bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1800: Novel NSDHL inhibitor (Compound 9) exerts anti-proliferative and cytotoxic activity in breast cancer cells
Authors: Yoon So-Hyun , Kim Hoe Suk , Baek Moonjou , Ryu Seungyeon , Lee Sangeun , Lee Han-Byoel , Lee Bong-Jin , Han Wonshik 
Published: June 2022

Abstract
Background: NAD(P) Dependent Steroid Dehydrogenase-Like (NSDHL) is an enzyme involved in post-squalene cholesterol biosynthesis. We recently suggest new insights into the critical role of the NSDHL involved in breast tumor growth and metastasis and its potential for targeted cancer therapy. Compound 9, which is a novel inhibitor of NSDHL, was kindly provided by Dr. Lee B-J in Seoul National University College of Pharmacy. This study aimed to investigate the anti-cancer potential of Compound 9 in breast cancer.
Methods: Therapeutic potential of Compound 9 (10~100 μM) was investigated in several human breast cancer cell lines. Total intracellular cholesterol level was measured using Total Cholesterol Assay Kit. Cell cycle analysis using DNA staining with PI, apoptosis analysis using Annexin V/PI-labeling, and transwell migration assay were performed. The Synergistic anticancer effect of compound-9 and paclitaxel was evaluated by crystal violet assay. Western blot and immunofluorescent staining were assessed for investigating the mechanism by which Compound 9 exerts the anti-cancer effect.
Results: Time-dependent intracellular uptake of Compound 9 by breast cancer cells was observed. Compound 9 induced cytotoxic, anti-proliferative, and apoptotic effects and cell cycle arrest (G0/G1), and suppressed migration activity on diverse breast cancer cell lines in a time- and dose-dependent manner. Total intracellular cholesterol level was reduced by Compound 9. Combination with Compound-9 and Paclitaxel led to synergistic cytotoxicity. Compound-9 increased the autophagy-related proteins (P62, LC3II) but decreased the anti-apoptotic proteins (XIAP, BCL2).
Conclusion: Our data show that Compound 9 exerts strong anti-proliferative and cytotoxic activity in breast cancer cells, suggesting potential additional utility as an anti-cancer drug. Further studies are necessary to validate the potential anti-cancer effect of Compound-9 in breast tumor mice models.
Citation Format: So-Hyun Yoon, Hoe Suk Kim, Moonjou Baek, Seungyeon Ryu, Sangeun Lee, Han-Byoel Lee, Bong-Jin Lee, Wonshik Han. Novel NSDHL inhibitor (Compound 9) exerts anti-proliferative and cytotoxic activity in 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 1800.
Abstract 1803: Lethal synthesis: Potent anticancer activity of a glycine uptake inhibitor in tumor cells with mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) knocked down
Authors: Rather Gulam Mohmad , Bertino Joseph R. 
Published: June 2022

Abstract
Methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme with dehydrogenase and cyclohydrolase activity. MTHFD2 is expressed in embryonic tissues and not in adult tissues, and by generating formate for purine biosynthesis, enhances proliferation. It is over expressed in many cancers, including breast cancer, and has become an important cancer drug target. Knockdown (KD) of MTHFD2 in breast cancer cell lines MCF7 and T47D, slowed proliferation and resulted in an increase in early apoptosis and a S-phase block. Lack of MTHFD2 causes a dependence on glycine, and in the absence of glycine, proliferation of the MCF-7 cell line with MTHFD2 knocked down was inhibited even further. A known specific glycine transporter type-I (GlyT1) inhibitor, ORG 25935 potently inhibited growth of MCF7 cell with MTHFD2 KD, while it had less of an effect on T47D cells with MTHFD2 KD. Furthermore, both cell lines with MTHFD2 KD showed increase in expression of GlyT1 (SLC6A9) at both mRNA and protein level, using the qPCR and western blotting, respectively. The metabolomics studies showed that intracellular glycine, and NAD+ pools are more reduced in control cells compared to MTHFD2 KD cells on treatment with GlyT1 inhibitor, suggesting that this inhibitor causes glycine depletion in the cells. These data encourage the development of inhibitors of MTHFD2 for use in combination with glycine transport inhibitors.
Citation Format: Gulam Mohmad Rather, Joseph R. Bertino. Lethal synthesis: Potent anticancer activity of a glycine uptake inhibitor in tumor cells with mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) knocked down [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 1803.
Abstract 1805: RAB10, a new target to tackle SMAD4 deficient cancers
Authors: Marcireau Christophe , Erasimus Hélène , Kolnik Vanessa , Lacroix Frederic , D’agostino Stephane , Lemaitre Olivier , Rohaut Alexandre , sanchez Isabelle , Sidhu Sukhvinder , Thill Gilbert , Debussche Laurent , Didier Michel 
Published: June 2022

