bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A83: Digital quantitative immunohistochemistry for analysis of CCSP-2 and 15-PGDH expression in colon cancer
Authors: Park GyeongMin , Cho Charles Jungje , Shin Ji-Young , Do Eun-Ju , Ryu Yeon-Mi , Lee Gil-Je , Kim Sang-Yeob , Yun Youngkuk , Myung Seung-Jae 
Published: May 2016

Abstract
The analysis using quantitative immunohistochemistry (IHC) with diagnostic and prognostic biomarkers is a powerful tool for scientific and clinical research in colon cancer at early stages. The potential utility of distinct protein expression depending on the stages of colon cancer has generated interest in diagnostic and prognostic biomarkers of colon cancer. Colon cancer secreted protein-2 (CCSP-2) has been reported as a novel protein expressed in colon adenomas and cancers but not in normal colon tissue. Thus, this protein has emerged as a potential prognostic marker at early stages. In addition, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been useful as a diagnostic or prognostic marker for colon cancer. To clarify the assessment parameters for CCSP-2 and 15-PGDH in colon cancer, we evaluated its clinical, molecular and survival associations in colon cancer, according to stages of colon cancer and the tumor microenvironment, such as immune cells, by multiplex immunohistochemistry. Formalin fixed paraffin embedded (FFPE) samples of patients' primary tumor were obtained and stained for markers include CD3, CD8, Cytokeratin, Ki-67, CCSP-2 and 15-PGDH by using PerkinElmer Opal system. Digital imaging and analysis were done using PerkinElmer Nuance and Inform software system. Density plot analysis revealed distributions of CCSP-2 and 15-PGDH in colon cancer tissues. The expression of CCSP-2 and 15-PGDH correlated with stages of colon cancer. Thus, CCSP-2 and 15-PGDH, as proteins that distinctly expressed in colon adenomas and adenocarcinomas, may be useful diagnostic and prognostic markers for detection of colorectal tumors.
Citation Format: GyeongMin Park, Charles Jungje Cho, Ji-Young Shin, Eun-Ju Do, Yeon-Mi Ryu, Gil-Je Lee, Sang-Yeob Kim, Youngkuk Yun, Seung-Jae Myung. Digital quantitative immunohistochemistry for analysis of CCSP-2 and 15-PGDH expression in colon cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A83.
Abstract A96: First-in-class orally available immune checkpoint antagonists for cancer therapy
Authors: Sasikumar Pottayil G. , Naremaddepalli Sudarshan S. , Gowda Nagaraj , Adurthi Sreenivas , Dhodheri Samiulla , Dhudashia Amit , Ramachandra Raghuveer , Ramachandra Murali 
Published: May 2016

Abstract
Highly durable clinical responses observed with antibodies to immune checkpoint receptors such as CTLA4 and PD1 have revolutionized the outlook of cancer therapy. However, while these antibodies show impressive clinical activity, they suffer from the shortcomings including the need to administer by intravenous injection and immune-related adverse events due to the breaking of immune self-tolerance. Sustained target inhibition as a result of a long half-life (&gt;15-20 days) and &gt;70% target occupancy for months are likely contributing to irAEs observed.
Herein we report the discovery of the first-in-class small molecule PD-L1 antagonists that are amenable for oral dosing to achieve potent anti-tumor activity but with a shorter pharmacokinetic profile as a strategy to better manage irAEs.
A focused library of compounds mimicking the interaction of PD1 with PD-L1 was designed and synthesized. Screening and analysis of the resulting library led to the identification of compounds capable of functional disruption of the PD-L1 signaling. Further optimization of the initial hits resulted in compounds with desirable physico-chemical properties and exposure upon oral administration.
Disruption of the PD1-PDL1 interaction by lead compounds was confirmed in binding assays. Potent activity comparable to that obtained with an anti-PD1 antibody in rescuing lymphocyte proliferation and effector functions inhibited by PD-L1 was observed with lead compounds. In a panel of functional assays, the lead compounds showed selectivity against other immune checkpoint pathways including CTLA4, TIM3, LAG3 and BTLA. In syngeneic pre-clinical models of melanoma and colon cancers, significant efficacy comparable to that observed with an anti-PD1 antibody in inhibition of both primary tumor growth and metastasis was noted upon once a day oral dosing. In a 14-day repeated dose toxicity studies, the lead compound was well tolerated at &gt;100x of the efficacious doses.
The findings demonstrating the inhibition of PD-L1 pathway resulting in activation of T cells and anti-tumor activities support further development of these orally bioavailable agents. IND-enabling studies with one of the lead compounds are underway towards advancing it to the clinic.
Citation Format: Pottayil G. Sasikumar, Sudarshan S. Naremaddepalli, Nagaraj Gowda, Sreenivas Adurthi, Samiulla Dhodheri, Amit Dhudashia, Raghuveer Ramachandra, Murali Ramachandra. First-in-class orally available immune checkpoint antagonists for cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A96.
Abstract B100: ASN003, a unique B-RAF inhibitor with additional selective activity against PI3K and mTOR kinases, shows strong antitumor activity in multiple xenograft models
Authors: Thompson Scott K. , Jaleel Mahaboobi , Nyavanandi Vijay Kumar , Ramachandra Murali , Subramanya Hosahalli , Basavaraju Aravind , Sihorkar Vaibhav , Smith Roger A. , Rao Niranjan , Gupta Sandeep , Reddy Sanjeeva P. 
Published: May 2016

