bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3096: Development of pyrrolopyrimidine-based ACK1 inhibitors for cancer therapeutics
Authors: Matar Angelie , Marusyk Yuliya , Ranatunga Sujeewa , Rowsell Tegan , Amin Narmin , Walker Hannah , Tran Timothy , Yang Kathy , Duckett Derek , Reuther Gary , Lawrence Harshani , Lawrence Nicholas 
Published: June 2023

Abstract
Activated CDC42-associated tyrosine kinase 1 (ACK1) is an enzyme encoded by the TNK2 gene. Studies have shown ACK1 phosphorylates proteins in oncogenic pathways active in lung, leukemia, ovarian, breast, and prostate cancers. Some of these phosphorylated proteins include tyrosine-kinase B (AKT), androgen receptor (AR), tumor suppressor WWdomain oxidoreductase (WWOX), proto-oncogene tyrosine-protein kinase (FYN), and growth factor receptor bound protein 2 (Grb2). ACK1 plays a pivotal role in leukemia, breast, and prostate cancer making it an attractive anticancer drug target. The development of novel ACK1 inhibitors using a pyrrolopyrimidine scaffold is described using molecular modeling and structure-activity relationships (SAR) studies. The synthesis of a focused library using a fragment-based design strategy will be highlighted as well as progress to optimize these compounds for potency, selectivity, and cell permeability. To gain structural insights for the development of novel, potent and selective ACK1 inhibitors, we have obtained X-ray structures of our compounds bound to human ACK1. We will describe the use of molecular docking to predict the binding mode of our compounds using both reported and our new ACK1 co-crystal structures. The key residues in the ATP binding pocket of ACK1 that are exploited for inhibitor design and kinase selectivity and synthetic routes to promising compounds will be discussed. We will present the KDs of the most potent compounds derived using a differential scanning fluorimetry (DSF) thermal shift assay and cellular activities in UKE1 leukemia and MB-231 breast cancer cell lines. We will present preliminary assessment of drug-like properties, used to optimize the inhibitor class for selection of a candidate for mouse studies. Overall, our work will highlight identification/optimization of novel ACK1 inhibitors via a fragment-based approach using pyrrolopyrimidine scaffolds and their potential use as anticancer agents. We will present the synthesis, SAR analysis, and the binding mode of these inhibitors.
Citation Format: Angelie Matar, Yuliya Marusyk, Sujeewa Ranatunga, Tegan Rowsell, Narmin Amin, Hannah Walker, Timothy Tran, Kathy Yang, Derek Duckett, Gary Reuther, Harshani Lawrence, Nicholas Lawrence. Development of pyrrolopyrimidine-based ACK1 inhibitors for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3096.
Abstract 3521: CCND2 promotes proliferation in Drosha and DICER1 driven tumors
Authors: Fraire Claudette R. , Obalapuram Uma , Tiburcio Patricia D. , Desai Kavita , Chen Kenneth S. 
Published: June 2023

Abstract
Mutations in microRNA processing genes such as DROSHA and DICER1 consist of 1.5-2% of pediatric cancers including a brain tumor called pineoblastoma. We developed a genetically engineered mouse model of Drosha- and Dicer1- driven pineal tumors. These tumors develop without microRNAs and express early pineal developmental markers. Gene set enrichment analysis revealed E2F target genes to be highly expressed in these tumors. One of the most upregulated genes in these tumors is cyclin D2 (Ccnd2). Additionally, these tumors stain positively for Rb phosphorylation. In a Wilms tumor cell line (WiT49) with Drosha knocked down, RNA sequencing revealed that CCND2 was the most upregulated gene. Similarly, in patient-derived xenografts (PDXs) of DICER1-related tumors such as pleuropulmonary blastoma (PPB), we observed high expression of CCND2 and positive staining for Rb phosphorylation. To test the dependence of Rb phosphorylation in Drosha and Dicer tumors, we next treated a Drosha pineal tumor allograft with a CDK4/6 inhibitor, palbociclib, and observed tumor growth suppression. Additionally, treatment of DICER1 mutant PPB PDXs with palbociclib had similar results. These experiments suggest that CDK4/6 is important for tumor proliferation in Drosha and DICER1 driven cancers.
Citation Format: Claudette R. Fraire, Uma Obalapuram, Patricia D. Tiburcio, Kavita Desai, Kenneth S. Chen. CCND2 promotes proliferation in Drosha and DICER1 driven tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3521.
Abstract 3597: SUV420H2-mediated regulation of collective invasion in triple-negative breast cancer
Authors: Whitt Emily Campbell , McLane Laura M. , Vertino Paula M. 
Published: June 2023

