bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B104: Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations
Authors: Shariati Maryam , Bristow Christopher A , Carugo Alessandro , Heffernan Tim , Zheng Xiaofeng , Peoples Michael D , Tripathy Debu , Meric-Bernstam Funda 
Published: March 2020

Abstract
Molecular alterations in the PI3K/AKT/mTOR pathway occur frequently in estrogen receptor-positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2-negative (HER2-negative) advanced or metastatic breast cancer (MBC) are often treated with palbociclib, an FDA approved CDK4/6 inhibitor, in combination with endocrine therapy. In clinical studies (NCT01942135), the combination of fulvestrant plus palbociclib was associated with improved progression-free survival compared with fulvestrant plus placebo, irrespective of PIK3CA mutational status. The purpose of this study is to identify synthetic lethality partner that can be targeted in combination with palbociclib to improve its therapeutic response. We demonstrate that the in vitro efficacy of CDK4/6 inhibitor is reduced in the presence of PIK3CA/AKT1 mutations using ER-positive isogenic breast cancer cell lines. Utilizing a shRNA library screen targeting cancer related human kinases, we identified that genomic suppression of discoidin domain receptor 1 (DDR1), a tyrosine kinase active in various cancers, is synthetic lethal with palbociclib. Performing sulforhodamine B (SRB) proliferation assay, DDR1 knockdown by shRNA significantly reduced growth of PIK3CA/AKT1 mutant as well as wild type ER-positive cell lines. In addition, DDR1 pharmacological inhibitor, 7rh benzamide, activated the P53/P21 pathway and enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Likewise, we found that combined treatment of palbociclib and 7rh further induced cell cycle arrest through decreasing G2-M phase population and reducing FoxM1 and Rb phosphorylation in mutant cell lines. Our data indicate that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be an effective rational strategy approach for targeted therapy of ER-positive, HER2-negative breast cancer harboring PIK3CA/AKT1 mutations.
Citation Format: Maryam Shariati, Christopher A Bristow, Alessandro Carugo, Tim Heffernan, Xiaofeng Zheng, Michael D Peoples, Debu Tripathy, Funda Meric-Bernstam. Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B104. doi:10.1158/1535-7163.TARG-19-B104
Abstract B115: Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes
Authors: Kalev Peter , Hyer Marc L , Fletcher Mark , Zhang Peili , Aguado-Fraile Elia , Mandley Everton , Tuncay Yesim , Konteatis Zenon , Travins Jeremy , Marks Kevin M , Marjon Katya 
Published: March 2020

Abstract
Methylthioadenosine phosphorylase (MTAP) is the enzyme in the methionine salvage pathway that metabolizes the byproduct of polyamine biosynthesis, 5′-methylthioadenosine (MTA). The MTAP gene is deleted in approximately 15% of all human cancers and results in accumulation of MTA that partially inhibits protein arginine methyl transferase 5 (PRMT5) function. Recent studies have demonstrated that loss of the MTAP gene sensitizes cancer cells to genetic depletion of PRMT5 and the upstream metabolic enzyme methionine adenosyltransferase 2 alpha (MAT2A). We have developed a first-in-class, highly potent, orally bioavailable MAT2A inhibitor, AG-270, which is currently under investigation in a phase 1 clinical trial (ClinicalTrials.gov NCT03435250). AG-270 selectively inhibits the growth of HCT116 MTAP-/- cells compared to HCT116 MTAP+/+ cells in vitro and in vivo. We utilized RNA sequencing and proteomic approaches to study the underlying mechanism of action for AG-270. The results of these analyses demonstrated that AG-270 treatment induces substantial splicing changes in an MTAP selective manner. The majority of these abnormal splicing events were detained introns, which included genes involved in cell cycle regulation and DNA damage response. Moreover, AG-270 treatment resulted in accumulation of DNA damage and increased mitotic defects in HCT116 MTAP-/- cells. Furthermore, we demonstrated substantially advantageous combination benefits between AG-270 and anti-mitotic taxanes in in vitro cell lines and in in vivo patient-derived xenograft models of non-small cell lung, pancreatic and esophageal cancers. These findings uncover relevant combination strategies targeting MTAP-deleted malignancies, and provide preclinical mechanistic proof-of-concept to explore such combinations in the clinical setting.
