bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1170: Designing a biomarker-based bedside tool-kit for the clinical evaluation of bladder cancer
Authors: Dabke Isha R. , Pearce Richard , Kallifatidis Georgios , Lokeshwar Balakrishna 
Published: August 2019

Abstract
Cancer of the urinary bladder (UBC) ranks second in incidence and mortality among the genitourinary cancers causing over 16,000 deaths annually. Currently, the precise diagnosis of bladder cancer involves cystoscopy and cytology, both expensive and painful procedures. Morphologically, malignancies of the bladder can be divided into two subtypes: luminal and basal, which express distinct cytokeratin and stem cell markers and have differing sensitivities to therapy. Although diagnosis based on molecular signatures has the potential to be effective, a verification of their expression in strictly compartmentalized epithelial subtypes is not presently available. The implications of this project are the formation of a bedside tool-kit based on prognostic stem cell biomarkers that can be used following biopsy to efficiently evaluate cancer subtype and provide a preliminary diagnosis.
Towards that goal, we analyzed mRNA expression profiles in five established bladder cancer cell lines (RT-4, 5637, T24, HT-1376, 253J), ranging from a grade I (RT-4) to a grade IV cancer cell line (253J). Based on existing literature, these cell lines were classified into either the luminal or basal subtype of bladder cancer. Through RT-PCR and Western Blot studies, genomic expression levels of eleven biomarkers (luminal: UPK, GATA-3, RAB-25, E-Cadherin; and basal: CK-6, p63, CD44S, CD44V, CyclinB1, EGFR, CD49) were analyzed in these cell lines.
Cell viability following exposure to two chemotherapy drugs: Gemcitabine and Cisplatin, commonly used to treat bladder cancer, were assayed by colorimetric and clonogenic colony-forming assays. Literature states that though basal cancers are more aggressive, they are paradoxically more sensitive to chemotherapy compared to luminal UBC.
Less aggressive/luminal UBC cell lines showed higher mRNA levels for luminal biomarkers, and expressed GATA-3 100% of the time. The more invasive/basal cell lines showed only a slight upregulation of basal biomarkers, but expressed CD44S 100% of the time.
Furthermore, MTT Assays showed a significant toxic effect of Gemcitabine on basal cell lines earlier (t=24 hr vs 48/72 hr) than luminal cell lines. However, Cisplatin did not show a significant difference in luminal vs. basal UBC suggesting that the two subtypes of UBC have similar sensitivity to Cisplatin.
The study presented here suggests that a PCR-based, biomarker toolkit can aid in an efficient classification of bladder cancers at the bedside, and treatment can be personalized based on the UBC subtype.
Citation Format: Isha R. Dabke, Richard Pearce, Georgios Kallifatidis, Balakrishna Lokeshwar. Designing a biomarker-based bedside tool-kit for the clinical evaluation of bladder 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 1170.
Abstract 1199: Identification of candidate regulators of genomic instability in human lung adenocarcinoma through a new cross-species in silico analysis
Authors: Rao Chinthalapally V. , Farooqui Mudassir , Zhang Yuting , Kumar Gaurav , Panneerselvam Janani , Yarla Nagendra , Asch Adam S. , Yamada Hiroshi Y. 
Published: August 2019

Abstract
(a) Chromosome instability (CIN), a type of genomic instability that is mitotic error-driven, has a deep impact on carcinogenesis and cancer recurrence. High CIN is a marker for poor prognosis in various cancers, including lung adenocarcinoma. In the tumor genome, CIN can be indicated with Copy Number Alterations (CNA) as its surrogate indicator. Although a diverse array of genes can cause CIN at the cellular level, genes responsible for tumor CNA remain elusive. In this study, we set out to identify genes whose expression shows correlation with CNA in human lung adenocarcinoma.
