bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1070: SCR6106, an oral and brain penetrant SERD demonstrated anti-tumor activities in vitro and in vivo
Authors: Zhou Feng , Liu Lei , Yang Guimei , Gu Peng , Xue Liting , Yang Wenqing , Chen Ping , Tang Renhong 
Published: July 2021

Abstract
Benefits of endocrine therapy in treating hormone receptor (HR)-positive (HR+) BC are well recorded in clinic. However, ~40% to 50% of HR+ patients eventually developed to endocrine resistance and disease relapsed. Fulvestrant, a selective estrogen receptor degrader (SERD) is approved to treat HR+ metastatic breast cancer in patients with disease progression after endocrine therapy. However, due to its poor bioavailability, it is given by intramuscular injection, which makes inconvenience in administration. Additionally, approximately 14% of hormone positive patients with advanced breast cancer are diagnosed with brain metastases, while, at present, there are no FDA-approved systemic therapies for the treatment of breast cancer brain metastases. Therefore, to develop a new generated oral and brain-penetrant SERD to overcome these challenges is believed to be needed. SCR6106, discovered and currently being developed by Simcere, is a novel, potent, orally delivered and non-steroidal SERD that both antagonizes and degrades ERα. SCR6106 showed high potency on inducing ERα protein degradation (DC50=0.29 nM) and anti-proliferation (IC50=0.43 nM) in MCF7 cells. In addition, SCR6106, showed high activities on ERα degradation and anti-proliferation in a panel of ER+ breast cancer cell lines. Meanwhile, ER target genes transcription were evaluated and SCR6106 exhibit strong suppressive phenotype in T-47D. SCR6106 demonstrated more potent than fulvestrant on anti-tumor growth in vivo. In MCF7 xenograft model, SCR6106 at 3 mpk QD induced 113% tumor growth inhibition (TGI), compared to fulvestrant 56.8% TGI at 250 mpk. Compared to fulvestrant, SCR6106 demonstrated stronger ERα degradation and inhibition of ER target genes transcription in tumors, which was consistent with anti-tumor activities. SCR6106 displayed good oral bioavailability in multiple pre-clinical species, which supports its oral administration in human. Significantly, SCR6106 possess a high BBB permeability, the B/P ratio is more than 4 in pre-clinical species. The exposure of SCR6106 observed in mouse brain is much higher than the IC90 value of anti-proliferation (MCF7), and SCR6106 demonstrated anti-tumor activities in a MCF-7 intracranial tumor xenograft model. In conclusion, SCR6106 is a novel, potent and oral SERD, which demonstrated anti-tumor activities in vitro and in vivo. It showed high potential ability to cross the blood-brain barrier, and could be used to treat HR+ patients with brain metastasis.
Citation Format: Feng Zhou, Lei Liu, Guimei Yang, Peng Gu, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang. SCR6106, an oral and brain penetrant SERD demonstrated anti-tumor activities in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1070.
Abstract 1084: Targeting MET and RON to overcome cetuximab resistance in colorectal cancer
Authors: Graves-Deal Ramona , Bogatcheva Galina , Damalanka Vishnu , Klampfer Lidija , Janetka James W. , Coffey Robert J. , Singh Bhuminder 
Published: July 2021

Abstract
Using a novel 3D culture system, we previously showed that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to cetuximab resistance in colorectal cancer (CRC) cells. CC derived from HCA-7 cells were sensitive to cetuximab, whereas similarly derived SC were resistant; we also generated cetuximab-resistant (CC-CR) upon prolonged exposure of CC to cetuximab. Both de novo and acquired modes of cetuximab resistance in SC and CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. Moreover, MET and RON ligands, HGF and HGFL, respectively are synthesized as inactive precursors and require cleavage by proteases (HGFA, Matriptase, and Hepsin) to be biologically active. Herein, to inhibit HGF/HGFL cleavage in cetuximab-resistant cells, we employed inhibitors of proteases of HGF/HGFL (ZFH7116 and VD2173) and were able to overcome both de novo and acquired cetuximab resistance. We are now in the process of engineering cetuximab-sensitive CC cells to overexpress HGF or HGFL to test if ligand overexpression imparts cetuximab resistance and if this resistance can be overcome by inhibition of HGF/HGFL proteases and/or by crizotinib. To understand the broader significance of these resistance mechanisms, we have identified a set of KRAS wild-type human CRC patient-derived tumor xenografts (PDXs) that show increased MET/RON phosphorylation. A comparative RNA-seq analysis showed that PDXs with high pMET/pRON levels could be segregated from PDXs with low pMET/pRON levels. Differential response of these PDXs and their organoid (PDO) derivatives for cetuximab resistance and response to crizotinib addition based on their pMET/pRON levels will be presented.
