bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-222: Optimization and preclinical characterization of highly potent and stable anti-CD70 ADCs for the potential treatment of CD70 positive cancers
Authors: Skidmore Lillian , Cox Kari , Kirtley Jessica , Le Tiep , Firdos Juhi , Manibusan Anthony , Fang Shiao-Yan , Beck Andy , Bhowmik Shiva , Knudsen Nick , Wang Jianing , Sun Ying , Ayala Armando , Powell Alyssa , Wahl Alan , Tian Feng , Humphreys Robin 
Published: July 2016

Abstract
Antibody drug conjugates (ADCs) require coordinated optimization of antibody, linker, and payload to generate potent, specific, and stable cancer therapeutics. CD70 is an attractive ADC tumor target due to its limited expression in normal tissues and over-expression in many solid tumors and hematologic malignancies. Utilizing Ambrx's site-specific EuCODE technology, we have generated and evaluated multiple ADCs with different combinations of linkers and payloads for treatment of CD70 positive cancers. In vitro activity identified specific CD70 ADCs with picomolar potency/activity against CD70 positive cancer cell lines. Conjugation of drug-linkers at different sites in the antibody and modification of linker design improved in vitro activity and in vivo stability of lead CD70 ADCs. Optimized anti-CD70 ADCs were evaluated for pharmacokinetic profile and demonstrated to be efficacious in reducing tumor burden and significantly prolonging survival in an in vivo orthotopic xenograft model of multiple myeloma. In summary, we have generated encouraging preclinical in vitro and in vivo data with stable, site-specific, DAR = 2 anti-CD70 ADCs for the potential treatment of CD70 positive cancers such as multiple myeloma.
Citation Format: Lillian Skidmore, Kari Cox, Jessica Kirtley, Tiep Le, Juhi Firdos, Anthony Manibusan, Shiao-Yan Fang, Andy Beck, Shiva Bhowmik, Nick Knudsen, Jianing Wang, Ying Sun, Armando Ayala, Alyssa Powell, Alan Wahl, Feng Tian, Robin Humphreys. Optimization and preclinical characterization of highly potent and stable anti-CD70 ADCs for the potential treatment of CD70 positive cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-222.
Abstract LB-232: Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy
Authors: Som Avik , Raliya Ramesh , Akers Walter , Ippolito Joseph , Singamaneni Srikanth , Biswas Pratim , Achilefu Samuel 
Published: July 2016

Abstract
Introduction: The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors and restricts it growth.
Methods: We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Biochemical simulations were used to simulate pH changes in vivo using the particle. In vitro and in vivo assays were used to determine pH changes. IV injections of the nanoparticles were implemented in a xenograft model of fibrosarcoma to determine growth changes.
Results: Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) dissolution in vivo increases pH asymptotically to 7.4. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pHe over time. The persistent neutralization of tumor pHe from nano-CaCO3 induces tumor growth stasis.
Conclusions: We have been able to create a novel nanoparticle based on widely existing in vivo components (Calcium and CO3) that safely equilibrates acidic pH of tumors up to normal physiological pH. As expected, this modulation restricts growth of implanted tumors in vivo. Future studies will study the effect of these particles on metastasis, and synergy with other therapeutic modalities.
Citation Format: Avik Som, Ramesh Raliya, Walter Akers, Joseph Ippolito, Srikanth Singamaneni, Pratim Biswas, Samuel Achilefu. Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-232.
Abstract LB-234: A persistently activated signaling network regulates the DNA damage secretory program to promote cancer resistance driven by the therapeutically damaged tumor microenvironment
Authors: Sun Yu , Zhang Boyi , Chen Fei , Chiao Paul 
Published: July 2016