Citation Format: Peter Kalev, Marc L Hyer, Mark Fletcher, Peili Zhang, Elia Aguado-Fraile, Everton Mandley, Yesim Tuncay, Zenon Konteatis, Jeremy Travins, Kevin M Marks, Katya Marjon. Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B115. doi:10.1158/1535-7163.TARG-19-B115
Abstract B134: IMPDH1 and IMPDH2 as therapeutic targets in acute lymphoblastic leukemia
Authors: Dieck Chelsea , Oshima Koichi , Ambesi-Impiombato Alberto , Ferrando Adolfo 
Published: March 2020

Abstract
Acute lymphoblastic leukemia (ALL) tumors are dependent on purine biosynthesis for proliferation and survival and relapsed ALL is particularly associated with transcriptional up-regulation of this pathway. Increased dependency on purine biosynthesis highlights IMPDH (inosine monophosphate dehydrogenase), the rate-limiting enzyme in guanosine production, as a potential therapeutic target for the treatment of ALL. To assess the role of IMPDH1 and IMPDH2 in ALL development and progression, we generated NOTCH1-induced leukemias from Impdh1 knockout and Impdh2 conditional knockout mice. In addition, we have completed whole exome sequencing and RNAseq profiling of 12 pairs of ALL xenografts corresponding to matched diagnostic and relapsed ALL samples and have performed dose response assays with the IMPDH inhibitor mizoribine. Additionally and towards the identification of synthetic lethal genetic vulnerabilities with IMPDH inhibition in ALL we have performed a genome wide CRISPR screen in REH ALL cells with the IMPDH inhibitor mizoribine. Overall, these studies highlight the therapeutic potential for IMPDH inhibitors for the treatment of ALL.
Citation Format: Chelsea Dieck, Koichi Oshima, Alberto Ambesi-Impiombato, Adolfo Ferrando. IMPDH1 and IMPDH2 as therapeutic targets in acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B134. doi:10.1158/1535-7163.TARG-19-B134
Abstract B142: Co-culture of tumor organoids with immune cells for immuno-oncology drug development
Authors: Li Zhongliang , Zhou Jun , Zhang Rui , Wang Fei , Wang Shuzong , Xu Xiaoxi , Huang Yujun , Li Henry 
Published: March 2020

Abstract
Hubrecht organoid technology (HUB) can in vitro preserve and propagate patient-derived epithelial cancer cells whilst still maintaining tumour heterogeneity and genetic features. Co-culture of tumor organoids with peripheral blood lymphocytes or tumor-infiltrating lymphocytes (TIL) can potentially expand tumor-specific T cells that mediate explicit killing of tumor organoids. Recapitulating the tumor microenvironment (TME) by co-culture of tumor organoids with immune cells is highly attractive for immuno-oncology (IO) drug development, and will provide an efficient and refined approach for assessing the immune modulatory and tumor killing effects of IO drug candidates, such as monoclonal antibodies, CAR-T, CAR-NK and small molecules. In this study, we aimed to establish and validate IO assay platform using co-culture methods of organoids with various immune cells. We used the HUB organoid approach to create panels of patient-derived (PDO), patient-derived-xenograft (PDX)-derived organoids (PDXO) and murine tumor-derived tumor organoids, followed by co-culturing with corresponding cytotoxic T cells. We developed tumor organoid killing assays using both flow cytometry-based methods and real-time imaging by IncuCyte as readouts in 96-well format. Tumor-reactivity of T cells to organoids was analysed by T cell proliferation, IFNg ELISA in the culture medium, and intracellular staining of IFNg in T cells. Co-culture of tumor organoids expressing various antigens was also used to evaluate antibody dependent cell mediated cytotoxicity (ADCC) by NK cells, and complement dependent cytotoxicity (CDC) and antibody dependent phagocytosis by macrophages for monoclonal antibody drugs. We have profiled the expression of immune inhibitory molecules on various tumor organoids and assessing the effect of immune checkpoint blockade (e.g. anti-PD-1/PD-L1) in organoid-immune cell co-culture. Our preliminary data demonstrated the feasibility of in vitro patient-derived model system in the field of IO research using tumor organoid co-culture with immune cells, and their application in IO target and drug discovery.