(b) We employed a novel cross-species in silico analysis. Our previous lung RNAseq results from lung cancer-prone CIN mice indicated 348 misregulated genes (92 up-regulated, 256 down-regulated; 2-fold cutoff, P&lt;0.05). We hypothesized that some of the genes misregulated in CIN mice are involved in genomic instability in tumors. With in silico analysis with a human cancer genome database, we identified five human genes as candidate regulators of CNA in human lung adenocarcinoma: MMP13, NUF2, CCL22, ZNF366, and GPR114. High expression of MMP13, CCL22, ZNF366, and GPR114 was correlated with low CNA, suggesting their role in suppressing CIN. High expression of NUF2 was correlated with high CNA, suggesting its role in increasing CIN.
(c) MMP13 (Matrix Metalloprotease 13) is a protease involved in the breakdown of extracellular matrix. NUF2 (yeast NUF2 Kinetochore Protein homolog) is involved in the mitotic process, the misregulation of which directly leads to CIN. CCL22 (C-C Motif Chemokine Ligand 22), ZNF366 (Zinc Finger Protein 366), and GPR114 (G protein-coupled receptor 114, aka ADGRG5) are generally markers for subsets of immune cells (likely dendritic cells). This result led us to further hypothesize that infiltration of CCL22-, ZNF336-, and/or GPR114-positive immune cells inhibits pre-tumor cells and tumor cells with high CNA.
(d) The removal mechanism of cells with genomic instability is poorly understood. This is the first time that candidate markers for the immune cells directly or indirectly involved in removal of CIN cells have been identified. This study may aid in fine-tuning cancer-preventive immunotherapy that targets lung cells with genomic instability.
Citation Format: Chinthalapally V. Rao, Mudassir Farooqui, Yuting Zhang, Gaurav Kumar, Janani Panneerselvam, Nagendra Yarla, Adam S. Asch, Hiroshi Y. Yamada. Identification of candidate regulators of genomic instability in human lung adenocarcinoma through a new cross-species in silico analysis [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 1199.
Abstract 1248: Not BCL2 but BFL1 is overexpressed and have strong correlation with NF-kB pathway in diffuse large B-cell lymphoma
Authors: Lee Chansub , Song Hyojin , Song Seulki , Kim Daeyoon , Park Jihyun , Lee Sungyoung , Yun Hongseok , Kim Sheehyun , Yoon Sung-Soo , Koh Youngil 
Published: August 2019

Abstract
Venetoclax, anti-apoptotic BCL2-selective inhibitor, has demonstrated efficacy in B-cell multiple lymphoid malignancies. However, several studies have shown that the other anti-apoptotic BCL2 family genes can increase the risk of venetoclax resistance. Accordingly, compounds targeting other BCL2 family are actively being developed. So it is necessary to find which BCL2 family genes is overexpressed in certain tumors. We profiled BCL2 family genes expression with RNA-seq across different types of lymphoid malignancies (follicular lymphoma, burkitt lymphoma, diffuse large b-cell lymphoma, multiple myeloma, and acute leukocyte leukemia). Log2-transformed TMM-normalized RPKM was used for expression levels. As is known, BCL2 and MCL1 was highly expressed in follicular lymphoma and multiple myeloma, respectively. Interestingly, we discovered BFL1, one of anti-apoptotic BCL2 family genes, is overexpressed in both activated B-cell (ABC) and germinal center B-cell (GCB) type diffuse large B cell lymphoma (DLBCL). It has been well known that BFL1 is a pro-survival NF-kB target gene and indeed NF-kB pathway is highly activated in ABC-DLBCL. Also recent studies have shown that activation of this pathway can occur in GCB-DLBCL. Using gene set enrichment analysis, we confirmed that high expression of BFL1 is associated with negative regulation of intrinsic apoptosis and activation of NF-kB in B-cell. Also we discovered that NF-kB pathway activation in correlation with BFL-1 is especially dominant in DLBCL compared to other lymphoid malignancies. Among NF-kB signal related molecules (TNF receptors or Toll-like receptors), CD40 expression significantly correlated with BFL1 expression. In contrast, BCL2, another important apoptosis related gene, showed a negative association with the NF-kB pathway in DLBCL. We could validate our observation using microarray data. In conclusion, BFL1, which may controls intrinsic apoptosis and have strong correlation with NF-kB, is overexpressed in DLCBL. We suggest not venetoclax but BFL1 inhibitor may exert clinical benefit in DLBCL.
