bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B135: Discovery of BGS2019, a highly potent and selective covalent inhibitor of GMPS using IMTACTM platform
Authors: Chen Hang , Ha Heather , Stanley Robert , Huang Cindy , Cai Qian , Yuan Irene , Cao Ping 
Published: March 2020

Abstract
Guanosine monophosphate synthetase (GMPS) is a glutamine amidotransferase catalyzing amination of xanthosine monophosphate (XMP) to form GMP. It is a enzyme involved in de novo purine biosynthesis. T and B lymphocytes, and certain cancer cells, such as malignant melanoma are dependent on de novo synthesis of purine nucleotide for activation and proliferation. GMPS is an attractive target for drug discovery and development to treat autoimmune diseases, organ transplant rejection, and cancers. Mycophenolate acid (MPA), an active ingredient of Mycophenolate Mofetil (Cellcept) has been used for organ transplantation and autoimmune diseases. MPA is a natural product which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme upstream of GMPS. Using IMTACTM (Isobaric Mass Tagged Affinity Characterization) platform to perform global proteome ligand screen in live cancer cells, a highly potent and highly selective irreversible inhibitor against GMPS was discovered. Here we report the identification, in vitro characterization and in vivo evaluation of this molecule BGS2019. Target engagement of BGS2019 was determined by In-Gel-Fluorescent assay in cell with an EC50 of 15.6nM. It inhibited GMPS enzymatic activity with an IC50 of 6nM. The mechanism of BGS2019 in cell-based assays was tested, which showed the accumulation of IMP (the substrate for GMPS) and the reduction of GMP, GDP and GTP, upon BGS2019 treatment. BGS2019 was evaluated for its cell growth inhibition activity in several cancer cell lines and it suppressed cancer cell growth with IC50 values from 30nM to 100nM. In vivo administration of BGS2019 was well tolerated in mice and exhibited tumor suppression in animal model.
Citation Format: Hang Chen, Heather Ha, Robert Stanley, Cindy Huang, Qian Cai, Irene Yuan, Ping Cao. Discovery of BGS2019, a highly potent and selective covalent inhibitor of GMPS using IMTACTM platform [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 B135. doi:10.1158/1535-7163.TARG-19-B135
Abstract C005: NT5C2 small molecule inhibitor for the reversal of 6-MP resistance in acute lymphoblastic leukemia
Authors: Dieck Chelsea , Reglero-Gomez Clara , Zask Arie , Stockwell Brent , Ferrando Adolfo 
Published: March 2020

Abstract
Activating mutations in the cytosolic 5’-nucleotidase II (NT5C2) gene drive resistance to chemotherapy with 6-mercaptopurine (6-MP) in acute lymphoblastic leukemia (ALL) highlighting NT5C2 as a potential therapeutic target. In efforts to reverse 6-MP therapy resistance, we performed high throughput screens to identify small molecule inhibitors of NT5C2. Using a high throughput malachite-green based NT5C2 nucleotidase assay, we identified HTP_2 as a lead compound with low micromolar inhibitory activity against NT5C2 R367Q mutant recombinant protein. HTP_2 reverses 6-MP resistance in Nt5c2+/R367Qmutant mouse lymphoblasts and NT5C2 R29Q mutant expressing human cell lines. In addition, HTP_2 treatment results in increased sensitivity to 6-MP therapy in NT5C2 wild-type cells, highlighting the role of wild-type NT5C2 activity in the clearance of 6-MP. These results support a potential therapeutic use for NT5C2 inhibitors in potentiating the effects of 6-MP based chemotherapy in NT5C2 wild-type cells as well as NT5C2 mutant cells. Overall, this study presents a framework for the development of a NT5C2 inhibitor for the reversal of 6-MP resistance in relapsed ALL patients.
Citation Format: Chelsea Dieck, Clara Reglero-Gomez, Arie Zask, Brent Stockwell, Adolfo Ferrando. NT5C2 small molecule inhibitor for the reversal of 6-MP resistance 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 C005. doi:10.1158/1535-7163.TARG-19-C005
Abstract C012: Real-world use of circulating tumor DNA (ctDNA) in the clinical management of patients with solid tumors: A single institution’s experience
Authors: Behdad Amir , Wehbe Firas , Williams Carmen , Qiang Wenan , Vasilopoulos Athanasios ,   Massimo Cristofanilli MD FACP
Published: March 2020