Abstract
TGFb pathway is an important signaling process that regulates the homeostasis of epithelial, stromal or immune cells. Misregulations of this pathway contribute to different pathologies such as cancer, fibrosis, nash or inflammatory diseases. SMAD4 genetic alterations, either via genomic loss or via mutations, can be found in many cancer types. SMAD4 is mutated or deleted in 10-15% of colorectal cancers and in 20-50% of pancreatic cancer. The poorer prognosis of colorectal cancers and pancreatic cancers patients harboring SMAD4 alterations makes SMAD4 deficiency interesting to harness for therapy. Anticancer opportunity created by loss of SMAD4 function/protein could be addressed by identifying synthetic lethal genes that encode for druggable proteins. CRISPR/CAS9 is a revolutionary discovery to produce gene knockout. CRISPR/CAS9 viability screen is a tool of choice to pinpoint new synthetic lethality interactions. In this work, to extend the genetic vulnerabilities of SMAD4-deficient tumors, we conducted a pooled genome-wide loss of function CRISPR/Cas9 screen in sets of 4 non-isogenic colorectal and pancreatic cancers cancer cell lines harboring wild-type and mutant SMAD4. We identified known and novel genetic alterations that make SMAD4-altered colorectal cancers & pancreatic cancers cells vulnerable. We will present the validation of the Ras-related protein Rab-10 (RAB10) as synthetic lethal gene with SMAD4 alteration.
Citation Format: Christophe Marcireau, Hélène Erasimus, Vanessa Kolnik, Frederic Lacroix, Stephane D’agostino, Olivier Lemaitre, Alexandre Rohaut, Isabelle sanchez, Sukhvinder Sidhu, Gilbert Thill, Laurent Debussche, Michel Didier. RAB10, a new target to tackle SMAD4 deficient cancers [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 1805.
Abstract 1808: Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells
Authors: Sehgal Drishti , Nethi Susheel Kumar , Merali Carmen , Merali Salim , Panyam Jayanth , Prabha Swayam 
Published: June 2022

Abstract
Mesenchymal stem cells (MSCs) are being investigated for several therapeutic applications, including cancer, inflammation, tissue repair, and transplantation because of their ability to home to injured and inflamed tissues. Despite the large number of preclinical studies investigating engineered MSCs as therapeutic agents and numerous clinical trials investigating MSCs for other therapeutic applications, there have only been a handful of clinical trials investigating MSCs for treating solid tumors, and none have progressed beyond Phase I/II. Inefficient tumor homing ability and a lack of understanding of fundamental mechanisms may contribute to the limited translational success of MSC-based therapies. We hypothesized that nanoengineering MSCs with anticancer drugs induces oxidative stress, and MSCs counteract this stress by activating Nrf2, which increases the expression of various antioxidant proteins, including CXCR4, a key mediator of MSC tumor homing. We performed global label-free, unbiased proteomics on nanoengineered MSCs using modified in-Stage technology. Our studies indicated that MSCs nanoengineered with paclitaxel underwent significant changes in the overall proteome compared to either untreated MSCs or MSCs loaded with blank nanoparticles. Analysis of molecular function profile revealed that loading paclitaxel in MSCs significantly enhanced the expression of proteins involved in the antioxidant and catalytic activity and protein binding. The biological process profile also showed a similar increase in defense response and an increase in metabolic processes. It was further found that MSCs nanoengineered with PTX lead to significant upregulation of nrf2, the master regulator of antioxidant responses, and CXCR4, a direct target of Nrf2 and a key mediator of tumor homing. Also, an increase in CXCR4 expression was directly proportional to paclitaxel loading in cells. These studies suggest nanoengineering of MSCs impacts their biology, which likely contributes to their improved tumor homing capacity in vivo.
Citation Format: Drishti Sehgal, Susheel Kumar Nethi, Carmen Merali, Salim Merali, Jayanth Panyam, Swayam Prabha. Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem 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 1808.
Abstract 1822: Selective inhibition of ZCCHC11/ZCCHC6 TUTases with genetic and pharmacological tools supports a role in glioblastoma cell growth
Authors: Triboulet Robinson , Sadykov Khikmet , Johnson Jessica L. , Snyder Andrew R. , Knutson Sarah K. , Kumar Pavan , Mayo Christopher B. , Hawley Dillon , Madanjian Andrew , Stein Ross L. , Wilson David M. , Harvey Darren M. , Ghosh Shomir , Campbell Robert M. 
Published: June 2022