Abstract
Various genes in RAS-RAF and PI3K pathways are frequently mutated in a wide variety of solid tumors. Concurrent double mutations are also observed quite often in a broad range of tumor types. Combined inhibition of both pathways has been shown to impart greater efficacy in multiple tumor models in animals. In order to simultaneously block these pathways, we have discovered and characterized several molecules showing dual inhibition of the RAS-RAF and PI3K pathways. ASN003 has been identified as a lead compound with potent and highly selective inhibitory activity against B-RAF, PI3K and mTOR kinases (low nM IC50). Within the PI3K family, ASN003 has high selectivity for inhibition of PI3Kα and PI3Kδ over PI3Kβ. In cell-based mechanistic studies, ASN003 did not increase phospho-ERK levels in the KRAS mutant cell line HCT116 and thus may not cause paradoxical activation of RAS/MAPK pathway in tumors. Consistent with its dual inhibition profile, ASN003 showed strong antiproliferative activity in cell lines with B-RAF and PI3K pathway mutations as well as vemurafenib (B-RAF inhibitor)-resistant cell lines. ASN003 suppressed the phosphorylation of downstream targets of B-RAF, PI3K and mTOR in pharmacodynamic studies in multiple tumor models, indicating appropriate target engagement. In in vivo efficacy studies, ASN003 showed regression in a B-RAFV600E mutant A375 xenograft model and also caused significant tumor growth inhibition in RKO and A2058 tumor models, which harbor mutations in PIK3CA or PTEN genes, respectively, in addition to the B-RAF V600E mutation. Dual targeting of the B-RAF and PI3K pathways with ASN003 has the potential to treat and/or prevent the acquired resistance to selective B-RAF inhibitors, and may also treat a broader patient population and provide greater efficacy and survival benefit than selective B-RAF inhibitors or selective PI3K pathway inhibitors alone. Due to the lack of paradoxical activation, treatment with ASN003 may not cause skin toxicities seen with pure B-RAF inhibitors. ASN003 is currently in preclinical development and is expected to enter Phase I/II clinical trials by early 2016.
Citation Format: Scott K. Thompson, Mahaboobi Jaleel, Vijay Kumar Nyavanandi, Murali Ramachandra, Hosahalli Subramanya, Aravind Basavaraju, Vaibhav Sihorkar, Roger A. Smith, Niranjan Rao, Sandeep Gupta, Sanjeeva P. Reddy. ASN003, a unique B-RAF inhibitor with additional selective activity against PI3K and mTOR kinases, shows strong antitumor activity in multiple xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B100.
Abstract B122: Sumoylation regulates nuclear signaling of ErbB4 intracellular domain
Authors: Knittle Anna M. , Sundvall Maria , Vaparanta Katri , Elenius Klaus 
Published: May 2016