Abstract
Background: The analysis of circulating tumor DNA (ctDNA) is becoming an instrumental tool in the practice of precision oncology. It not only provides a non-invasive method to study the mutational composition of solid tumors, particularly when there are limitations in tissue acquisition, but also helps capturing the biological heterogeneity and genomic evolution of advanced tumors. There is tremendous variability in utilization of ctDNA among oncologists in in various solid tumors and currently there are no guidelines. Methods: We evaluated the results of all Guardant360 ctDNA tests that were requested for clinical management in advanced cancers in our academic tertiary cancer center. We identified and annotated the most common genomic alterations and variants for each disease type. Moreover, we collected variant allele frequency variants (VAF) from each report and disease. The results for each type of neoplasm were compared to the others. Results: A total of 2199 tests for 1402 patients were performed between 2015 to January 2019. The test volume increased from 162/year in 2015 to 733/year in 2018. The tests were most commonly requested in patients with the diagnosis of advanced breast adenocarcinoma (ABC)(36%), followed by non-small cell lung cancer (NSCLC)(21%), colorectal cancer (CRC)(5%). 88% of reports included at least one alteration, with a median of 3 alterations per case and median of highest VAF of 1.1%. Prostate small cell carcinoma, contained the largest number of alterations/case (median: 9.5) and highest VAF (median: 7.1%). Among common neoplasms CRC had a significantly higher VAF (Median: 5.4%), compared to NSCLC and ABC (median &lt;1%). Overall the most commonly mutated genes, in order of prevalence, included TP53 (90% of positive cases), PIK3CA (36%), EGFR (31%), NF1 (21%), and ERBB2 (20%). Conclusions: Utilization of ctDNA in the management of patients with solid tumors is drastically increasing. The data indicates that tests can identify genomic abnormalities in the majority of cases but, the number of mutations and VAF is variable in different types of tumors reflecting underlying biology and molecular heterogeneity. ctDNA should be used in the management of advanced solid tumors to improve understanding of disease genomic alterations and facilitate treatment selection.
Citation Format: Amir Behdad, Firas Wehbe, Carmen Williams, Wenan Qiang, Athanasios Vasilopoulos, Massimo Cristofanilli MD FACP. Real-world use of circulating tumor DNA (ctDNA) in the clinical management of patients with solid tumors: A single institution’s experience [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 C012. doi:10.1158/1535-7163.TARG-19-C012
Abstract C024: Ribitol enhances O-mannosylation of α-DG in breast cancer cells
Authors: Lu qi L , Lu Pei J , Tucker Jason D , Branch Elizabeth K , Guo Fei , Blaeser Anthony R 
Published: March 2020

Abstract
O-mannosylation of a-dystroglycan (α-DG) is an important modification in most tissues in mammals and plays diverse roles, from acting as viral receptors to neuronal development. The glycosylation produces a laminin-binding glycan (matriglycan) identified in nearly all epithelial cells in a differentiation-related manner. Reduction or loss of matriglycan has been implicated in cancer development and metastasis, and specifically associated with high-grade tumors and poor prognoses in breast cancers. Enhancing matriglycan expression has been proposed as potential therapeutics. In the current study, we demonstrate that ribitol, considered to be an end product of metabolism, increases levels of CDP-ribitol, the substrate for the ribitol-5-phosphate transferases FKRP and FKTN, and consequently significantly enhances the expression of matriglycan in the MCF7 breast cancer cells. This effect is FKRP and LARGE dependent and ribitol treatment does not alter the expression of glycosyltransferases known to be critical for the synthesis of matriglycan. Enhanced expression of matriglycan is related to cell cycle progression with highest levels in S and G2 phases. This is the first time that glycosylation of a-DG is shown to be up-regulated in cancer cells by a metabolite. Our data show another layer of modulation and illustrate the complexity of matriglycan expression in cancer cell proliferation and progression.
Citation Format: qi L Lu, Pei J Lu, Jason D Tucker, Elizabeth K Branch, Fei Guo, Anthony R Blaeser. Ribitol enhances O-mannosylation of α-DG in breast cancer cells [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 C024. doi:10.1158/1535-7163.TARG-19-C024
Abstract C034: Cancer-specific intracellular delivery of therapeutic antibodies against RAS
Authors: McGuire Michael J , Li Susan , Allred Curtis A , Venugopal Indu , Gormley Claire , Brown Kathlynn C 
Published: March 2020