Abstract
In cancer clinics, an in vivo form of the senescence-associated secretory phenotype (SASP) is driven by a DNA damage secretory program (DDSP) provoked by side effects of genotoxic therapeutics including chemotherapy and radiation which fuel advanced pathologies particularly cancer resistance. However, the complete mechanism underlying DDSP development in the tumor microenvironment (TME) remains unclear. Here we report that genotoxic agents frequently used in clinical oncology induce a gene expression pattern distinct from the one that is shaped by non-genotoxic drugs. Specifically, the zinc finger and scan domain containing 4 (Zscan4) is upregulated upon DNA damage in stromal cells and engaged in DNA damage response (DDR) in genotoxic settings. Apart from the established functions in telomere elongation and genomic integrity of stem cells, Zscan4 is central for the Rap1/TRF2 assembly and orchestrates the long term DDR signaling in differentiated stromal cells. In response to DNA damage, the mammalian target of rapamycin (mTOR) is phosphorylated in the cytoplasm of stromal cells and relays DDR signals, a phenomenon different from human cancer cells. There are physical interactions between the mTOR and the IKK complexes, events functionally implicating the NF-κB machinery that is regulated by both the IL-1α/IRAK1 and mTOR/Raptor axes. We determined that mTORC1 is a critical mediator of DDSP programmatic implementation by conducting signals from upstream molecules including p38 and PI3K/Akt, molecules activated in DNA damage events. We revealed that the ligand IL-1α signals through IL-1R and TAK1, the latter a member of the mitogen-activated kinase kinase kinase (MAPKKK) family that induces a proinflammatory cascade by activating JNK/p38 and NF-κB. Further, targeting p38, mTOR or TAK1 with small molecule inhibitors in vivo significantly abrogated cancer resistance acquired from the TME in chemotherapeutic cycles. Overall, our study substantiates p38, mTOR and TAK1 as a group of new candidates for future TME-oriented intervention to minimize resistance provoked by anticancer regimes, and suggests that anti-p38/mTOR/TAK1 agents may be repurposed to sensitize tumors by effectively targeting the TME. Our data disclose a novel mechanism of SASP (or DDSP) signaling in classical therapeutic settings, thus opening new avenues to improve clinical outcomes in the current era of precision medicine.
Citation Format: Yu Sun, Boyi Zhang, Fei Chen, Paul Chiao. A persistently activated signaling network regulates the DNA damage secretory program to promote cancer resistance driven by the therapeutically damaged tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-234.
Abstract LB-284: Multiscale systems pharmacology model for time sequence combination chemotherapy in breast cancer
Authors: Ait-Oudhia Sihem 
Published: July 2016

Abstract
Background: HER2-positive (HER2+) breast cancer (BC) is more quickly-growing and aggressive than other types of BC. Trastuzumab (TZM) is a humanized monoclonal antibody directed against HER2 receptor. It is clinically used for BC in combination with paclitaxel (PAC) in a 24 h sequence treatment during the first week of therapy followed by a simultaneous administration during the subsequent weeks. To our knowledge there is no scientific rationale for such therapeutic regimes. We propose to develop and optimize a sequential combination of PAC+TZM to optimize their anti-tumoral activity, and hence, HER2+ BC patients’ outcome.
Method: Six therapeutic regimens were investigated in vivo on Balbc nude mice xenografted with BT474 cells, a human breast cancer cell line that overexpresses HER2 receptor, including 1) a tumor priming regimen (TPR) with PAC administered 24 h prior to TZM, 2) reverse-TPR with TZM administration first then PAC 24 h later, 3) simultaneous administration of both drugs, 4) PAC alone, 5) TZM alone, 6) vehicle as a control. The doses were 10 and 3 mg/kg for PAC and TZM. The anti-tumoral response in all treatment arms was monitored over time through the measurement of the reduction in tumor volumes as well as animals survival.
Results: In vivo studies showed a greater tumor volume shrinkage response in the animals from the TPR treatment arm compared to the other therapeutic schemes with: 1) an enhanced in vivo antitumor response, and 2) a longer animal survival. These results support our in vitro findings of drug synergy and apoptosis.
Conclusion: TPR anti-tumor results are promising. The proposed research will develop and employ a systems pharmacology model based on our results to hypothesize optimal regimens for the association (PAC+TZM) breast cancer killing, which will be tested in vivo.
Citation Format: Sihem Ait-Oudhia. Multiscale systems pharmacology model for time sequence combination chemotherapy in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-284.
Abstract LB-286: Dynamic alternative splicing correlates with drug synergy and induces novel gene regulatory networks in MCF7
Authors: Chen Xintong , Bashir Ali , Stolovitzky Gustavo , Losic Bojan 
Published: July 2016

