bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2635: Inhibiting deoxycytidine kinase significantly inhibits tumor growth in xenograft models of castration resistant prostate cancer
Authors: Radu Caius G. , Schultz Kenneth A. , Lückerath Katharina , Shepard H Michael , Czernin Johannes 
Published: June 2022

Abstract
Mammalian cells synthesis deoxyribonucleoside triphosphate (dNTP) precursors for DNA replication via the de novo pathway (DNP), and to a lesser extent, via the nucleoside salvage pathway (NSP). Evidence suggests that rapid tumor cell growth associated with increased dNTP needs results in elevated NSP activity. As deoxycytidine kinase (dCK) is the rate-limiting enzyme of the NSP, and the only enzyme that can supply cells with all dNTP precursors for DNA replication, dCK has been implicated as a promising therapeutic target. Data from the Cancer Cell Line Encyclopedia demonstrated that most human cancer cell lines have elevated dCK gene expression (2- to 17-fold) therefore suggesting selective susceptibility of tumor cells to dCK inhibition. Accordingly, a potent first-in-class oral dCK inhibitor, TRE-515, was evaluated as a single agent in two human castration-resistant prostate cancer (CRPC) models. In the first CRPC model, C4-2, TRE-515 was administered intraperitoneally once a day for eight consecutive days (50 mg/kg, QDx8). TRE-515 significantly inhibited tumor growth (50.7%, p=0.021, relative to vehicle control), with 50% of the TRE-15 treated tumors regressing during the eight-day treatment window. In a repeat C4-2 study, TRE-515 monotherapy trended toward tumor growth inhibition, (53.7%, p=0.061, relative to vehicle control). A second CRPC model, 22Rv1, was then selected as it has been shown to carry DNP mutations, suggesting enhanced sensitivity to dCK inhibition. In this study, TRE-515 was dosed orally two times a day for 28 days (75 mg/kg, BIDx28) and plasma deoxycytidine (dC) concentrations (a substrate for dCK) were measured 7 hours after the morning dose on day 21. TRE-515 alone significantly inhibited tumor growth (49.9%, p=0.0004, relative to vehicle control), and growth inhibition was associated with a 77% increase in plasma dC levels (p&lt;0.0001), relative to vehicle control, consistent with TRE-515 inhibitory activities on dCK. These data are in agreement with a previously reported study on target enzyme inhibition by TRE-515 which employed a clinically validated PET probe imaging of dCK. Taking together these results support the therapeutic potential for TRE-515 to selectively inhibit cancer cells that rely on dCK for DNA synthesis and rapid malignant proliferation. As such, TRE-515 is currently being evaluated in a phase 1 open-label, dose escalation study in solid tumors (NCT #05055609).
Citation Format: Caius G. Radu, Kenneth A. Schultz, Katharina Lückerath, H Michael Shepard, Johannes Czernin. Inhibiting deoxycytidine kinase significantly inhibits tumor growth in xenograft models of castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2635.
Abstract 2637: Inhibition of novel kinase MAP3K19 reverses EMT and kills triple negative breast cancer cell lines
Authors: Nguyen Khoa , Cheng Thomas , Alzoubi Madlin , Elliott Steven , Lee Sean , Drewry David , Collins-Burow Bridgette , Brognard John , Burow Matthew 
Published: June 2022