Abstract
The purpose of the study was to determine if genetic and pharmacological inhibition of terminal uridyltransferases (TUTases) ZCCHC11 and ZCCHC6 could modulate Glioblastoma (GBM) cell growth in vitro. ZCCHC11 (also known as TUT4 and TENT3A) and ZCCHC6 (also known as TUT7 and TENT3B) catalyze uridylation of diverse RNA species. Recent evidence indicates that genetic perturbation of ZCCHC11/6 expression can disrupt cell proliferation of both immortalized and patient-derived primary GBM cell lines (Kim et al., Mol Cell 2020). We confirmed that genetic inhibition of ZCCHC11/6 with siRNA or CRISPR can decrease viability of U-87 MG and A-172 GBM cell lines, and we identified DK-MG as another GBM cell line with sensitivity to ZCCHC11/6 knockdown. Herein, we report the first novel, potent, and selective inhibitor of ZCCHC11/6, TS-1. Biochemically, TS-1 can block ZCCHC11/6-mediated uridylation of an RNA substrate in vitro (IC50 = 0.65 nM for recombinant ZCCHC11 protein; IC50 = 9.6 nM for recombinant ZCCHC6 protein). ZCCHC11/6 inhibitor TS-1 could decrease cell viability in U-87 MG, A-172 and DK-MG cells (cell viability IC50s ranging between 0.7-1.5 μM) and induce apoptosis and cell cycle arrest. A cellular assay detecting uridylation of miR-191 as a marker for ZCCHC11/6 activity was developed and validated. TS-1 strongly decreased uridylation of miR-191 in U-87 MG, A-172 and DK-MG cells (IC50 ranging between 10-40 nM). In contrast, TS-2, a weakly active enantiomer of TS-1 (enzyme IC50 = 0.15 μM and 1.8 μM against ZCCHC11 and ZCCHC6, respectively), had less impact on cell viability, apoptosis, cell cycle and uridylation in cells. In conclusion, we have verified ZCCHC11/6-dependency in a set of GBM cell lines and we have also developed a first-in class potent and selective small molecule that reduces in vitro Glioblastoma cell proliferation through selective inhibition of TUTases activity.
Citation Format: Robinson Triboulet, Khikmet Sadykov, Jessica L. Johnson, Andrew R. Snyder, Sarah K. Knutson, Pavan Kumar, Christopher B. Mayo, Dillon Hawley, Andrew Madanjian, Ross L. Stein, David M. Wilson, Darren M. Harvey, Shomir Ghosh, Robert M. Campbell. Selective inhibition of ZCCHC11/ZCCHC6 TUTases with genetic and pharmacological tools supports a role in glioblastoma cell growth [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 1822.
Abstract 1860: NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer
Authors: Blain Stacy Wister , Chand Arianna , Pedraza-Ortiz Lina , VanInwegen Allison , Yan Lingyu , Wu Yun , Chen Grace , Jilishitz Irina 
Published: June 2022

