bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1004: Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma
Authors: Gleba Justyna J. , Marlow Laura A. , Miller Erin E. , Miller James L. , Alasonyalilar-Demirer Aylin , Guo Yi , Mody Kabir , Roberts Lewis R. , Alberts Steven R. , Truty Mark J. , Patel Tushar C. , Copland John A. 
Published: July 2021

Abstract
Cancer cells increase lipid metabolism by up-regulation lipogenic enzymes such as stearoyl-CoA desaturase 1 (SCD1). It is the rate-limiting enzyme in the de novo synthesis of fatty acids (FAs), catalyzing the conversion and biosynthesis of saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). We developed SSI-4, a novel highly specific SCD1 inhibitor. The anti-tumor activity ofSSI-4 was examined against different cholangiocarcinoma (CCA) models that included human and mouseCCA cell lines, CCA patient-derived xenografts (PDX) NOD SCID gamma (NSG) mouse models, and CCA PDX derived organoids. Using cell proliferation assay, we examined twelve CCA cell lines and 4 were very sensitive to SSI-4 (1-40 nM IC50). The remaining CCA cell lines showed moderate to no sensitivity to SSI-4. Studies at the protein level have shown that SCD1 is present in both sensitive and non-sensitive cells. Thus, SCD1 must be present in sensitive cells but is not predictive of response to an SCD1 inhibitor. In an effort to identify biomarkers predicting response to therapy, we performed assays, such as lipid, lactate, or energy phenotype which identified elevated lactate and unsaturated fatty acid levels as well as a glycolytic energy phenotype. In vivo, CCA PDX models have demonstrated that SSI-4strongly inhibited tumor growth. Immunohistochemical analysis of CCA tumors revealed elevated glycolytic genes in sensitive cells and thus, a potential predictive biomarker. We are currently pursuing a better understanding of the relationship between glycolysis and fatty acid synthesis/metabolism. We are also testing novel combination therapy of SSI-4 with the standard of care and other drugs to develop novel treatments for CCA. Using CCA PDX derived organoids showed synergistic antitumor activity of SSI-4in combination with cancer standard of care drugs such as gemcitabine and cisplatin. Collectively, we expect to develop a biomarker-driven selection of CCA patients sensitive to SCD1 inhibitors and novel SSI-4 combination therapy leading to improved patient survival.
Citation Format: Justyna J. Gleba, Laura A. Marlow, Erin E. Miller, James L. Miller, Aylin Alasonyalilar-Demirer, Yi Guo, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, John A. Copland. Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1004.
Abstract 1012: In vitro antitumor effect of AZD4547 in ovarian cancer cell lines
Authors: Seo Ji Hae , Lee Seungmee , Cho Chi-Heum , Shin So-Jin 
Published: July 2021

Abstract
Of all the gynecological cancer, ovarian cancer is the most fatal malignancy. In particular, strong chemotherapy resistance in ovarian cancer raises the need for new therapeutic strategy. Since fibroblast growth factor (FGF) signaling pays an important role in malignant transformation, tumor growth, angiogenesis, and chemoresistance, fibroblast growth factor receptor (FGFR) inhibitors are being assessed in clinical trials for several FGFR-driven cancer. FGFRs is known to be highly dysregulated in ovarian cancer, however the effect of FGFR inhibition in ovarian cancer has not been elucidated. In this study, we investigated the anti-tumor effects of AZD4547, an FGFR1-4 inhibitor, in various types of ovarian cancer cell line. AZD4547 markedly inhibited proliferation and stimulated apoptosis of ovarian cancer cells. In addition, AZD4547 inhibited cell migration and invasion under non-toxic condition. Moreover, AZD4547 reduced the sphere forming ability and the self-renewal capacities of ovarian cancer stem cells (CSCs) which are strongly resistant to paclitaxel. Furthermore, AZD4547 exhibited anti-angiogenic effect on human umbilical vein endothelial cells. Based on these anti-tumor effect of AZD4547 in ovarian cancer cell lines, we suggests AZD4547 as a promising agent for ovarian cancer treatment.
Citation Format: Ji Hae Seo, Seungmee Lee, Chi-Heum Cho, So-Jin Shin. In vitro antitumor effect of AZD4547 in ovarian cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1012.
Abstract 1016: A new biomarker in hematological malignancies
Authors: Borgovan Theo 
Published: July 2021