Abstract
The Triple-Negative Breast Cancer (TNBC) subtype is a breast cancer subpopulation whose phenotype lacks estrogen and progesterone growth receptors, and lacks HER2 amplification. This contrasts with the Luminal and HER2+ subpopulations for which clinical precision therapies exist to target cancer proliferation and improve prognoses. Consequently, the discovery of new targets is necessitated by the TNBC subtype, which has the poorest patient outcomes. Our studies have identified MAP3K19 as one such potential target. MAP3K19 an understudied protein kinase with poorly characterized physiological functions outside of its roles in the Mitogen-Activated Protein Kinase (MAPK) signaling cascade. Broadly, the MAPK signaling has been associated with cell proliferation and differentiation in pathways both intracellular and extracellular, which in the context of cancer cell biology warrants investigation into cancer cell behavior as well as the associated tumor microenvironment (TME). The Published Kinase Inhibitor Set (PKIS) is an open-access drug panel designed by GlaxoSmithKline to identify novel kinases. Preliminary PKIS cell-viability screening identified GSK1440913, GW494601, and GSK907232A as compounds with the most adverse effects on cell phenotype and growth in TNBC lines MDA-MB-231 and PDX-derived TU-BcX-49S. Analysis of common targets revealed MAP3K19 a common target, suggesting its importance in cancer cell growth and proliferation. AT-9283, a more specific MAP3K19 inhibitor, was used to support the initial results. Treatment with AT-9283 resulted in a dose-dependent killing effect. Furthermore, MAP3K19 inhibition resulted in decreased EMT gene signatures by qPCR. To summarize, MAP3K19 was identified by the PKIS screen as a major kinase in TNBC. Treatment with AT-9283, a more specific MAP3K19 inhibitor, resulted in cellular death and reversal in EMT gene signature by qPCR. Future directions for this project involve genetic knock-down and overexpression of MAP3K19 to evaluate its roles in biology and its signaling mechanisms.
Citation Format: Khoa Nguyen, Thomas Cheng, Madlin Alzoubi, Steven Elliott, Sean Lee, David Drewry, Bridgette Collins-Burow, John Brognard, Matthew Burow. Inhibition of novel kinase MAP3K19 reverses EMT and kills triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2637.
Abstract 2677: JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models
Authors: Hauptschein Robert , Woodcock Simon , Belfield Andrew , Mason Helen , Keppel Dorottya , Markova Svetlana , Kim Kyuri , Roller Shane , Phillips Caroline , Jones Clifford D. , Humphreys Robin C. 
Published: June 2022

Abstract
Activation of the mitogen-activated protein kinase (MAPK) pathway by oncogenic mutations in RAS and RAF is a frequent driver of human cancer. Targeting specific components of the pathway is a precise and rational route to deliver benefits to cancer patients with high unmet therapeutic needs. The RAF kinase proteins (ARAF, BRAF, CRAF) are core pathway components which mediate MAPK signaling. Mutations in these critical signaling proteins leads to constitutive activation of the MAPK pathway and tumor growth. Using state of the art screening methodologies and medicinal chemistry we discovered and developed a next generation pan-RAF kinase inhibitor, JZP815, which potently inhibits wild-type and mutant RAF kinases in cell-free and cell-based assays. JZP815 is a selective RAF kinase inhibitor that suppresses all 3 RAF kinase family members at low-to-sub nanomolar potencies in cell-free assays. Moreover, in tumor cells JZP815 does not induce significant paradoxical pathway activation, observed with approved 1st generation BRAF-selective inhibitors, while demonstrating equivalent potencies for MAPK pathway inhibition driven by either mutant RAF monomers or RAS-induced RAF dimers in tumor cells. JZP815 significantly inhibited tumor growth as a single agent in multiple mouse xenograft solid tumor models harboring RAS and/or BRAF mutations. Furthermore, JZP815’s favorable pharmacokinetic profile sustained on-target pathway pharmacodynamic responses in a predictable dose and time dependent manner. JZP815 demonstrated enhanced activity when combined with inhibitors of other MAPK pathway components in both class 2 and class 3 mutant BRAF patient-derived tumor cells ex vivo, and KRAS mutant NSCLC and CRC xenografts in vivo. In summary, JZP815 is a potent and selective pan-RAF inhibitor that is orally bioavailable in multiple preclinical species with a well-behaved safety profile and pharmacokinetic properties predicted to provide drug exposure required for target engagement in humans, and therefore suitable for advancing into first-in-human trials.
Citation Format: Robert Hauptschein, Simon Woodcock, Andrew Belfield, Helen Mason, Dorottya Keppel, Svetlana Markova, Kyuri Kim, Shane Roller, Caroline Phillips, Clifford D. Jones, Robin C. Humphreys. JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2677.
Abstract 2678: LLL12B, a novel small molecule STAT3 inhibitor induces apoptosis and suppresses cell migration and tumor growth in triple-negative breast cancer cells
Authors: Pan Li , Chen Xiang , Rassool Feyruz V. , Li Chenglong , Lin Jiayuh 
Published: June 2022