Citation Format: Chansub Lee, Hyojin Song, Seulki Song, Daeyoon Kim, Jihyun Park, Sungyoung Lee, Hongseok Yun, Sheehyun Kim, Sung-Soo Yoon, Youngil Koh. Not BCL2 but BFL1 is overexpressed and have strong correlation with NF-kB pathway in diffuse large B-cell lymphoma [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 1248.
Abstract 1249: The role of PRMT5 in MYC-driven medulloblastoma
Authors: Chaturvedi Nagendra K. , Kesherwani Varun , Kling Matthew J. , Ray Sutapa , McGuire Timothy R. , Joshi Shantaram S. , Sharp J. Graham , Coulter Don W. 
Published: August 2019

Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor, accounting for about 20% of all brain tumors in children. Children with Group 3 MB (aberrant MYC) show the worst prognosis, with &lt;50% survival. Recently, the role and association of protein arginine methyl transferase (PRMT) 5 have been closely associated with aberrant MYC function in various cancers including other brain tumors such as glioblastoma. However, the role of PRMT5 and its association with MYC in MB have not been explored. Here we provide preliminary data indicating PRMT5 as a novel regulator of MYC and implicating PRMT5 as a potential therapeutic target in MYC-driven MB. Using cell lines, our results showed PRMT5 overexpression in MYC-driven MB compared to non-MYC MB. The results from co-immunoprecipitation experiment in MYC-driven MB cells demonstrated that MYC physically associates with PRMT5 by direct protein-protein interaction. In addition, cycloheximide chase experiment showed that PRMT5 regulates MYC stability. Knockdown of PRMT5 using siRNA in MYC-driven MB cells significantly decreased cell growth and MYC expression. We also tested the therapeutic potential of targeting PRMT5 against MB cell lines using a small molecule inhibitor EPZ015666. We observed a dose-dependent efficacy of EPZ015666 in suppressing cell growth in MYC-driven MB cell lines. We also observed a superior efficacy of this inhibitor against MYC-driven MB cells compared to non-MYC MB cells. Together, our results implicate the regulation of MYC oncoprotein by PRMT5, and suggest that targeting PRMT5 could be a potential therapeutic strategy for MYC-driven MB and other MYC-driven cancers.
Citation Format: Nagendra K. Chaturvedi, Varun Kesherwani, Matthew J. Kling, Sutapa Ray, Timothy R. McGuire, Shantaram S. Joshi, J. Graham Sharp, Don W. Coulter. The role of PRMT5 in MYC-driven medulloblastoma [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 1249.
Abstract 1272: Whole genome Crispr screening to identify potential SERD molecule resistance mechanisms
Authors: Marcireau Christophe , Berthelot Karine , Williart Alice , Fournet Hamida , Debono Delphine , Thill Gilbert , Erasimus Helene , Chassin Dorine , Lanneau Christophe , Yaligara Veeanagouda , Orsini Cecile , Didier Michel , Mikol Vincent , Bouaboula Monsif , Debussche Laurent 
Published: August 2019

Abstract
Metastatic breast cancer results in substantial morbidity and mortality for women afflicted with this disease. Approximately 80% of breast cancers express the estrogen receptor. The cancer cell survival and proliferation is driven by the activation of the estrogen receptor. SAR439859 is an effective endocrine therapy for breast cancer selectively and effectively degrading the estrogen receptor. A phase 1/2 study of SAR439859 alone and/or in combination with palbociclib in postmenopausal women with estrogen receptor positive advanced breast cancer was initiated last year by Sanofi.