Citation Format: Ramona Graves-Deal, Galina Bogatcheva, Vishnu Damalanka, Lidija Klampfer, James W. Janetka, Robert J. Coffey, Bhuminder Singh. Targeting MET and RON to overcome cetuximab resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1084.
Abstract 1087: CXCR2 and its ligands modulate chemotherapy resistance in pancreatic ductal adenocarcinoma
Authors: Molczyk Caitlin , Prajapati Dipakkumar R. , Saxena Sugandha , Goel Paran , Varney Michelle , Singh Rakesh K. 
Published: July 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest survival rates of cancers, with a five-year relative survival of 9%. The significant factor contributing to low survivorship is the intrinsic resistance to chemotherapy. In the present study, we elucidate a targetable pathway that facilitates resistance in these cells. One inflammatory pathway used in cancer progression is CXCR2, which binds chemokines CXCL 1-3 and 5-8. Our group and others have shown an association of CXCR2 with tumor progression, angiogenesis and metastasis in PDAC, and chemotherapy resistance in other cancers. In this study, we test the hypothesis that CXCR2 is integral in PDAC chemotherapy resistance. We generated gemcitabine resistant cell lines (GemR) from the parent cell lines of T3M4 (WT KRAS) and CD18/HPAF (Mutant KRAS) with 40- and 67-fold higher resistance in comparison to the parent cell lines, respectively. Using qRT-PCR and ELISA, we profiled chemokines' expression, CXCL1, 5, and 8, on parent- and GemR-cell lines. We observed a higher basal level expression of CXCL1, 5, and 8 ligands in GemR cells than the parent cell lines. Further treatment with gemcitabine, the parent cell lines had a higher increase in CXCL1 and 8 ligand expression in comparison with GemR cell lines. With further investigation of T3M4, we found a dose-dependent and time-dependent increase for CXCL1 and CXCL8. CXCL5 had a constant high expression with all doses of gemcitabine. With our initial observations of gemcitabine treatment enhancing CXCR2 ligands in PDAC cells, we evaluated the effects of the small molecule CXCR2 antagonist SCH 479833 (SCH 47) in combination with gemcitabine treatment on the parent and GemR cell lines. We used the relative IC50 and half the relative IC50 for both the gemcitabine and SCH 47 treatment doses. We observed that a lower concentration of gemcitabine in the presence of the SCH 47 was more effective than the higher concentration of gemcitabine without SCH 47 for the GemR-cell lines. Together, our observations show chemotherapy-resistant PDAC cell lines express higher CXCR2 ligand levels at baseline, with parent cell lines increasing expression with chemotherapy treatment. We also show an advantageous combination treatment of CXCR2 antagonist with lower gemcitabine concentration. Overall, these results show a promising future for CXCR2 antagonism in the treatment of resistant PDAC tumors.
Citation Format: Caitlin Molczyk, Dipakkumar R. Prajapati, Sugandha Saxena, Paran Goel, Michelle Varney, Rakesh K. Singh. CXCR2 and its ligands modulate chemotherapy resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1087.