Abstract
Persistent STAT3 signaling has been recognized as a cancer therapeutic target in some cancer types including triple-negative breast cancer, and the development of effective small molecule STAT3 inhibitors for potential cancer therapy is desirable. In this study, we tested a novel oral bioavailable small molecule STAT3 inhibitor, LLL12B in MDA-MB-231, SUM159, and 4T1 triple-negative breast cancer cells. Triple-negative breast cancer cells frequently express persistent STAT3 phosphorylation and its cell viability is sensitive to STAT3 knockdown by siRNA. LLL12B selectively inhibited IL-6 mediated induction of STAT3 phosphorylation but had little effect on IFN-γ mediated induction of STAT1 phosphorylation or EGF mediated induction of ERK phosphorylation. LLL12B inhibited STAT3 phosphorylation, induced cell apoptosis, and reduced cell colony formation in triple-negative breast cancer cells. In addition, LLL12B inhibited cell migration of triple-negative breast cancer cells. Furthermore, LLL12B suppressed tumor growth of MDA-MB-231 triple-negative breast cancer cells in a mammary fat pad syngeneic mouse model. Together, our findings suggest that targeting persistent STAT3 signaling pathway by novel small molecule LLL12B may be a potential approach for triple-negative breast cancer therapy.
Citation Format: Li Pan, Xiang Chen, Feyruz V. Rassool, Chenglong Li, Jiayuh Lin. LLL12B, a novel small molecule STAT3 inhibitor induces apoptosis and suppresses cell migration and tumor growth in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2678.
Abstract 2683: Activation of MAP kinase pathway in breast cancer cell lines by polyisoprenylated cysteinyl amide inhibitors (PCAIs) causes cell death
Authors: Lazarte Jassy Mary , Tawfeeq Nada , Jin Yonghao , Lamango Nazarius 
Published: June 2022

Abstract
Female breast cancer has now surpassed lung cancer as the most common cancer overall in both sexes with an estimated 2.3 million new cases, representing 11.7% of all cancer cases worldwide in 2020. Triple negative breast cancer (TNBC) has been the subject of intensive studies due to its aggressive nature which makes it difficult to treat. Since inclusive treatment for this type had been elusive for decades, it is thus imperative to develop new therapeutic agents to mitigate its deadly effects. PCAIs are novel compounds designed to mimic the essential posttranslational modifications of G-proteins such as KRAS. This study elucidates the effect of the PCAIs downstream of KRAS, specifically on the mitogen activated pathway kinase (MAPK) enzymes. Two breast cancer cell lines, MDA-MB-468 and MDA-MB-231, were used to determine the levels of phosphorylation in several MAPK pathway enzymes. After exposure of the cells to varying concentrations of PCAIs (NSL-YHJ-2-27) for 48 hours, western blot results showed remarkable differences in the phosphorylated levels of the respective enzymes in cells treated with 5 µm of the PCAIs as compared to the control (NSL-YHJ-2-62). Interestingly, the cell lines reacted differently after treatment, in which MDA-MB-468 cells showed increased levels of phosphorylated MEK, ERK, and 90RSK by 122, 273 and 242%, respectively. However, in MDA-MB-231, only the phosphorylated 90RSK showed an increase of 105% and no changes in the other two enzymes. Moreover, a very distinct difference was observed in the levels of phosphorylated BRAF (p-BRAF) and CRAF (p-CRAF). In MDA-MB-231 cells, no change in p-BRAF levels while a 184% increase in p-CRAF were observed. In MDA-MB-468, p-BRAF increased by 41% and p-CRAF decreased by 58%. The differences in the response of the cell lines may reflect their unique genetics. These results show the ability of the PCAIs to interfere with the MAPK pathway. As this signaling cascade plays a very important role in cell response as well as in the progression of cancers, therefore, therapeutics targeting this pathway have a great potential in the development of treatments not only for TNBC but also for other kinds of cancers.
Citation Format: Jassy Mary Lazarte, Nada Tawfeeq, Yonghao Jin, Nazarius Lamango. Activation of MAP kinase pathway in breast cancer cell lines by polyisoprenylated cysteinyl amide inhibitors (PCAIs) causes cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2683.
Abstract 2686: Is ARV7 a regulator of prostate cancer stemness and plasticity
Authors: Furlan Tobias , Handle Florian , Cronauer Marcus V. , Santer Frédéric R. 
Published: June 2022