Abstract
The members of the ErbB family (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4) of receptor tyrosine kinases (RTK) regulate key cellular processes including proliferation, differentiation, and survival, and play critical roles in several human malignancies. The alternatively spliced ErbB4 JM-a isoform was the first RTK found to signal by a mechanism involving proteolytic release of an intracellular receptor domain (ICD) upon ligand binding. The released ErbB4 ICD can translocate into the nucleus, where it functions as a transcriptional coregulator. ErbB4 ICD has been shown to regulate mammary epithelial development in vivo. Furthermore, nuclear ErbB4 immunoreactivity is frequently observed in clinical breast cancer samples. Although these findings suggest that ErbB4 signaling via ICD is biologically significant, the factors that regulate subcellular distribution and nuclear functions of ErbB4 ICD are largely unknown.
We hypothesized that ErbB4 ICD is likely to be regulated by different mechanisms than the ones controlling conventional RTK signaling. One regulatory mechanism that is often employed by nuclear proteins is the small ubiquitin-like modifier (SUMO) system. SUMO proteins modify protein substrates covalently, and alter their function through changes in activity, stability, or subcellular localization.
Here, we demonstrate by pull-down and western blotting of cell culture lysates that ErbB4 ICD is modified by SUMO. Full-length ErbB4 was not sumoylated, indicating that SUMO is a specific regulatory modification for the soluble ICD. By using site-directed mutagenesis followed by sumoylation assays, we mapped the major SUMO acceptor site in ErbB4. Wild type and sumoylation deficient mutant of ErbB4 did not differ in their ability to activate canonical RTK signaling pathways downstream of ErbB4. However, fractionation experiments of MCF-7 breast cancer cells showed weaker nuclear targeting of sumoylation deficient mutant compared to wild-type ErbB4 ICD. Protein inhibitor of activated STAT3 (PIAS3), a SUMO E3 ligase that could stimulate the ErbB4 ICD sumoylation, modulated the transcriptional coregulatory activity of ErbB4 ICD in luciferase reporter assays, as well as the function of ErbB4 ICD in HC11 mouse mammary epithelial cell differentiation. Based on these findings we propose that the SUMO system regulates nuclear localization and signaling of ErbB4 ICD.
Citation Format: Anna M. Knittle, Maria Sundvall, Katri Vaparanta, Klaus Elenius. Sumoylation regulates nuclear signaling of ErbB4 intracellular domain. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B122.
Abstract B141: Predictive value of genetically engineered endogenous mouse models in preclinical therapeutic studies
Authors: Gupta Aayush , Trajkovic-Arsic Marija , Heid Irina , Teichman Nicole , Kalederis Evdokia , Braren Rickmer , Siveke Jens 
Published: May 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with an alarming resistance to both chemotherapeutics and targeted therapy approaches. Genetically engineered mouse models (GEMM) of PDAC reflect molecularly and pathophysiologically the carcinogenesis and cancer progression observed in humans, thus being excellent tools for preclinical evaluation of new therapies.
To successfully predict and characterize the effect of chemotherapies and targeted approaches in PDAC, we use a complex and highly aggressive GEMM of endogenous PDAC, Ptf1a +/Cre Kras +/LSL-G12D p53Lox/Lox (CKP) mice. To do so, we established a highly usable GEMM-based therapy platform including multi-parametric MR imaging using CKP mice, in which tumors develop within the first 6 weeks of age (Bardeesy et al, 2006).
Animals receive a T2w scan on a 3T clinical MRI scanner for detection and staging of solid tumors for study enrolment at defined inclusion criteria (tumour volume 200-400 mm3). Mice get a weekly scan throughout the study until endpoint criteria are met. Upon reaching the endpoint criteria, mice are sacrificed and tumor material is processed for histopathological and RNA/Protein analysis, isolation and culturing of primary tumor cells. Tumors are assessed macro- and microscopically and graded. Proliferation, apoptosis and analysis of respective downstream effectors are characterized. Further comprehensive analysis depending on the respective phenotypical features is then carried out. Primary cell lines are generated for further functional and molecular characterization including but not limited to cell viability, drug sensitivity, expression and methylation profiling.
Through this platform, we have successfully been able to target key signaling pathways and to identify promising novel chemotherapeutic and targeted combinations for PDAC. Here we want to highlight the vital need to develop improved preclinical tools to characterize individual tumors throughout the course of treatment. We propose that such a platform is highly relevant and usable for predicting responses to chemotherapeutic and targeted agents.
Citation Format: Aayush Gupta, Marija Trajkovic-Arsic, Irina Heid, Nicole Teichman, Evdokia Kalederis, Rickmer Braren, Jens Siveke. Predictive value of genetically engineered endogenous mouse models in preclinical therapeutic studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B141.
Abstract B156: TP53 loss creates therapeutic vulnerability in colorectal cancer
Authors: Liu Yunhua , Lu Xiongbin 
Published: May 2016

Abstract
TP53, a well-known tumour suppressor gene, is frequently inactivated by mutation or deletion in a majority of human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of p53 regulators and their poor drugability. Here, we demonstrate that genomic deletion of TP53 frequently encompasses neighbouring essential genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such an essential house-keeping gene that is virtually co-deleted with TP53 in many types of human cancer. It encodes the largest and catalytic subunit of RNA polymerase II complex, which is specifically inhibited by α-Amanitin. Our analysis of clinical samples and cancer cell lines in The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopaedia (CCLE) reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal tumours. Suppression of POLR2A with α-amanitin or short-hairpin RNAs, selectively inhibits proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited due to its liver toxicity. However, we found that α-amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with dramatically reduced toxicity. Here, we show that low doses of α-amanitin-conjugated anti-EpCAM (Epithelial Cell Adhesion Molecule) antibody lead to complete tumour regression in murine models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a novel therapeutic approach for cancers harbouring such common genomic alterations.
Citation Format: Yunhua Liu, Xiongbin Lu. TP53 loss creates therapeutic vulnerability in colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B156.
Abstract B16: Cetuximab activates Foxo3a via the MAPK p38 to induce apoptosis and reduce cell proliferation in colorectal cancer cells
Authors: Marzi Laetitia , Combes Eve , VIE Nadia , Tosi Diego , Ayrolles-Torro Adeline , Larbouret Christel , Denis Vincent , Linares Laetitia K. , Montagut Clara , Iglesias Mar , Martineau Pierre , Lam Eric W-F , Del Rio Maguy , Gongora Céline 
Published: May 2016