Abstract
Breast cancer is the second most common cancer in women and metastasis is the leading cause of breast cancer-related mortality. While the factors leading to metastasis remain poorly understood, epigenetic changes in the cancer cell are likely strongly associated with the shift from primary tumor to metastasis. There are several breast cancer subtypes, the most aggressive of which is triple-negative breast cancer which is difficult to treat in part because it is prone to metastasis. In the early stages of metastasis, cells from the primary tumor invade the surrounding tissue before breaking away and seeding metastases. In some cases, tumor cells invade as clusters of cells that migrate as a group and maintain their cell-cell contacts through a process known as collective invasion. These clusters of collectively invading cells have been shown to seed circulating tumor cell clusters that are more efficient at forming metastases than single tumor cells. SUV420H2 is a histone methyltransferase that trimethylates histone H4 lysine 20 (H4K20me3), an epigenetic mark associated with transcriptional repression. Triple-negative breast cancer has lower levels of SUV420H2 and H4K20me3 levels than more luminal subtypes. Our lab and others have found that downregulation or inhibition of SUV420H2 promotes increased plasticity in the epithelial-to-mesenchymal transition, a transcriptional program associated with cancer metastasis. Our objective was to use a three-dimensional tumor spheroid system to determine the role of SUV420H2 and H4K20me3 on breast cancer invasion. We found that in immortalized non-tumorigenic breast cells grown as spheroids in an extracellular matrix, knockdown of SUV420H2 promotes invasion. Treatment of triple-negative breast cancer spheroids with an inhibitor of SUV420H2 (A196) also leads to an increase in invasion, as well as a shift in invasive phenotype from one where cells invade as single cells to a one where cells invade as collective chains emanating from the central spheroid. This suggests that reduced levels of SUV420H2 and the associated changes in histone marks and transcriptional programming in triple-negative breast cancer promote a phenotypic shift from single cell to collective invasion and may be one factor contributing to the increased metastatic potential of this subtype. Future studies will focus on characterizing the effects of SUV420H2 loss on gene and protein expression as well as chromatin in invading cells in tumor spheroids.
Citation Format: Emily Campbell Whitt, Laura M. McLane, Paula M. Vertino. SUV420H2-mediated regulation of collective invasion in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3597.
Abstract 3616: Investigating proto-oncogene PBF-induced cell migration and invasion
Authors: Kocbiyik Merve , Manivannan Selvambigai , Zha Ling , Brookes Katie , Read Martin L , McCabe Chris J , Smith Vicki E 
Published: June 2023