Abstract
Therapy options for advanced and castration-resistant prostate cancer (CRPC) include the use of drugs targeting directly/indirectly the ligand binding domain (LBD) of androgen receptor (AR) such as enzalutamide (Enza) and abiraterone acetate. However, primary or acquired treatment failures are frequently observed and have been associated with the expression of truncated AR variants devoid of the LBD. In particular, the AR variant AR3, also known as ARV7, is detected in over 80% of CRPC specimen and is increasingly expressed in metastatic lesions. In PC models ARV7 expression causes treatment resistance to Enza. Moreover, ARV7 expression leads to increased expression of mesenchymal markers and stem cell signature genes. CDH2 (N-Cadherin) expression is increased by ARV7 binding to regulatory elements in intron 1 of CDH2, which is antagonized by full length (FL) AR. Based on these observations we hypothesize that ARV7 is a marker and regulator of PC stemness and/or plasticity.
ARFL or ARV7 mRNA and protein was detected in cell lines and tissue samples by standard procedures including qRT-PCR, RNA in situ hybridization (RISH), immunofluorescence (IF) and western blotting using the monoclonal ARV7 antibody RM7. ARFL or ARV7 stably expressing LNCaP were obtained by lentiviral transduction. LNCaP cells resistant to Enza (LNCaP-Enza) were generated by exposure to increasing concentrations (up to 5 µM) of the drug. Transcriptome analysis in LNCaP-Enza vs. LNCaP was done by RNAseq and Gene Set Enrichment Analysis.
ARV7 mRNA was detectable in LNCaP, albeit gene expression was 2.3% - 2.6% of the known ARV7 positive cell lines 22Rv1 and VCaP, respectively. RISH and IF demonstrated that only a fraction (~10%) of LNCaP cells expressed ARV7 mRNA and nuclear localized ARV7 protein. ARV7 mRNA was also detected in isolated epithelial and stromal areas in treatment-naïve prostate cancer specimen by RISH. In contrast, all LNCaP-Enza cells were positive for nuclear ARV7 protein. Transcriptome analysis of LNCaP-Enza cells showed enrichments for published ARV7 gene expression signatures.
Insular spots of ARV7 mRNA were detected in treatment-naïve tissue and in isolated cells of the castration-sensitive cell line LNCaP suggesting that these cells could be intrinsically resistant against LBD-targeting drugs and responsible for the failure of various endocrine therapies. This project will further analyze whether this subpopulation possesses stem cell (-like)/plasticity characteristics and whether these are regulated by ARV7.
Citation Format: Tobias Furlan, Florian Handle, Marcus V. Cronauer, Frédéric R. Santer. Is ARV7 a regulator of prostate cancer stemness and plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2686.
Abstract 2698: ERα and NAMPT crosstalk at enhancers drives Fulvestrant resistance in metastatic breast tumors
Authors: Mogol Ayca N. , Chien Christine , Zuo Qianying , Raghavendra Akshara S. , Tripathy Debu , Landesman Yosef , Erdogan Zeynep Madak 
Published: June 2022