CRISPR/Cas9 is a recent and revolutionary technology for efficient and directed alterations of the genome. CRISPR allows users to introduce DNA double-strand breaks at precise locations in the genome using complementary guide RNAs (SgRNA). These double strand breaks can be repaired by non-homologous end joining DNA repair mechanism. This DNA repair mechanism is an error prone DNA repair process which can lead to gene invalidation.
We aimed at investigating the potential SAR439859 resistance mechanisms. A better understanding of resistance mechanisms is needed to overcome this potential problem and to propose complementary therapeutic solutions. We conducted a whole genome CRISPR screening in a breast tumor cell line with a thermofisher commercial SgRNA library (ref: M04305) to identified genes involved in potential SAR439859 resistance phenomena. CRISPR screening steps will be presented from the cell line selections to results analysis.
Citation Format: Christophe Marcireau, Karine Berthelot, Alice Williart, Hamida Fournet, Delphine Debono, Gilbert Thill, Helene Erasimus, Dorine Chassin, Christophe Lanneau, Veeanagouda Yaligara, Cecile Orsini, Michel Didier, Vincent Mikol, Monsif Bouaboula, Laurent Debussche. Whole genome Crispr screening to identify potential SERD molecule resistance mechanisms [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 1272.
Abstract 1282: Understanding the kinomic contributions to tyrosine kinase inhibitor resistance in triple negative breast cancer
Authors: Lefebvre Cory , Litchfield David , Allan Alison 
Published: August 2019

Abstract
There is an increasing need to develop targeted therapies for triple negative breast cancer (TNBC), as conventional chemotherapy, anti-hormone or anti-HER2 therapies are ineffective at combatting systemic disease. TNBC tumors often have increased expression of receptor tyrosine kinases such as EGFR (epidermal growth factor receptor) and the hepatocyte growth factor (HGF) receptor, c-Met; presenting as potential targets for treatment. However, targeted anti-Met and anti-EGFR therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that dynamic changes in the kinome contribute to the acquired resistance of TNBC tumors to c-Met and EGFR inhibitors. Using MDA-MB-468 and MDA-MB-231 TNBC cell lines, we investigated the effects of the c-Met inhibitors cabozantinib and tivantinib and the EGFR inhibitor erlotinib on cell proliferation and activation of target receptors and downstream signalling pathways. We observed that cabozantinib and erlotinib significantly inhibited the proliferation (p≤0.05) of one and/or both TNBC cell lines in a cytostatic fashion. Similarly, tivantinib demonstrates growth inhibitory effects but in a mostly cytotoxic manner; consistent with recent reports of its mechanism in inhibiting microtubule polymerization. Exposure to erlotinib (24 hrs) resulted in decreased expression of phosphorylated and total EGFR in both TNBC cell lines and a decrease in activation (phosphorylated:total expression) of ERK1/2 in MDA-MB-468 cells (p≤0.05). Tivantinib and cabozantinib did not appear to have any effects on activation of c-Met or ERK1/2 in MBA-MB-231 or MDA-MB-468 cells following 24-hour exposure. Ongoing studies are aimed at implementing a novel kinomics strategy using SILAC and multiplexed inhibitor beads for kinase enrichment to investigate the dynamic changes in the kinome of susceptible and resistant cell lines in response to erlotinib and cabozantinib. With better understanding of the underlying mechanisms, we can potentially discover targets that could attenuate induced resistance to tyrosine kinase inhibitors.
Citation Format: Cory Lefebvre, David Litchfield, Alison Allan. Understanding the kinomic contributions to tyrosine kinase inhibitor resistance in triple negative breast 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 1282.