Abstract
Drug combination therapies in the cancer setting often succeed where mono-therapies fail, facilitating durable and robust responses that may curtail metastases and even be accompanied by milder side-effects. Here we incorporate transcriptional splicing dynamics with a gene level expression analysis to assess the transcriptional landscape of MCF-7 (ER+) cell-lines across mono or combination therapies in a time course short-read RNA-seq experiment. We leverage the most comprehensive known splicing database of MCF7 to assess the sensitivity and specificity our short-read splicing inference by interrogating the long-read PacBio isoform sequencing (IsoSeq) MCF7 database. We infer robust isoforms which are strongly associated with phenotypic synergy and demonstrate their novel functional role by computing gene-gene coexpression networks which are sensitive to their expression.
Briefly, we use RNA-seq to study the transcriptional response over time (0, 3, 6, 9, 12, and 24 h) for three drugs (A, B and C) and their combinations (AB, AC and BC) in MCF-7 (ER+) breast cancer cells lines. Cell viability measurements show that one of the combinations (AB) is strongly synergistic, whereas the other two (AC and BC) are merely additive. We show that in addition to a novel transcriptional signature driven by differential expression, the combination AB transcriptional landscape is characterized by persistent alternative splicing signatures mostly comprised of genes which are not differentially expressed with respect to A or B, but whose functional role has been dramatically changed by the addition (deletion) of a key regulatory protein domain encoded by the extra(missing) exon. We integrate this synergistic splicing signal into a gene regulatory network (GRN) via adaptive network refinement to show that it strongly contributes to the emergence of extensive transcriptional cascades by creating and removing key gene-gene correlations and altering the modular structure of the network. Using this approach we show that a key (heretofor poorly understood) isoform of Protein beta-arrestin-1 (ARBB1), which participates in the desensitization of G-protein coupled receptors through intracellular response to Estrogen, becomes enriched in the calcium ion-dependent exocytosis coexpression module for synergistic therapies only, despite being absent in the baseline MCF-7 long-read PacBio IsoSeq data.
Our results directly show that alternative splicing is crucial in any molecular characterization of phenotypic drug synergy in drug-tumor interactions.
Citation Format: Xintong Chen, Ali Bashir, Gustavo Stolovitzky, Bojan Losic. Dynamic alternative splicing correlates with drug synergy and induces novel gene regulatory networks in MCF7. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-286.
Abstract LB-291: Environment or accident? A more stringent bound on environmental contributions to cancerogenesis
Authors: Bilke Sven , Meltzer Paul S. 
Published: July 2016

Abstract
Finding the right balance between cancer prevention and early detection is essential for an efficient anti-cancer strategy. Yet, the underlying biological question “how much cancer risk results from chance, how much from environmental factors’’ continues to be controversial. Recently, the “bad luck’’ hypothesis was strengthened based on observing a tight correlation between a tissues cancer risk and its number of stem cell divisions [1]. This interpretation was later challenged by pointing out that certain even drastic changes of environmental risk factors would not affect theat correlation [2]. Based on this argument they derived an estimate of the upper bound of environmental contributions to canceriogenesis. Here we argue that the argument made in [2] did not fully appreciate that typically several mutations are requited before cancer initiation occurs [3]. We show that by incorporating this aspect into the analysis the correlation between the number of stem cell divisions and cancer risk would respond to changes of environmental factors. We re-analyze the data in [1] to derive a slightly more stringent upper bound of the environmental risk contributions for a number of cancers than the ones obtained in [2]. [1] C. Tomasetti, B. Vogelstein, Science 347(6217), 78-81 (2015) [2] S. Wu, S.Powers et al., Nature 529, 43-47 (2015) [3] C. Nordling, British Journal of Cancer 7(1), 68-72 (1953)
Citation Format: Sven Bilke, Paul S. Meltzer. Environment or accident? A more stringent bound on environmental contributions to cancerogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-291.
Abstract LB-295: Food-based approach to cancer prevention: A phase I assessment of amorphous confections in modulating exposure and metabolism of black raspberry compounds in the oral cavity
Authors: Ahn-Jarvis Jennifer H. , Clinton Steven K. , Grainger Elizabeth M. , Simpson Christina , Gu Junnan , Teegarden Matthew D. , Riedl Kenneth M. , Knobloch Thomas J. , Weghorst Christopher M. , Schwartz Steven J. , Vodovotz Yael 
Published: July 2016

Abstract
Background: Oral cancer remains a major global malignancy, largely due to persistence of tobacco use worldwide. Preventive strategies focusing upon high risk individuals due to long term tobacco use or presence of pre-malignancy are needed. Based upon strong epidemiologic and laboratory evidence we have developed a black raspberry food-based product targeting this population and have tested variations in a phase I trial.
Objective:
1. To test three amorphous solids (glassy, elastic, and viscous) containing a bioactive rich black raspberry (BRB) fraction in a confectionary system for compliance.
2. To investigate the impact of amorphous structure in modulating oral exposure and metabolism of black raspberry compounds in the oral cavity as measured by differences in duration of black raspberry exposure and profile of black raspberry metabolites from saliva.
Methods: A four week, phase I, randomized, parallel study design with 60 non-smoking adults was used to investigate three amorphous forms having different release rates (prolonged, intermediate, and rapid), each at two doses (4 or 8 g BRB/day). Salivary kinetics and changes in black raspberry composition among and within individuals were assessed. HPLC with Tandem MS/MS was used to quantify and characterize black raspberry compounds from the confections and profile them in the saliva.
Results: All confections were well accepted having excellent adherence (94 ± 2%). Toxicities were limited to a grade I toxicity (NIH criteria). Oral residence time was 74% longer and saliva volume was 42% greater with glassy than the other two amorphous forms. Anthocyanin (cyanidin-3-glucoside) and ellagitannins were prevalent compounds in the saliva.
Conclusions: Three amorphous confectionary forms of a BRB food-based delivery vehicle demonstrated excellent compliance, with the glassy form showing potential for greater oral distribution, suggesting the potential for greater bioactivity. Food science and technology provides many strategies to develop novel and fully characterized food products for cancer prevention trials.
Citation Format: Jennifer H. Ahn-Jarvis, Steven K. Clinton, Elizabeth M. Grainger, Christina Simpson, Junnan Gu, Matthew D. Teegarden, Kenneth M. Riedl, Thomas J. Knobloch, Christopher M. Weghorst, Steven J. Schwartz, Yael Vodovotz. Food-based approach to cancer prevention: A phase I assessment of amorphous confections in modulating exposure and metabolism of black raspberry compounds in the oral cavity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-295.
Abstract LB-297: Antitumor immune response passively prevents and eliminates skin tumors on the mouse model of human papillomavirus cancers
Authors: Joh Joongho , Ghim Shinje , Chilton Paula M. , Park Jino , Wilcher Sarah A. , Proctor Mary L. , Jenson Alfred B. 
Published: July 2016