Abstract
Background: Extracellular vesicles (EVs) are biologically active nanoparticles. EVs from explant prostate cancer induce a neoplastic phenotype in normal prostate cell lines. We have also shown EVs from mesenchymal stem cells (MSC) can have a healing effect, reversing the malignant phenotype in prostate and colorectal cancer; as well as mitigating radiation damage to marrow. The role of EVs in leukemia and its microenvironment remains to be studied, and may provide insight for therapeutic advances. We hypothesize that EVs derived from normal MSC can have a healing effect, inhibiting the growth of myelogenous leukemia.
Methods: Kasumi AML cells lines were seeded in a 96 well plate with various concentrations of MSC-derived EVs. Vesicles were isolated usingan established differential centrifugation technique, and were co-cultured with Kasumi. To study cellular proliferation we measured fluorescence after 60 min. Fluorescence intensities were normalized to control wells containing non-EV treated cells alone.
Results: Proliferation of AML cells after one day of co-culture with MSC-EVs respectively was inhibited in a dose dependent manner. Three days of co-culture with similar doses resulted in ~40% and ~80%reduction in proliferation when normalized to control. At day 6 of co-culture growth was inhibited by ~80% at both EV concentrations when normalized to control.
Summary/Conclusion: MSC-derived EVs inhibits the growth of the AMLcell line in vitro. This effect is seen as early as 1 day of co-culture andpersists out to 3, and 6 days implicating an miRNA-mediated mechanismthat has been discussed in previous works. We feel this is perhaps a modelof how a normal marrow works to suppress early cancer.As leukemia develops the cross-talk between AML and its microenvironmentalters the MSCs to promote a survival signal favouring AMLgrowth. Future work involves the capacity of AML-derived EVs to alterthe phenotype of normal marrow towards a pro-leuekmic phenotype.Employing mathematical models to quantify and ultimately predict thesechanges allows for precise therapeutic intervention.
Citation Format: Theo Borgovan. A new biomarker in hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1016.
Abstract 1033: The anticancer compound avicin D targets lysosomal functions
Authors: Braig Friederike , Gutterman Jordan U. , Acosta-Alvear Diego 
Published: July 2021

Abstract
This study investigates the mechanism by which avicins—plant-derived triterpenes with potent anticancer activity—alter lysosomal functions. The anticancer properties of avicins have been known for over two decades, yet the precise mechanism of action of avicins remains unknown. To elucidate their mechanism of action, we conducted a pooled CRISPR interference (CRISPRi) genetic screen in Jurkat T-cell leukemia cells treated with avicin D. Our screen revealed that the depletion of genes encoding lysosomal components protected cells from the drug's cytotoxic effects. Consistent with this finding, blocking lysosomal functions with chloroquine protected cells from avicins. Moreover, blocking the lysosomal cholesterol transporter NPC1 abolished avicin cytotoxicity, hinting that avicins—which resemble steroidogenic molecules—use the same cellular factors required for cholesterol transport. Together, these results suggest a causal relationship between a requirement for lysosomal functions and avicin cytotoxicity. The top hit whose depletion sensitized cells to avicin D was the endoplasmic reticulum (ER) stress sensor ATF6, which is a membrane-tethered transcription factor capable of detecting sphingolipid lipotoxicity in the ER membrane. Consistent with this result, recent observations indicate that avicins alter the cell's sphingolipid and cholesterol balance (1), suggesting that avicins induce ER stress by disrupting ER membrane homeostasis. Together, our results support a potential mechanism of action wherein avicins are pro-drugs activated in lysosomes and induce organelle stress by altering the cell's lipid balance. We are currently working on elucidating the molecular mechanisms by which avicins and their putative metabolic products disrupt organelle homeostasis. We anticipate that our study will reveal the molecular circuitry that controls the cell's response to avicins and may open new avenues for therapeutic intervention in cancer.
1. Garrido CM, Henkels KM, Rehl KM, Liang H, Zhou Y, Gutterman JU, Cho K-J. Avicin G is a potent sphingomyelinase inhibitor and blocks oncogenic K- and H-Ras signaling. PMC7272413
Citation Format: Friederike Braig, Jordan U. Gutterman, Diego Acosta-Alvear. The anticancer compound avicin D targets lysosomal functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1033.
Abstract 1041: Targeted inhibition of c-MET, Axl and DDR signaling pathways by merestinib enhances gemcitabine/nab-paclitaxel standard chemotherapy activity in pancreatic cancer models
Authors: Shi Eda , Schwarz Margaret A. , Hassan Md Sazzad , von Holzen Urs , Schwarz Roderich E. , Awasthi Niranjan 
Published: July 2021