Abstract
Antibodies and peptides directed against the switch regions of RAS can disrupt interactions with its downstream effector proteins, blocking downstream pro-tumorigenic signaling. However, these biologic therapies are unable to reach the intracellular environment. We have overcome this problem using peptidic molecular guidance system (MGSs) that have the unique ability to bind specifically to epithelial-derived cancer cells, and upon binding, trigger rapid internalization and trafficking to a specific subcellular location. Using an unbiased phage display approach, we have identified a series of cancer specific MGSs that deliver cargo to discrete subcellular locations. Chemical optimization results in MGSs with 1-10 nM affinity for their cellular target, serum stability &gt;48 hours, and 50-1000-fold specificity for cancer cells compared to normal control cells. The rate of MGS internalization is rapid with t1/2 of 10-30 minutes, achieving intracellular concentrations up to 1.5 µM. Using these MGSs as delivery agents, we have delivered a function blocking RAS antibody (Y13-259), resulting in a reduction of p-ERK and apoptosis in KRAS mutant cell lines. The effect is MGS dependent. The MGS-Antibody homes to tumors in an animal model resulting in significant suppression in tumor growth compared to untreated animals. Free MAb does not impact tumor growth. Using MGSs to delivery MAb for intracellular targets is a paradigm change for immunotherapy and represents a new approach for controlling intracellular protein-protein interactions. Combination of these cancer-specific delivery agents with effectors of RAS signaling, such as antibodies and other biologics, has therapeutic potential for KRAS-driven cancers.
Citation Format: Michael J McGuire, Susan Li, Curtis A Allred, Indu Venugopal, Claire Gormley, Kathlynn C Brown. Cancer-specific intracellular delivery of therapeutic antibodies against RAS [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 C034. doi:10.1158/1535-7163.TARG-19-C034
Abstract C068: Toward precision medicine for platinums
Authors: Koblinski Jennifer E , Peterson Erica J , Hampton James D. , Harrell J Chuck , Farrell Nicholas P 
Published: March 2020

Abstract
Over half of all cancer patients will receive a platinum drug during their treatment. Recent interest in our labs involve exploiting the high affinity of a discrete class of platinum-based anticancer agents, polynuclear platinum complexes (PPCs), for sulfated glycosaminoglycans (sGAGs). sGAGs are increasingly seen as potential biomarkers and molecular targets in many forms of cancer. sGAG expression levels were quantified in patient derived xenograft (PDX) and cellular models of triple negative breast cancer (TNBC) and ovarian cancer. PPCs, but not carboplatin, show increased levels of tumor uptake and efficacy in models expressing high levels of sGAGs. sGAGs may provide a viable target for PPCs, producing a significant advantage over clinical platinum agents in this setting.
Citation Format: Jennifer E Koblinski, Erica J Peterson, James D. Hampton, J Chuck Harrell, Nicholas P Farrell. Toward precision medicine for platinums [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 C068. doi:10.1158/1535-7163.TARG-19-C068
Abstract C070: CLR 180099, a lipid raft targeted phospholipid-drug conjugate, shows potent improved safety and efficacy against colorectal tumors
Authors: Longcor Jarrod , Pinchuk Anatoly , Hoover Randall , Friend John 
Published: March 2020

Abstract
Lipid rafts (LR) are specialized regions or microdomains within the cell membrane that are highly enriched with cholesterol and sphingolipids. The presence of LR in tumor cell membranes is as much as 10 fold higher than in normal tissue. Our phospholipid ether (PLE) molecules [18-(p-iodophenyl)octadecyl phosphocholine] have a high affinity for binding and being transported into cells via LRs(1). In this study, we report the development of CLR 180099, a LR targeting phospholipid-drug conjugate (PDC), consisting of a PLE with a cleavable peptide linker (non-cathepsin cleavage) bound to a flavagline (FLV) analogue, a highly potent inhibitor of cell proliferation and simulator of apoptosis. We first study the presence of LR on a large panel of cancer cell lines. Then, we evaluated the uptake of multiple PLE conjugates in a similar panel of cancer cell lines. Then CLR 180099 was assessed for uptake and the release of the FLV in in vitro tumor cell lines. Finally, we present a series in vitro anti-proliferation assays in multiple cell lines and in vivo tolerability as compared to free FLV and efficacy of CLR 180099 in HCT 116 colorectal cancer xenograft. Presence of LR was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the PDC. Importantly, CLR 180099 demonstrated significant improvement in tolerability of FLV versus free FLV. These results suggest that PLEs could be used to make PDCs that improve tolerability and efficacy of the warhead molecule. The ability to specifically deliver a variety of warheads/payloads to a broad range of tumor cells offers a unique advantage of PDCs. These findings support the continued development of CLR 180099 PDC as a novel targeted therapy. The PDC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this PDC will be available commercially.
Citation Format: Jarrod Longcor, Anatoly Pinchuk, Randall Hoover, John Friend. CLR 180099, a lipid raft targeted phospholipid-drug conjugate, shows potent improved safety and efficacy against colorectal 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 C070. doi:10.1158/1535-7163.TARG-19-C070
Abstract C072: Discovery of highly potent and selective covalent inhibitors of FGFR4
Authors: Chen Hang , Slemmons Katherine , Ha Heather , Stanley Robert , Cai Qian , Yuan Irene , Helman Lee , Cao Ping 
Published: March 2020