Abstract
The proto-oncogene pituitary tumor transforming gene binding factor (PTTG1IP/PBF) is overexpressed in multiple tumors and associated with tumor progression. PBF mediates several tumorigenic processes, including cell motility, whereby it potently induces cancer cell migration and invasion. PBF is phosphorylated by Src kinase at Y174 and mutation of this residue (Y174A) renders PBF unable to induce cell invasion, suggesting that phosphorylation mediates the stimulation of cancer cell motility by PBF. This study aimed to further elucidate the mechanism of PBF-induced cell motility. PBF-Y174 is also the key residue in a YXXΦ endocytosis motif. Both PBF phosphorylation and endocytosis were found to be essential for PBF-induced cell motility as mutants which disrupted either process were unable to stimulate thyroid and breast cancer cell migration and invasion. To elucidate molecular events downstream of PBF overexpression, phosphoproteomic and RNA-Seq analyses of normal thyroid cells (Nthy-ori 3-1) with stable PBF overexpression were performed and showed an enrichment in molecules involved in cell adhesion and cytoskeleton organisation. These findings prompted further investigation into a physiological role for PBF in cell motility. We utilised a novel Pbf knockout (Pbf−/−) mouse model generated through CRISPR/Cas9-mediated deletion of Pbf exon 4 in C57BL/6N mice to determine the impact of Pbf deletion on cellular mechanisms. Mouse embryonic fibroblasts (MEFs) were isolated at embryonic day 13.5 and used as primary cultures. Pbf−/- MEFs showed a significant reduction in migration and invasion compared with wild-type (Pbf+/+) MEFs. Interestingly, the loss of one functional copy of Pbf in heterozygote MEFs (Pbf+/−) resulted in an intermediate decrease in motility suggesting a gene-dosage effect. Initial immunofluorescent studies of Pbf−/− MEFs suggest alterations in focal adhesions (FAs). In Pbf+/+ MEFs focal adhesion kinase (FAK) and paxillin staining highlighted FA structures that were normally elongated and aligned with actin stress fibers. In contrast, Pbf−/- MEFs demonstrated a significant reduction in FAK and paxillin staining with smaller, punctate and more radially distributed FAs. These studies demonstrate a physiological role for PBF in cell adhesion and migration and further elucidate the mechanism by which PBF induces cell motility in tumor progression.
Citation Format: Merve Kocbiyik, Selvambigai Manivannan, Ling Zha, Katie Brookes, Martin L Read, Chris J McCabe, Vicki E Smith. Investigating proto-oncogene PBF-induced cell migration and invasion. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3616.
Abstract 3634: Overexpression of PLK1 activates IL4/JAK/STAT6 signaling in prostatic tumor-microenvironment
Authors: Wang Ruixin , Liu Xiaoqi 
Published: June 2023

Abstract
The correlation between PLK1 expressions with prostate cancer (PCa) stages was identified by analyzing the transcriptome profile of PLK1 in patients from the Cancer Genome Atlas (TCGA) database, and scoring the protein expression in a clinical tissue microarray (TMA) cohort. Integrating our prostate-specific PLK1 knock-in mouse model, we established an oncogenic role for PLK1 in PCa progression. To elucidate the underlying mechanism, we investigated the impact of PLK1 overexpression on prostatic tumor microenvironment (TME) in vivo. In addition, in vitro co-culture systems with both epithelial cells and macrophages were designed to uncover the regulatory function of PLK1 in macrophage polarization. We found that PLK1 induces phosphorylation of JAK3, activates the JAK/STAT6 pathway in cancer cells, and increases the secretion of IL4, which enables macrophage polarization towards the M2 phenotype in TME—ultimately accelerating PCa development. Finally, pharmaceutical inhibition of STAT6 signaling significantly reverses the PLK1-mediated M2 polarization and, subsequently, inhibits the progression of PCa. Our findings provide clinical and pre-clinical evidence to characterize the role of PLK1 in promoting PCa and novel insights into the regulatory mechanism of PLK1 in the TME. We also provide strong support for the clinical potential of targeting STAT6 for advanced PCa therapy.
Citation Format: Ruixin Wang, Xiaoqi Liu. Overexpression of PLK1 activates IL4/JAK/STAT6 signaling in prostatic tumor-microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3634.
Abstract 3731: The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant transformation in MYC-driven lymphoma
Authors: Nakanishi Shima , Li Jiannong , Berglund Anders E. , Kim Youngchul , Zhang Yonghong , Zhang Ling , Yang Chunying , Mirmira Raghavendra G. , Cleveland John L. 
Published: June 2023