Abstract
Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) is frequently caused by compensatory CDK2 activity. We have developed a novel strategy to kill CDK4i resistant tumor cells using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. IpY is specific for p27, and this reduces toxicity relative to that seen with the small molecule ATP-competitive CDK4/6i or CDK2i. NP-ALT blocks DNA replication in HR+ breast cancer (BC) cells and mouse models, but unlike CDK4/6i or CDK2i treatment, it induces ROS-dependent necroptosis to kill the tumor cells. This RIPK1/RIPK3-dependent cell death is more specific for HR+ lineages, but the combination of NP-ALT and palbociclib in TNBC cells causes synergy to induce necroptosis. We found that NP-ALT was still able to induce necroptosis in cell lines resistant to palbociclib, including those harboring genetic perturbations detected clinically in patients resistant to palbociclib. HR+ cell lines engineered to overexpress CDK6, FGFR, cyclin E, or cyclin D or ones that have loss of FAT1 or RB were still sensitive to NP-ALT. We tested other CDK2i, including CYC065, a CDK2/9 inhibitor and PF-06873600, a CDK4/6/2 inhibitor, and and found that while they were able to block DNA replication, only NP-ALT was able to induce ROS-dependent death in the resistant lines. We have shown that IpY reduces tumor volumes in resistant in vivo models as well, without causing adverse effects. Thus, NP-ALT and p27 targeting has several differentiators, which might provide clinical advantages: a) its low toxicity due to the tight specificity of the peptide for the p27 target and b) its ability to kill tumor cells as opposed to just causing cytostasis. Concarlo is currently developing NP-ALT into a therapeutic lead for the treatment of drug-resistant breast cancer.
Citation Format: Stacy Wister Blain, Arianna Chand, Lina Pedraza-Ortiz, Allison VanInwegen, Lingyu Yan, Yun Wu, Grace Chen, Irina Jilishitz. NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast 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 1860.
Abstract 1863: Mouse strain variations in drug-induced lung stromal responses
Authors: Leon Carlos M. , Gong Zheng , Li Qing , Shi Jiayuan , Zuo Wulin , Hasham Muneer G. , Shultz Lenny , Li Sheng , Ren Guangwen 
Published: June 2022

Abstract
Chemotherapy has significantly improved the survival of cancer patients. However, the vast variation in treatment responses remains a major issue in the clinic. It is imperative to understand the molecular mechanisms underlying treatment failure in specific populations of patients. Genetic diversity has been recognized to mainly account for the differences in drug responses among patients. Yet, it is not feasible to map the responsible genetic variants within millions of single-nucleotide polymorphisms in the human genome in clinical settings with a limited number of subjects and insufficient genomic information. Genetically diverse mice are an ideal tool to overcome the limitations in clinical studies and model drug responses in hosts that require genetic susceptibility and resistance factors. Recent studies have also implicated a critical role for host cells (i.e., the tissue microenvironment) in building a protective “niche” for tumor cells enabling their escape from chemotherapeutic treatments. Notably, the host regenerative response upon chemotherapy “injury,” which is regarded as an intrinsic host mechanism to repair damaged tissues, may be exploited by tumor cells for their local recurrence or distant metastases. In this study, using a lung injury model, we determined how drug-induced lung stromal wound healing responses differed among eight inbred mouse strains (BALB/cJ, NSG, C57BL/6J, CH3/HeJ, CBA/J, SJL/J, A/J, and NOD/ShiLtJ). Upon either cisplatin or doxorubicin stimulation, the wound healing-associated genes Il-6, Spp1, Cxcl1, and Ccl2 were all found upregulated in lung stromal cells but showed a great variation across different strains. Furthermore, we performed single-cell RNA sequencing on the lung stromal cells and immune cells isolated from three selected mouse strains (BALB/cJ, C57BL/6J, and NOD/ShiLtJ) without and with doxorubicin treatment in vivo. The transcriptomic analyses revealed strain-specific and non-specific therapy-elicited gene signatures in different types of lung tissue cells. Collectively, our results signify an association between genetic backgrounds and drug-induced host responses in mice. The next steps of the study aim to understand how genetic diversity would functionally impact drug-induced lung tissue regeneration, lung inflammation, and post-therapy tumor relapse or metastasis in the lung.
Citation Format: Carlos M. Leon, Zheng Gong, Qing Li, Jiayuan Shi, Wulin Zuo, Muneer G. Hasham, Lenny Shultz, Sheng Li, Guangwen Ren. Mouse strain variations in drug-induced lung stromal responses [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 1863.
Abstract 187: High-throughput screening of cancer spheroids demonstrates sensitivity to combination chemotherapy
Authors: Katz Elad , Deehan Maureen R. , Petty Russell D. , Davies Paul 
Published: June 2022