Abstract
Hepatocellular carcinoma (HCC) accounts for 65% of all cases of liver cancers, ranking the 6th most common cancer and the 2nd cause of cancer mortality. HCC has more than 700,000 new cases/year and 600,000 deaths/year. Sorafenib is currently the standard of care for advanced disease, provides a response rate of ~2% and median survival &lt;11 months. The fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4)-Klotho β (KLB) signaling pathway regulates bile acid synthesis and is also a key driver in certain subtypes of HCC (around 30%). We generated BGS2219 and BGS2223 through FGFR4 structure-based design. BGS2219 and BGS223 are potent, selective and irreversible FGFR4 inhibitors. BGS2219 inhibits FGFR4 with an IC50 of 4nM and has greater than 2500 fold selectivity over FGFR1, 2 and 3. BG2219 took effects in both HCC and RMS tumor cell lines. In vivo administration of BG2219 was well tolerated in mice at all dosages with no body weight loss and and inhibited tumor growth in a dose -dependent fashion in HCC xenograft model. Complete tumor regression was observed at 40mg/kg. BGS2219 was tested in a combo therapy regimen with R1507 (anti-IGFR1 mab) in RMS (rhabdomyosarcoma) xenograft model in mice and showed that BG2219 plus R1507 significantly reduce the tumor volume in comparison with R1507 alone. BGS2223 is derived from BG2219, with improved oral bioavailability. BGS2223 has no hit in Cerep Screen safety panel and no activity detected in hERG assay at 10mM. In vivo oral administration of BG2223 in mice was well tolerated with no body weight loss and showed dose-dependent tumor growth inhibition in HCC CDX model at all dosages. Tumor regression was achieved at high dose treatment. BGS22 treatment in vivo in HCC tumor bearing mice caused alteration of CYP7A1 and FGF19 expression, which were utilized as biomarkers for FGFR4 inhibition.
Citation Format: Hang Chen, Katherine Slemmons, Heather Ha, Robert Stanley, Qian Cai, Irene Yuan, Lee Helman, Ping Cao. Discovery of highly potent and selective covalent inhibitors of FGFR4 [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 C072. doi:10.1158/1535-7163.TARG-19-C072
Abstract C080: The combination of MEK and MDM2 inhibitors demonstrates promising antitumor efficacy in MAPK altered patient-derived thyroid and colorectal cancer models
Authors: Pairawan Seyed , Evans Kurt , Kopetz Scott , Akcakanat Argun , Zhao Ming , Tapia Coya , Busaidy Naifa , Dumbrava Ecaterina , Meric-Bernstam Funda 
Published: March 2020

Abstract
Purpose: Genomic alterations in the mitogen activated protein kinase (MAPK) pathway are common in colorectal and thyroid cancer. However MEK inhibition alone has limited efficacy. We investigated the combinatorial antitumor efficacy of MEK (Selumetinib; AZD6244) and MDM2 inhibition (AMG232) in wild-type TP53 colorectal and thyroid cancers with MAPK alterations. Methods: One thyroid (BRAF mutated) and three colorectal cancer cell lines (KRAS mutated) were used to evaluate the anti-tumor effect of selumetinib combined with AMG232 in vitro. Sulforhodamine B and colony formation assays were utilized to determine the cytotoxicity of each single targeted agent and combination and to obtain the half maximal inhibitory concentration (IC50). The efficacy of the combination was evaluated in athymic mice with subcutaneously implanted patient-derived xenografts (PDX) of different histologic backgrounds (5 colorectal and 2 thyroid cancer) and with different genomic MAPK pathway alterations. Selumetinib (25 mg/kg in 6 models, and 15 mg/kg in 1 model) and AMG232 (15 mg/kg) were administered daily through oral route. Results: Selumetinib demonstrated synergistic activity with AMG232 across all four cell lines with combination indices ranging from 0.37 to 0.72. The antitumor efficacy was enhanced when combining the two agents in all seven PDX models and achieved statistical significance in six of seven PDX models compared to either single agent therapy alone. Treatment/Control ratio % ((median tumor volume of treatment group / control group) x 100) was obtained from each combination arm across in vivo experiments (31 % (range 12%-62%)) and it was greater than monotherapy alone (Selumetinib 51%; range 21%-76%, AMG232 77%; range 38%-100%). Conclusions: Our preclinical findings demonstrate enhanced anti-tumor efficacy when combining Selumetinib with AMG232, which supports further evaluation of MEK/MDM2 inhibition in patients with MAPK altered colorectal and thyroid cancer with wild-type TP53 status.
Citation Format: Seyed Pairawan, Kurt Evans, Scott Kopetz, Argun Akcakanat, Ming Zhao, Coya Tapia, Naifa Busaidy, Ecaterina Dumbrava, Funda Meric-Bernstam. The combination of MEK and MDM2 inhibitors demonstrates promising antitumor efficacy in MAPK altered patient-derived thyroid and colorectal cancer models [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 C080. doi:10.1158/1535-7163.TARG-19-C080