Citation Format: Zhongliang Li, Jun Zhou, Rui Zhang, Fei Wang, Shuzong Wang, Xiaoxi Xu, Yujun Huang, Henry Li. Co-culture of tumor organoids with immune cells for immuno-oncology drug development [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B142. doi:10.1158/1535-7163.TARG-19-B142
Abstract C002: Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors
Authors: Cash Thomas , Aguilera Dolly , Macy Margaret E , Hoffman Lindsey , Dorris Kathleen , McCracken Courtney , Hanberry Bradley , Castellino Robert , MacDonald Tobey , Wetmore Cynthia 
Published: March 2020

Abstract
Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) control the transition between G1 and S phases of the cell cycle and are dysregulated in a number of pediatric brain and solid tumors. Abemaciclib, a selective and potent small molecule CDK4/6 inhibitor that crosses the blood brain barrier, limits cell proliferation by suppressing phosphorylation of RB, leading to G1 arrest. Methods: We conducted a phase 1 trial of abemaciclib to determine the maximum tolerated dose (MTD), describe toxicities, and pharmacokinetic (PK) parameters of abemaciclib in pediatric patients with recurrent or refractory solid and CNS tumors. A stratum for newly diagnosed patients with diffuse midline glioma continues to enroll. A CDK mutation was not required, and patients with known RB1 mutations were excluded. Abemaciclib was administered orally twice daily on days 1-28 of a 28-day cycle. Four dose levels were planned (100, 130, 170, and 220 mg/m2/dose) and evaluated using a rolling-six design. Patients were enrolled to a dose expansion cohort at the MTD to ensure adequate PK sampling and safety. PK and pharmacodynamic (PD) analyses are ongoing. Results: The median age of 34 eligible patients was 13.8 years (range: 2.9 - 23.2). Seven (21%) patients had a solid tumor [osteosarcoma (N=2), neuroblastoma (N=1), rhabdomyosarcoma (N=1), desmoplastic small round cell tumor (N=1), clear cell sarcoma (N=1), and MRT of kidney (N=1)] and 27 (79%) patients had a malignant brain tumor [high-grade glioma (N=12), DIPG (N=5), ATRT (N=3), medulloblastoma (N=3), ependymoma (N=2), PNET (N=1), and CNS neuroblastoma (N=1)]. Twenty-three patients were evaluable for DLT. There were 2 cycle 1 DLTs, grade 4 thrombocytopenia and grade 3 vomiting and diarrhea, both occurring at dose level 3. The most common treatment-related cycle 1 adverse events were leukopenia (69%), neutropenia (53%), thrombocytopenia (44%), hypoalbuminemia (41%), anemia (38%), hypophosphatemia (34%) and diarrhea (34%). Conclusions: The pediatric MTD of abemaciclib was 130 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly hematologic toxicity. PK and PD will be used to further inform if 130 mg/m2/dose is the pediatric recommended phase 2 dose.