Abstract
We have designed and manufactured a miniaturized 3D cell culture format called NaviPlate. The NaviPlate contains a novel geometry to support the generation of cancer spheroids for robust and sensitive complex biological assays. Cells added to the NaviPlate spontaneously form spheroids, consistent with the cell line phenotype reported in the literature when using U-bottom multi-well formats. In addition, we have been able to perform assays such as cytotoxicity with a minimum number of 200 cells/well, representing a 5-50-fold improvement on existing 3D cell culture assays.Using the NaviPlate, we examined the response to chemotherapy of four commonly used cancer cell lines: LNCaP, AR mutant lymph-node derived prostate cancer; A549, KRAS mutant/EGFR wt NSCLC; HCT116, KRAS mutant/p53 wt colon cancer; and MDA-MB-231 triple negative breast cancer. First, the lines were exposed to three types of chemotherapy with distinct modes of action: 5-FU (DNA damage), Docetaxel (inhibition of microtubular polymerization) and Flavopiridiol (pan-CDK inhibition). Except for Flavopiridiol in A549 cells, all cell lines were resistant to chemotherapy, when grown in 3D, inside the NaviPlate. Furthermore, we were able to show that this resistance was dependent on the 3D formation of spheroids, as HCT116 cells exposed to chemotherapy before forming spheroids were still sensitive to treatment. Interestingly, in A549 cells, which form less tight spheroids, the effect of 3D clustering was less profound on the response to monotherapy. Lastly, we explored NaviPlate as a platform to identify best chemotherapy combination partners. We combined the three chemotherapies in all cell lines, with most combinations efficiently killing the spheroids. On note, the commonly used combination of 5-FU and Docetaxel had no statistically significant effect on the viability of either A549 or MDA-MB-231 cells.In conclusion, NaviPlate is an easy to use, cancer spheroid platform for the identification of chemotherapy combination partners and thus a useful tool for exploring personalized oncology approaches in the clinic.
Citation Format: Elad Katz, Maureen R. Deehan, Russell D. Petty, Paul Davies. High-throughput screening of cancer spheroids demonstrates sensitivity to combination chemotherapy [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 187.
Abstract 1884: Optical coherence tomography for label-free real 3D imaging of ex-vivo tumor cultures
Authors: Mitsi Maria , Urbane Riccardo , Simon Benjamin , Kuromi Yasushi , Hasebe Ryo , Dhar Sumeer 
Published: June 2022

Abstract
The use of advanced ex-vivo human organotypic cultures is rapidly growing in the field of oncology research and diagnostics, with a focus on patient-derived organoids and tumor tissue specimens cultured in artificial systems capable of replicating tumor development mechanisms. These mechanisms include metastasis, angiogenesis and formation of dysplasia. Our objective is to enhance the label-free imaging and analytical capabilities of these complex tissue samples to enable screening and diagnostics applications.SCREEN Holdings Inc., has developed a unique infrared laser-based optical coherence tomography (OCT) technology enabling non-invasive, label-free, three-dimensional (3D) imaging of tumoroids, epithelial cystic organoids, sprouting endothelial neo-vasculature and metastatic single cells. The imaging is carried out on the 3DProSeed hydrogel plates developed by Ectica Technologies, a glass-bottom 96-well plate featuring pre-casted, synthetic and optically clear hydrogels for ex-vivo tumor cultures.Here we present culture and imaging protocols with the resulting 3D tomographic reconstructions of endothelial sprouting vessels, cystic epithelial organoids of the colon and 3D invasion assays of highly metastatic glioma cells.
Citation Format: Maria Mitsi, Riccardo Urbane, Benjamin Simon, Yasushi Kuromi, Ryo Hasebe, Sumeer Dhar. Optical coherence tomography for label-free real 3D imaging of ex-vivo tumor cultures [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 1884.