Abstract 1118: Engineered cell line panel complemented with in vivo models to enable next-generation target therapy discovery in cancer
Authors: Zhang Zhixiang , Shi Xiaohe , Zuo Xiangyang , Gu Qingyang , Ji Qunsheng 
Published: July 2021

Abstract
Many cancer types are driven by specific gene aberrances, like gene fusions, mutations and copy number changes. It has led to the successful application of a number of target therapeutics, of which kinase inhibitors represent a good example. However, acquired resistance is almost inevitable at the end of any target therapy treatment, which makes it urgent a need to discover new-generation therapeutics. There are strong evidences suggesting acquired resistance should be largely attributed to certain secondary mutations, such as EGFRT790M, RETV804L and BTKC481S. At discovery stage it is critical to generate preclinical cancer models harboring these specific gene aberrances both in vitro and in vivo. Biopsy from patient with clinical resistance could be an optional starting point. But it is much more straightforward and efficient if these well-studied gene aberrance could be constructed and engineered into host cell lines directly. The transformed cell line can further be inoculated into host mice to make in vivo test feasible. Here we are reporting the establishment of a panel of engineered BaF3 cell lines for a series of cancer driver gene aberrances against EGFR, RET, ROS1, BTK and FLT3. Taking RET as example, we constructed the activating gene fusion of KIF5B-RET, along with its mutated versions, KIF5B-RETV804L and KIF5B-RETV804M. These 3 constructs were transfected into BaF3 cell line, respectively. After rounds of in vitro selection, the stable BaF3 cell line harboring KIF5B-RETWT, KIF5B-RETV804L or KIF5B-RETV804M was subjected into in vitro test of three multiple kinase inhibitors with RET inhibitory activity, including Ponatinib, Sunitinib and Sorafenib. Consistent to other reports, Ponatinib was demonstrated superior to the other two RET inhibitors when suppressing the two V804 mutated cell line growths. The in vivo growth of these cell lines have also been confirmed in house. Beyond these five target genes, we have been working on other driver genes to expand the panel scope continuously. HER2 exon20 ins, PDGFRaT674I and KITT670I models are already under development, while many others are on our radar. In summary, our ever-expanding panel of engineered cell lines complemented with in vivo models represents valuable assets to empower the discovery of next-generation target therapeutics against cancer.
Citation Format: Zhixiang Zhang, Xiaohe Shi, Xiangyang Zuo, Qingyang Gu, Qunsheng Ji. Engineered cell line panel complemented with in vivo models to enable next-generation target therapy discovery in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1118.
Abstract 1147: RNA-targeting approaches to modulate alternative RNA splicing in cancer
Authors: Leclair Nathan K. , Urbanski Laura , Brugiolo Mattia , Yurieva Marina , Graveley Brenton R. , Cheng Albert , Anczukow Olga 
Published: July 2021

Abstract
Alternative RNA splicing (AS) is a critical step in gene expression regulation. This differential inclusion of sequences in the mRNA is a source of functional transcriptomic diversity that allows multiple RNA isoforms to be expressed from the same gene. Dysregulation of AS is hallmark of cancer and leads to the expression of RNA isoforms that promote tumor initiation and maintenance. Understanding how tumor-associated RNA isoforms impact cancer biology is needed for the development of cancer therapies targeting AS. Here, we describe two approaches to modulate AS in cancer cells. First, we utilize CRISPR-Artificial Splicing Factors (CASFx), splicing factor domains fused to catalytically inactive Cas13 proteins, to direct splicing activity to a specific site using a guide RNA (gRNA). We demonstrate that this approach can be used to promote either exon inclusion or skipping in mRNA from several cancer-associated genes (e.g., HRAS, EP400, TRA2β, SRSF3) depending on the gRNA binding location and the splicing-factor domain fusion. Second, we develop antisense oligonucleotides (ASOs) that target a non-coding poison exon in the oncogenic splicing factor TRA2β. This exon functions as a regulatory “poison exon”, which induces RNA degradation when included, and is differentially spliced in multiple tumor types compared to their corresponding adjacent normal tissue. TRA2β-targeting ASOs promoting poison exon inclusion cause decreased TRA2β protein expression, increased cell death, and decreased proliferation across multiple cancer cell lines. Additionally, compared to cancer cells, normal cell lines were less affected by TRA2β-targeting ASO toxicity, demonstrating a therapeutic window for using this technology to specifically target cancer cells.