Citation Format: Thomas Cash, Dolly Aguilera, Margaret E Macy, Lindsey Hoffman, Kathleen Dorris, Courtney McCracken, Bradley Hanberry, Robert Castellino, Tobey MacDonald, Cynthia Wetmore. Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C002. doi:10.1158/1535-7163.TARG-19-C002
Abstract C021: Validation of the interaction between a candidate compound and the intended drug target by a phenotypic rescue approach
Authors: Grandmoursel Laure , Geerts Lieke , Servant Geraldine , Ham Miranda van der , Maier Armin , Aarbiou Jamil , Vlaming Marijn , DeGroot Jeroen , Schuler Julia , Waddell Ian , Zuurmond Anne-Marie 
Published: March 2020

Abstract
New targets for cancer treatment frequently emerge in literature, but the thorough target validation required to consider these targets for a drug discovery program is often lacking. In pharmacological or genetic perturbation studies using complex biological assays, undesired off-target effects cannot be easily distinguished from the intended mode of action at the desired target. This is especially evident in cancer drug development where it is important to discriminate on-target effects on cell viability from off-target effects resulting in non-specific loss of cellular fitness. Neglecting the possibility of being deceived by off-target effects can have tremendous scientific and financial impact on a drug discovery program. Ideally, confidence in a preclinical drug target and a modulating compound is boosted in an early stage by more extensive analysis and validation of the actual drug-target relationship. Rescue of a disease-relevant phenotype by genetic restoration of a target mutation is a gold standard approach in drug discovery by which target validation can be achieved. We aim to follow this approach targeting the BRAF V600E mutation in a number of well described melanoma lines as well as the MAP2K1 Q56P mutation in the non-small cell lung cancer cell line H1437. Target validation for both BRAF and MAP2K1 will be addressed by assessing viability, phenotypic changes and sensitivity to compound modulation upon CRISPR/Cas9 repair of the target mutation or by exogenous re-expression of the wild type variant. Compounds tested will be Vemurafenib for BRAF and Trametinib for MAP2K1. Further investigation into target validity will be done using a physiologically relevant 3D spheroid based co-culture system. Mimicking the tumor microenvironment increases the knowledge about “drug-ability” of a target and sustainability of the target modulation at an early time point in the development process. Such early in-depth validation of the relationship between a compound and the drug target is vital to mitigate the risk of failure at later steps of drug development.
Citation Format: Laure Grandmoursel, Lieke Geerts, Geraldine Servant, Miranda van der Ham, Armin Maier, Jamil Aarbiou, Marijn Vlaming, Jeroen DeGroot, Julia Schuler, Ian Waddell, Anne-Marie Zuurmond. Validation of the interaction between a candidate compound and the intended drug target by a phenotypic rescue approach [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C021. doi:10.1158/1535-7163.TARG-19-C021
Abstract C042: Inhibition of Dihydroorotate Dehydrogenase (DHODH) by RP7214 attenuates growth and promotes differentiation of AML cell lines
Authors: Viswanadha Srikant , Eleswarapu Satyanarayana , Vakkalanka Swaroop 
Published: March 2020

Abstract
Background: Dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme in pyrimidine synthesis, is overexpressed in certain cancers; blockade of which impedes tumor cell proliferation via cell cycle arrest. RP7214 is a novel and potent DHODH inhibitor that inhibited DHODH activity in enzyme and PHA induced HWB/PBMC proliferation with IC50 and EC50 values of 7.8 & 2.5/0.60 nM respectively. The objective of this study was to evaluate the single-agent activity of RP7214 on AML cell differentiation and growth. Methods: Viability of representative AML cell lines (U937, HL-60, THP-1, and KG-1) following incubation with RP7214 for 72 h as well as rescue in the presence of 300 µM Uridine was determined in an MTT-based assay. For differentiation experiments, THP-1 cells were incubated with RP7214 in complete media for 72 h. RNA was isolated, reverse transcribed to cDNA, and real-time PCR was performed to analyze CD11b gene expression. In addition, cell surface expression of CD11b in THP-1 cells incubated with RP7214 and the effect-reversal in presence of Uridine was evaluated by flow cytometry. Apoptosis and cell cycle were determined following incubation with RP7214 for 72 and 48 h respectively. Results: RP7214 inhibited AML cell proliferation in all the four cell lines tested with GI50 ranging from 2.4 to 7.6 µM. Addition of 300 µM Uridine caused a rightward shift with GI50 &gt;10 µM. RT-PCR analysis indicated an 80-fold increase in mRNA expression of the differentiation marker CD11b in THP-1 cells treated with 3 µM RP7214. Similarly, expression of the CD11b marker on THP-1 cell surface was enhanced by 40% following incubation with 5 µM compound; effect of which was reduced to 15% in the presence of 300 µM Uridine. RP7214 dose-dependently induced apoptosis (30-50% at 3 µM) and arrested cycle progression in the “S-phase” (40-45% at 3 µM) in U937 and THP-1 cells. Conclusions: Results demonstrate the utility of RP7214 as a potent DHODH inhibitor in AML acting via suppression of cellular pyrimidine pools and promoting differentiation to fully mature cells. The compound is currently being evaluated in IND-enabling tolerability studies with Phase-1 trial in AML expected to commence in 2020.
Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Swaroop Vakkalanka. Inhibition of Dihydroorotate Dehydrogenase (DHODH) by RP7214 attenuates growth and promotes differentiation of AML cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C042. doi:10.1158/1535-7163.TARG-19-C042
Abstract C092: Axl inhibitor TP-0903 augments chemo- and immunotherapy efficacy in pancreatic cancer
Authors: Zhang Yuqing , Arner Emily N , Toombs Jason E , Foulks Jason M , Warner Steven L , Brekken Rolf A 
Published: March 2020

Abstract
Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the United States with a 5-year survival less than 9%. Resistance to standard therapy and limited response to immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment remain a major challenge in the treatment of this disease. A key cellular program involved in therapeutic resistance is epithelial plasticity, which is associated with invasion and metastasis, as well as tumor cell evasion of immune surveillance. The receptor tyrosine kinase Axl is a critical driver of epithelial plasticity. High expression and activity of Axl is associated with poor prognosis, metastasis, and therapy resistance in multiple types of cancer including pancreatic cancer. Here, we show that an Axl inhibitor (TP-0903), has anti-tumor and therapy sensitizing effects in pre-clinical models of pancreatic cancer. Syngeneic orthotopic models treated with TP-0903 alone or combination with gemcitabine and/or immune checkpoint blockade (anti-PD-1) reduced primary and metastatic tumor burden. Therapy with TP-0903, gemcitabine or the combinations significantly reduced primary tumor weight (p&lt;0.05); however, anti-PD-1 alone had no effect. The incidence of micrometastasis was reduced from 62.5% in vehicle group to 14% with TP-0903, while the triple therapy (TP-0903/gemcitabine/anti-PD-1) completely eliminated micrometastasis in 9 animals. Furthermore, Nanostring analysis of the tumors demonstrated upregulated pro-inflammatory and immune activation genes in TP-0903-treated groups compared to the vehicle, indicating pharmacologic inhibition of Axl activation leads to a more immunostimulatory microenvironment. This effect was augmented when TP-0903 was combined with gemcitabine and anti-PD-1. Additionally, survival studies are being completed in genetically engineered mouse models treated with TP-0903 single agent or in combination with chemo- and immune-therapy. Consistent with the syngeneic model, preliminary evidence suggests that TP-0903 sensitizes the tumors to chemotherapy and immune checkpoint blockade, leading to a significant anti-tumor, anti-metastatic, and pro-survival effect on GEMMs of pancreatic cancer. These results support TP-0903 as a novel therapy for treatment of pancreatic cancer, a disease that is in desperate need for effective therapy.
Citation Format: Yuqing Zhang, Emily N Arner, Jason E Toombs, Jason M Foulks, Steven L Warner, Rolf A Brekken. Axl inhibitor TP-0903 augments chemo- and immunotherapy efficacy in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C092. doi:10.1158/1535-7163.TARG-19-C092