Abstract
The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given these functions, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which post-translationally modifies a single lysine residue (Lys-50) of eukaryotic translation initiation factor eIF5A in a process coined hypusination via two enzymes,deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where loss of eIF5A hypusination completely abolishes malignant transformation of MYC-overexpressing B cells in transgenic mice predestined to develop lymphoma. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-to-S phase cell cycle progression and DNA replication. Thus, this circuit controls MYC’s proliferative response at several levels and is activated in many tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies.
Citation Format: Shima Nakanishi, Jiannong Li, Anders E. Berglund, Youngchul Kim, Yonghong Zhang, Ling Zhang, Chunying Yang, Raghavendra G. Mirmira, John L. Cleveland. The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant transformation in MYC-driven lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3731.
Abstract 3808: MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs
Authors: Song Guisheng , Liu Ningning 
Published: June 2023

Abstract
Kupffer cells (KCs) account for 15% of the total liver cells. However, their roles in hepatocellular carcinoma (HCC) is poorly described. Clec4fCre-tdTomato knock-in mice expressing Cre recombinase and tdTomato-NLS under the KC-specific Clec4f promoter were hydrodynamically injected with oncogenic AKT and Nras (AKT/Ras) to induce HCC. A LoxP-stop-LoxP (LSL) system was used to express miR-206 in KCs of mice. AKT activation was observed in hepatocytes and KCs of HCC patients. Hydrodynamic injection (HDI) of AKT/Ras led to activation of AKT signaling in KCs and hepatocytes. AKT/Ras mice developed lethal HCC within 6-8 weeks post injection. Activation of AKT signaling led to M2 polarization of KCs, increased hepatic Tregs and exhaustion of CTLs. MicroRNA (miR) profiling revealed that AKT/Ras impaired miR-206 biogenesis in KCs by driving translation of Yin Yang 1 (YY1), a transcription repressor of miR-206. HDI of miR-206 into AKT/Ras mice fully prevented HCC, while all control mice died of HCC 6-8 weeks post injection. However, HDI of miR-206 only transfected ~ 20% of hepatocytes, indicating that it is unreasonable to conclude that the full prevention of HCC in AKT/Ras/miR-206 mice is caused by inhibited proliferation of HCC cells. We, therefore, posited that miR-206-mediated recovery of immune surveillance, at least in part, accounted for the full prevention of HCC in AKT/Ras/miR-206 mice. We next used the LSL system to overexpress miR-206 in KCs of Clec4fCretdTomato mice injected with AKT/Ras. KC-specific expression of miR-206 fully prevented HCC in AKT/Ras mice, while 100% control mice died of HCC. Mechanistically, AKT signaling in KCs drove CCL22 (C-C motif chemokine ligand 22) production by phosphorylating β-catenin that activates transcription of Ccl22. In contrast, miR-206 disrupted β-catenin signaling by targeting LEF1 (lymphoid enhancer-binding factor 1), an “architectural” transcription factor of β-catenin. CCL22 recruits Tregs. Indeed, KC-specific expression of miR-206 led to elevated CCL22, M2 to M1 transition of KCs, reduced hepatic Tregs, and elevated CTLs. Depletion of CTLs in AKT/Ras mice fully offset the ability of miR-206 to prevent HCC.
Conclusions: AKT-educated KCs initiate Treg recruitment via a regulatory loop consisting of YY1, β-catenin/LEF1, miR-206, and CCL22; once this loop is activated, AKT activates β-catenin axis, which drives CCL22 production, Treg recruitment and HCC growth; while KC-specific expression of miR-206 reversed this process by blocking β-catenin axis in KCs. miR-206 represents a novel immunotherapy against HCC.
Citation Format: Guisheng Song, Ningning Liu. MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3808.
Abstract 4009: Discovery of PLM-102, a highly potent 3rd generation FLT3 inhibitor, in drug-resistant FLT3-ITD-TKD mutated acute myeloid leukemia
Authors: Park Jin-Hee , Lee Jae-Seon , Oh Su-jin , Lee So-Deok , Choi Yong June , Kang Keon Wook , Moon Miran , Jang Soo Yeon , Kim Myung Jin , Kim Yong-Chul 
Published: June 2023