Abstract
Cetuximab is a monoclonal antibody against EGFR and is associated with 5-FU and irinotecan for the treatment of patients with colorectal cancer harboring wild type KRAS. However, cetuximab is ineffective in patients with constitutively active mutated KRAS and also in half of the patients with wild type KRAS. As cetuximab downstream cellular targets are not fully characterized, the aim of this study was to identify the signaling pathways activated by cetuximab in CRC cells. Our results show that in addition to inhibiting ERK and AKT, cetuximab also activates the mitogen-activated protein kinase (MAPK) p38. We have showed that p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation. FOXO3a phosphorylation and activation by p38 led to the up-regulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, FOXO3a silencing reduced cetuximab cytotoxicity, further confirming FOXO3a role in cetuximab effect. Collectively, our results identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells KRAS WT and define p38 as its main activator in this context.
Citation Format: Laetitia Marzi, Eve Combes, Nadia VIE, Diego Tosi, Adeline Ayrolles-Torro, Christel Larbouret, Vincent Denis, Laetitia K. Linares, Clara Montagut, Mar Iglesias, Pierre Martineau, Eric W-F Lam, Maguy Del Rio, Céline Gongora. Cetuximab activates Foxo3a via the MAPK p38 to induce apoptosis and reduce cell proliferation in colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B16.
Abstract B173: Galeterone shows anti-tumor activity in multiple pre-clinical models that express androgen receptor splice variants, supporting correlative patient data seen in ARMOR2
Authors: Jacoby Douglas B. , Zoubeidi Amina , Corey Eva B. , Mostaghel Elahe , Kwegyir-Afful Andrew K. , Ramalingam Senthilmurugan , Njar Vincent 
Published: May 2016

Abstract
Multiple experimental approaches were used to examine whether and by what mechanism galeterone affects prostate cancer growth in cells and tumors expressing androgen receptor (AR) splice variants, such as AR-V7. Galeterone is a selective, multitargeted, small molecule that disrupts androgen signaling at multiple points in the pathway. ARMOR3-SV is a Phase 3, randomized, open-label, multicenter, controlled clinical trial in metastatic castration resistant prostate cancer (mCRPC) patients whose tumors express AR splice variant-7 mRNA (AR-V7). AR-V7 is a truncated, constitutively active splice variant of the AR that lacks the ligand binding domain (LBD) and has been implicated in prostate cancer progression. The expression of AR-V7 occurs in approximately 14-26% of men with mCRPC prior to second-generation anti-androgens or chemotherapy, and AR-V7 expression has been clinically associated with resistance to enzalutamide (Xtandi) or abiraterone (Zytiga). Here we provide the pre-clinical and clinical rationale for the development of galeterone in mCRPC patients with AR-V7.
Our findings show that using multiple pre-clinical approaches, galeterone reduces in vitro prostate cancer cell proliferation, androgen receptor signaling and xenograft tumor growth using cells and tumors that express AR splice variants. Reductions in AR splice variant protein were also observed in cells that also co-express wild-type AR, and prostate cancer cells that lack wild type AR, but transiently express AR splice variant protein. Clinical data further support activity of galeterone in patients with truncated androgen receptors. Galeterone's unique mechanism of AR protein downregulation occurs in both splice variant and wild-type AR, supporting that galeterone-induced AR downregulation is independent of the AR LBD. Because preclinical and clinical data support an opportunity for treatment in this setting, Tokai Pharmaceuticals designed ARMOR3-SV to test galeterone vs. enzalutamide in men with metastatic castration-resistant prostate cancer whose tumors express the AR-V7 splice variant.
Citation Format: Douglas B. Jacoby, Amina Zoubeidi, Eva B. Corey, Elahe Mostaghel, Andrew K. Kwegyir-Afful, Senthilmurugan Ramalingam, Vincent Njar. Galeterone shows anti-tumor activity in multiple pre-clinical models that express androgen receptor splice variants, supporting correlative patient data seen in ARMOR2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B173.