Abstract
Infection by mouse papillomavirus (PV), MmuPV1, of T cell-deficient, B6.Cg-Foxn1nu/J nude mice revealed that four, distinct squamous papilloma phenotypes developed simultaneously after infection of experimental mice. Papillomas appeared on the muzzle, vagina, and tail at or about day 42 days post-inoculation. The dorsal skin developed papillomas and hair follicle tumors (trichoblastomas) as early as 26 days after infection. When this aggressive tumor was transplanted into normal congenic strains, the transplant immediately regressed while the transplanted tumor into B6.Cg-Foxn1nu/J continued to grow. This result suggested that T-cell deficiency is critical to tumor formation. Passive transfer of hyperimmune sera from normal congenic mice immunized with MmuPV1 virus-like particles (VLPs) to T cell-deficient strains of mice prevented infection by virions of experimental mice. A cell adoption study showed that activated CD8+ populations collected during the regression process of MmuPV1 tumor explants efficiently eliminated both growing and established tumors in the model. Consequently, this study will provide an efficient immunotherapeutic strategy that can be employed to HPV-positive patients, who are at a risk of cancer development.
Citation Format: Joongho Joh, Shinje Ghim, Paula M. Chilton, Jino Park, Sarah A. Wilcher, Mary L. Proctor, Alfred B. Jenson. Antitumor immune response passively prevents and eliminates skin tumors on the mouse model of human papillomavirus cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-297.
Abstract LB-298: Gut microbiota changes in response to treatment with ursodeoxycholic acid
Authors: Caporaso J Gregory , Pearson Talima , Yellowhair Monia , Martinez Jessica , Lance Peter 
Published: July 2016

Abstract
Compelling evidence suggests that the gut flora influences colorectal cancer risk through direct effects on colonic bile acid composition. Bile acids are widely implicated in the etiology of colorectal cancer and the strongest evidence is for the secondary bile acid deoxycholic acid. In a study of patients with prior colorectal adenomas who were randomized to ursodeoxycholic acid (n = 188 males, 64 females), a bile acid based intervention aimed at modulating bile acid composition, or placebo (n = 162 males, 89 females), we determined effects of the intervention on the gut microbiome through 16S rRNA sequencing and bile acid composition using mass spectrometry.
We observe a consistent shift in microbial community phylogenetic composition for males (t = 5.83, p = 3.6e-8) and females (t = 3.14, p = 0.003) treated with UDCA. No effect was observed in the placebo group for either males (t = -0.08, p = 0.93) or females (t = -0.09, p = 0.92). This suggests that UDCA treatment, but not placebo treatment, is having an effect on the gut microbial communities of study participants. Interestingly, the microbiomes of the UDCA group do not change more than those of the placebo group: rather the magnitude of change is similar in the two groups, but UDCA treatment seems to drive specific microbiome changes.
We also observe significant correlations between the gut microbiome composition and bile acid composition (r = 0.31, p&lt;0.001). Specifically we find that (prior to treatment) bile acids including CA, CDCA, and UDCA are negatively correlated with diversity (richness) and to a lesser extent the abundance of Bacteroidetes (phylum) in the gut.
These results are consistent with our previously reported observation that UDCA appears to have a greater effect in men for the prevention of colorectal adenomatous polyps, with risk-increasing effects for women. To our knowledge, this is the first study to correlate fecal bile acid levels with fecal microbial composition in humans or to assess the effect of the therapeutic bile acid UDCA on gut microbial composition. This study supports our observation that the efficacy of UDCA for the prevention of colorectal adenoma may be sex-dependent and suggests that the sex-specific effect may reflect differential effects of UDCA on the gut microbial community and the relationship between sex, the gut microbiome, and risk of colorectal adenomatous polyps.
Citation Format: J Gregory Caporaso, Talima Pearson, Monia Yellowhair, Jessica Martinez, Peter Lance. Gut microbiota changes in response to treatment with ursodeoxycholic acid. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-298.