Abstract 1284: Resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma
Authors: Patel Hima , Mishra Rosalin , Joan Garrett 
Published: August 2019

Abstract
Melanoma five year survival rates are only 15% for patients with advanced disease. About 50% of melanomas contain the BRAFT1799A transversion which encodes for the constitutively active BRAFV600E oncoprotein. This opened up avenues for development of BRAF inhibitors which resulted in a response rate of about 50% and median progression-free survival of about 5 months. Co-targeting the downstream MEK protein with a MEK inhibitor along with BRAF inhibitor resulted in response rates of about 70% and are now approved as standard of care for patients harboring the BRAF-mutant melanoma. In spite of these successes, their long-term efficacy has been limited due to acquired resistance to these inhibitors. In order to study mechanisms underlying resistance, we generated dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) resistant WM115 (WM115 TDR) and WM983 (WM983 TDR) cell lines by adding increasing concentration of the drugs to WM115 and WM983 cells with BRAFV600E mutation (parental cells). We observed that the resistant cells undergo a change in their morphology and continue to remain viable over increasing doses of dabrafenib and trametinib as compared to parental cells demonstrated by MTT cell proliferation assay and Matrigel 3D assay. TDR cells demonstrated maintenance of p-ERK levels at 4 and 24 hours which under the same conditions p-ERK was inhibited in the parental cells. Current studies underway include RNA sequencing in order to decipher differentially expressed genes in the parental and TDR which could mediate resistance to BRAF and MEK inhibitors. Additionally we will examine phosphorylated receptor tyorsine kinases (RTKs) using an array to identify divergences among activation of RTKs in parental versus TDR cells. Deciphering causes of resistance to BRAF and MEK inhibitors will help in the development of novel mechanism-based interventions aiding long-term patient prospects in BRAF-mutant melanoma.
Citation Format: Hima Patel, Rosalin Mishra, Garrett Joan. Resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma [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 1284.
Abstract 1326: WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor
Authors: Zhong Wei , Zhang Jinqiang , Mu Ahihua , Sun Claire 
Published: August 2019

Abstract
Aberrant activity caused by EGFRm+ (EGFRvIII/Del19/L858R) is implicated in the brain tumors such as GBM and DIPG, and metastatic CNS tumors of NSCLC, and cancer of HNSCC. To date, approved EGFRi has limited efficacy against brain tumors due to insufficient BBB penetration and/or poor activity against EGFRvIII. Moreover, GBM is a whole-brain disease and needs a BBB penetrable therapy for killing tumor cells beyond intact BBB. We report that WSD0922, a novel selective EGFRi, displays potent activity, excellent CNS penetration, good safety profile and preclinical anti-tumor efficacy. The IC50 of WSD0922 against EGFRm+ &lt;10nM and the ex-vivo GI50 in GBM PDX with EGFRvIII is ~20nM. WSD0922 is highly selective over other kinases. WSD0922 treatment resulted in dose dependent inhibition on EGFRvIII phosphorylation and AKT phosphorylation in GBM PDX model and the in vivo PD modulation correlated well with PK and efficacy. WSD0922 treatment significantly prolonged the survival of mice with intracranial tumor of EGFRm+ NSCLC. WSD0922 treatment resulted in tumor regression on cetuximab resistant PDX model of HNSCC. In screening platform of squamous lung cancer PDX models, WSD0922 demonstrated remarkable tumor regression in 3 PDX models (platinum sensitive/insensitive/EGFRm+). WSD0922 is well tolerated in GLP tox at dose ~10x clinical equivalent dose. In addition, WSD0922 is predicted to be CNS penetrable with decent PK in human. The phase 1 clinical trial in US will be initiated in early 2019 with a design of 3+3 basket trial. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with GBM, HNSCC (EGFR and/or EGFRvIII) and CNS metastasis of NSCLC (EGFRm+).
Citation Format: Wei Zhong, Jinqiang Zhang, Ahihua Mu, Claire Sun. WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor [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 1326.