Abstract
Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 25 ~ 30% of all acute myeloid leukemia (AML) cases and FLT3-ITD mutations are associated with a particularly unfavorable prognosis, with an increased risk of relapse and shorter overall survival (OS) compared with AML patients without the mutation. Even though multiple FLT3 inhibitors are in various stages of clinical evaluation, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments. Among them, a “gatekeeper” mutation (F691L) is resistant to most available FLT3 inhibitors. Here, we show the efficacy and mechanism of PLM-102, developed an orally available and highly selective small molecule, in overcoming drug-resistant FLT3-ITD-TKD mutations as a strong candidate of the 3rd generation of FLT3 inhibitor.
PLM-102 displays extraordinary potency of enzyme inhibitory activities of all FLT3 WT/mutants including F691L with IC50 values of &lt;1 nM. In FLT3-ITD-positive cell lines (MV4-11, MOLM-13, MOLM-14, Ba/F3-ITD-D835Y, Ba/F3-ITD-F691L), PLM-102 shows about 18~25-fold higher anti-proliferative activities than Gilteritinib. Also, PLM-102 potently inhibited the phosphorylation of FLT3 and its downstream signaling pathways, and induced apoptosis as evidenced by PARP-cleavage and caspase-3 activation.
Moreover, in AML-related xenograft mouse models (MV4-11, MOLM-14, Ba/F3-ITD-D835Y, Ba/F3-ITD-F691L), once-daily oral dose of PLM-102 significantly suppressed the tumor growth and achieved complete tumor regression. In addition, the outstanding efficacy of our compound has been confirmed in large tumor xenograft models. These results are very encouraging because large tumors have a limited blood supply and high interstitial fluid pressure, leading to a poor absorption of anticancer drugs. Pharmacokinetics of PLM-102 displayed higher bone-marrow exposure indicating better target engagement and benefits in the clinical translation in AML.
In conclusion, PLM-102 is a promising therapeutic candidate for the FLT3-ITD-mutated AML as well as the acquired resistance to current FLT3 inhibitors.
Citation Format: Jin-Hee Park, Jae-Seon Lee, Su-jin Oh, So-Deok Lee, Yong June Choi, Keon Wook Kang, Miran Moon, Soo Yeon Jang, Myung Jin Kim, Yong-Chul Kim. Discovery of PLM-102, a highly potent 3rd generation FLT3 inhibitor, in drug-resistant FLT3-ITD-TKD mutated acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4009.
Abstract 4130: Genetically modified hematopoietic stem cells for improvement of immunotherapies against solid malignancies
Authors: Font Laura Falceto , Jin Dan , Francis Connor P. , Dean Bayli DiVita , Figg John W. , McDonald Brianna , Flores Catherine 
Published: June 2023

Abstract
Hematopoietic stem cells (HSCs) are routinely used in the clinic to treat several diseases and their side effects, including cancers. Our group has previously shown that the combination of HSCs with two different immunotherapies improves survival in brain tumors, but it is still not curative. In this study, we wanted to explore whether modifying HSCs can drive them into a dendritic cell phenotype or suppress them from becoming immunosuppressive myeloid cells at the tumor microenvironment to increase survival when combined with immunotherapy in a glioma model. HSCs have been historically challenging to grow in vitro for long-term culture due to the short periods of time they remain undifferentiated, which creates an extra challenge for the genetic modification of HSCs. Here, we test different in vitro conditions for expansion and modification of murine and human HSCs by employing the following methods for modulation of HSCs: shRNA lentiviral delivery, overexpression constructs, RNA electroporation, CRISPR, and AAV. This study describes the efficacy of each method as well as the observed limitations of each technique on HSCs. Furthermore, preliminary data shows IL6R downregulation as a candidate for driving HSCs into the dendritic cell lineage. Ultimately, these genetically modified cells will be used as an adjuvant therapy to improve the efficacy of various immunotherapeutic strategies against solid malignancies.
Citation Format: Laura Falceto Font, Dan Jin, Connor P. Francis, Bayli DiVita Dean, John W. Figg, Brianna McDonald, Catherine Flores. Genetically modified hematopoietic stem cells for improvement of immunotherapies against solid malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4130.