Abstract
Approximately 70% of human breast cancers express estrogen receptor alpha (ERα), providing a potential for targeted endocrine therapy for patients. Unfortunately, 30-40% of ER+ patients still experience recurrence and metastasis, with a 5-year relative overall survival rate of just 24% for patients with metastatic disease. Previously, we described an increased reliance on NAD+ metabolism in metastatic breast cancer (MBC) cells, which are driven by clonal selection from monotherapy resistance and the metastatic organ microenvironment. In the current study, we investigated if inhibition of NAMPT to block NAD+ production would synergize with standard of care therapies for ER+ MBC. Combination therapy of the NAMPT Inhibitor, KPT9274 and the ERα agonist Fulvestrant (Fulv) synergistically reduced tumor burden in liver metastasis in vitro (combination index &lt; 1 in cell viability assays) and in vivo in mouse xenograft models. A synergistic effect was not observed when KPT-9274 was combined with Palbociclib or Tamoxifen, nor Fulv with other metabolic inhibitors. RNA-Seq analysis showed that NAMPT inhibition restored antiestrogenic activity of Fulv. Metabolomics analysis showed that NAMPT inhibition reduced abundance of metabolites associated with glucose and lipid metabolism. Mechanistically, chromatin immunoprecipitation showed that NAMPT is recruited to ERα binding sites in MBC xenografts and PDX tumors. Targeting metabolic adaptations in endocrine-resistant metastatic breast tumors is a novel approach that could lead to new combined therapies that reduce mortality.
Citation Format: Ayca N. Mogol, Christine Chien, Qianying Zuo, Akshara S. Raghavendra, Debu Tripathy, Yosef Landesman, Zeynep Madak Erdogan. ERα and NAMPT crosstalk at enhancers drives Fulvestrant resistance in metastatic breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2698.
Abstract 2701: Multivariate transcriptome analysis identifies networks and key drivers of metastatic castration-resistant prostate cancer
Authors: McKinney Lawrence P. , Singh Rajesh , Jordan I. King , Varambally Sooryanarayana , Sanda Martin G. , Dammer Eric B. , Lillard James W. 
Published: June 2022

Abstract
Prostate cancer (PCa) is the second most cancer-related cause of death in men. Most PCa are characterized as slow-growing or indolent, though some patients are at a high risk of for recurrent and eventually metastatic disease. The most lethal form of PCa is metastatic castration-resistant prostate cancer (mCRPC) that has progressed to the bone. The molecular mechanism underlying PCa progression to bone has not been fully elucidated. Here, we identify gene networks associated with CRPC bone metastasis and survival risk. Networks were investigated by using a novel weighted gene network co-expression analysis (WGCNA) method and examining overrepresentation of upstream regulators and signaling pathways within co-expressed transcriptome modules across clinically annotated transcriptomes from mCRPC patients (N=60). Functional Enrichment analysis was used, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction analysis, to identify biological functions of related hub genes overrepresented in our module of interest. WGCNA identified that cyan module was significantly associated with castration-resistant prostate cancer (CRPC) bone metastasis. KEGG and GO analysis results revealed genes in blue module were mainly related to collagen formation, cell signaling peptides, and bone regulation processes, including alkaline phosphatase, osteoblast formation, and endochondral ossification. Genes positively correlated with bone metastasis exhibited the following biological pathways: PI3K-Akt signaling, ECM-receptor interaction, and protein digestion and absorption pathways. This study provides novel insights into the biological pathways associated with CPRC metastasis to the bone. The module associated with bone metastasis and overall survival represent both known and novel pathways.
Citation Format: Lawrence P. McKinney, Rajesh Singh, I. King Jordan, Sooryanarayana Varambally, Martin G. Sanda, Eric B. Dammer, James W. Lillard. Multivariate transcriptome analysis identifies networks and key drivers of metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2701.
Abstract 2710: Associations between structural variant signatures and drug sensitivity in cell lines
Authors: Dalin Simona , Dubois Frank , Zhang Shu , Crane Alexander , Kalfon Jeremie , Noorbakhsh Javad , Beroukhim Rameen 
Published: June 2022

Abstract
Structural variants (SVs) within the cancer genome reflect defects in DNA damage repair, impact gene regulation, and alter the genomic landscape. SVs impact a larger fraction of the cancer genome than any other genetic aberration, yet their effects on modulating therapeutic response have been largely uncharacterized. Patterns of rearrangements, otherwise known as signatures, vary across tumor and tissue type, and can indicate underlying biological mechanisms responsible for cancer etiology. We have extracted SV signatures from whole genome sequencing data from hundreds of cancer cell lines. Using datasets indicating the cell lines’ response to over a thousand small molecule inhibitors, we have identified associations between SV signatures and response to therapeutics. These results will enhance our understanding of mechanisms underlying rearrangement signatures and nominate new biomarkers of drug response.
Citation Format: Simona Dalin, Frank Dubois, Shu Zhang, Alexander Crane, Jeremie Kalfon, Javad Noorbakhsh, Rameen Beroukhim. Associations between structural variant signatures and drug sensitivity in cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2710.