Citation Format: Nathan K. Leclair, Laura Urbanski, Mattia Brugiolo, Marina Yurieva, Brenton R. Graveley, Albert Cheng, Olga Anczukow. RNA-targeting approaches to modulate alternative RNA splicing in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1147.
Abstract 1166: Structurally defined glycosaminoglycan mimetics exhibit preference for proteins of the growth factor family
Authors: O'Hara Connor P. , Sankaranarayanan Nehru V. , Boothello Rio S. , Patel Bhaumik B. , Desai Umesh R. 
Published: July 2021

Abstract
Heparan sulfate (HS), a glycosaminoglycans of considerable structural diversity, has been implicated in a wide-variety of complex roles including regulation of cell signaling. Unfortunately, homogeneous HS is a dream that will likely be unfulfilled this century. To combat this, our lab has synthesized an array of non-saccharide glycosaminoglycan mimetics (NSGMs) that act as structural and functional mimetics of HS. A key advantage of our NSGMs is homogeneity, which enables assessing selectivity for recognition of target proteins with a high degree of confidence. A second advantage is the quantitative measurement of the affinity of these interactions, which affords a detailed understanding of the forces governing recognition of different proteins. Previously, we have shown a lead NSGM named G2.2 as a potent and selective inhibitor of colorectal cancer stem cells (CSCs) through phenotypic in-vitro and in-vivo assays. To improve upon the drug-like properties of G2.2, cholesterol-modified analogs (G2C, G5C, G8C) were designed to enhance potency and selectivity for protein target(s). Although the hypothesis is that G2.2 and its lipidic analogs target a ligand and/or a receptor belonging to CSC-relevant growth factors, the preferred target, if any, remains to be identified. More importantly, the relative order of preference in-vitro and its use in predicted in-vivo activity remains to be determined. In this work, we have performed a comprehensive biophysical screening of a panel of potential growth factor targets using biophysical methods to determine binding affinities, followed by quantitative measurement of the relative forces of interactions involved in target recognition. Our studies are complemented by computational experiments that provide a foundation for thermodynamic studies. Analysis of our results indicate that these NSGMs preferentially recognize certain growth factor proteins, suggesting that appropriately designed HS mimetics can be tailored to modulate a particular tyrosine kinase receptor pathway. More importantly, our results convey the principle that despite the presence of multiple sulfate groups, HS mimetics can be designed to exhibit selectivity for certain growth factor proteins. In fact, the sulfate groups on our molecules may actually contribute to the selectivity and potency of recognition, two central principles for the development of drugs.
Citation Format: Connor P. O'Hara, Nehru V. Sankaranarayanan, Rio S. Boothello, Bhaumik B. Patel, Umesh R. Desai. Structurally defined glycosaminoglycan mimetics exhibit preference for proteins of the growth factor family [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1166.
Abstract 1187: Optimizing gemcitabine in metastatic TNBC by rational PI3K/AKT combination
Authors: Merrill Nathan M. , Vandecan Nathalie M. , Apfel Athena M. , Ulintz Peter J. , Bao Liwei , Cheng Xu , Morikawa Aki , Merajver Sofia D. , Soellner Matthew B. 
