain tumors.
Citation Format: Lanlan Zhou, Wafik S. El-Deiry. Preclinical studies of the combination of ONC201, radiotherapy and Temozolomide against GBM, DIPG and ATRT cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4808.