Published: July 2021

Abstract
Metastatic triple-negative breast cancer (TNBC) has a median survival of 13 months, and only 5 months if brain metastases are present. Advances in immunotherapy are promising, but only add weeks to a few months of progression-free survival to this guarded prognosis. Thus, there is a large unmet need for innovations that improve patient outcomes in the metastatic setting when patients are refractory to first-line treatment. Recently, we published an innovative strategy to identify multi-omic molecular correlates of drug response in TNBC. From this work, we now apply the strategy to 3D cell culture models and patient derived xenografts (PDXs) that are more representative of in vivo drug response in real patients. In brief, we have tested the dose response for a panel of 387 investigational drugs and plotted this readout against molecular characterization in 35 TNBC cell lines and PDXs. Using linear regression, we have identified statistically significant positively and negatively correlating DNA, RNA, and protein predictors of drug efficacy. From this expanded multi-omic set, we have identified a multi-omic signature for sensitivity to gemcitabine, a drug widely used in TNBC, but at present, without any a priori knowledge of who is likely to benefit. Moreover, we noted a significant correlation of response with MERIT40, an AKT substrate. MERIT40 is critical for localization of BRCA1 to facilitate DNA damage repair. MERIT40 promotes resolution of DNA damage caused by chemotherapy, and thus, based on our published work and supporting literature, PI3K/AKT inhibition is a rational synergistic partner with gemcitabine. Moreover, further supporting our hypothesis, preliminary results indicate Chou-Talalay synergy at therapeutically relevant doses when gemcitabine is combined with PI3K/AKT inhibition. In future studies, we will evaluate the ability of the gemcitabine biomarker to predict response, and the efficacy of the prioritized combinations using ex vivo patient models of metastatic breast cancer established in our laboratory.
Citation Format: Nathan M. Merrill, Nathalie M. Vandecan, Athena M. Apfel, Peter J. Ulintz, Liwei Bao, Xu Cheng, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner. Optimizing gemcitabine in metastatic TNBC by rational PI3K/AKT combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1187.
Abstract 1189: Association of RAS pathway mutations with lower CD8+ T cell infiltration and 2-year survival rate in Stage-III colorectal adenocarcinoma patients
Authors: Jiang Zhipeng , Zhao Feilong , Chen Hui , Zhao Xiaochen , Bai Yuezong 
Published: July 2021

Abstract
Background: The oncogenic pathways, including WNT, TP53, RAS, PI3K and TGFβ, were associated with tumor progression in colorectal adenocarcinomas (CRC). However, a majority of CRC patients have mutations from multiple pathways simultaneously, which makes it difficult to identify the key pathway influencing prognosis of CRC. Herein, we aimed to evaluate the novel dominant pathway-typing method in predicting the prognosis of Stage-III CRC.
Methods: Clinicopathologic and molecular variation data of Stage-III CRC patients (n=152) were obtained from The Cancer Genome Atlas database (TCGA). Immune cell infiltration level of the tumor was calculated by xCell (https://xcell.ucsf.edu/). Oncogenic pathway genes were classified according to a TCGA study (PMID: 29625050). In each patient, the dominant pathway-typing were based on which pathway the genes with the highest variant-allele-frequency (VAF) belongs to.
Results: In all, 124/152 (82%) patients had mutation on at least one of the oncogenic pathway genes and 120/124 (97%) patients harbored mutations from two or more pathways simultaneously. According to their dominant pathway-typing method, the patients were classified into five groups: WNT (n=45), RAS (n=26), TP53 (n=36), PI3K (n=8) and TGFβ (n=9) groups. There was no significant difference in OS among the five groups. However, the two-year survival rate of RAS group was significantly lower than that of WNT (p=0.042) and TP53 (p=0.035) groups. Further, we found that the infiltration of CD8+ T cell was significantly lower in RAS group compared to WNT group (with median infiltration score: 0.005 vs 0.013, p=0.024). Importantly, we found that among the RAS group without CD8+ T-cell infiltration, 63% (5/8) patients were died within two years after diagnosis. While the two-year death rate of WNT and TP53 groups without CD8+ T cell infiltration were zero (0/6) and 14% (1/7). And the two-year death rate of RAS, WNT and TP53 groups with CD8+ T cell infiltration were 17% (1/6), 11% (3/27) and 8% (1/13), respectively.
Conclusion: RAS pathway mutation may be associated with low CD8+ T cell infiltration and promote the two-year death rate of stage-III CRC patients using dominant pathway-typing method. And further larger cohorts are needed to validate these findings and the underlying mechanisms.
Citation Format: Zhipeng Jiang, Feilong Zhao, Hui Chen, Xiaochen Zhao, Yuezong Bai. Association of RAS pathway mutations with lower CD8+ T cell infiltration and 2-year survival rate in Stage-III colorectal adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1189.