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in Western countries. Gemcitabine (Gem) plus nab-paclitaxel (NPT) is the standard chemotherapy treatment for PDAC leading to an average survival of 8.5 months. Activated signaling of c-MET, Axl and DDR1/2 pathways have been implicated in tumorigenic growth in many cancers including PDAC. Merestinib (Mer) is a potent, multikinase inhibitor that blocks c-MET, Axl and DDR1/2 pathways with IC50 values in the low nanomolar range. In this study, we investigated the antitumor potency of merestinib to enhance standard chemotherapy response in preclinical PDAC models.
Methods: In vitro cell proliferation assays of PDAC-associated cells were evaluated by colorimetric WST-1 reagent. The mechanism of action was determined by Immunoblot analysis. Tumor growth studies were conducted in 6-week-old female NOD/SCID mice in subcutaneous xenografts.
Results: In human PDAC AsPC-1 cell-derived subcutaneous xenografts, gemcitabine plus nab-paclitaxel and merestinib inhibited tumor growth while their combination had an additive effect. The net increase in tumor size was 357 mm3 in controls, 102 mm3 after Gem+NPT, 177 mm3 after Mer and 66 mm3 after Gem+NPT+Mer. Gemcitabine plus nab-paclitaxel and merestinib suppressed in vitro cell proliferation of PDAC epithelial cells and stromal cells. Importantly, the combination treatment demonstrated additive inhibitory effects. Inhibition in cell proliferation by Gem+NPT, Mer and Gem+NPT+Mer treatments was 54%, 14% and 82% (AsPC-1 cells, at medium dose levels), 54%, 4% and 73% (PANC-1 cells, at the highest dose level), 55%, 58% and 92% (PDAC-associated fibroblasts, at the medium dose level). Immunoblot analysis revealed that merestinib caused a decrease in the expression of phospho-c-MET, phospho-Axl, phospho-IGF-1R, phospho-AKT and an increase in apoptosis-related protein cleaved caspase-3 in PDAC cells either alone or in combination with gemcitabine plus nab-paclitaxel.
Conclusion: Simultaneous inhibition of c-MET, Axl and DDR1/2 pathways by merestinib has antitumor efficacy in PDAC and it can significantly improve the standard chemotherapy response. This therapeutic approach might lead to a clinically relevant combination to increase PDAC patients' survival.
Citation Format: Eda Shi, Margaret A. Schwarz, Md Sazzad Hassan, Urs von Holzen, Roderich E. Schwarz, Niranjan Awasthi. Targeted inhibition of c-MET, Axl and DDR signaling pathways by merestinib enhances gemcitabine/nab-paclitaxel standard chemotherapy activity in pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1041.
Abstract 1046: Synergistic cytotoxic effect of sulfated glycolipid PG545 in combination with ATR inhibition in ovarian cancer cells
Authors: Xiao Yinan , Deng Chaolin , Guan Ye , Jin Ling , Ray Upasana , Thirusangu Prabhu , Staub Julie , Xu Haotian , Shridhar Viji 
Published: July 2021

Abstract
Despite the advances in the molecular understanding of ovarian cancer (OC), improvements in therapy are still needed. PG545 is a highly sulfated small molecule and is currently in Phase I clinical investigation, which has shown promising antitumor activity in multiple tumor models, including ovarian, endometrial and pancreatic cancers. Ataxia telangiectasia and Rad3-related protein (ATR), plays a crucial role in maintaining genomic integrity by responding to a large spectrum of DNA damage, including double strand breaks (DSBs) that interfere with replication. Several ATR inhibitors have been developed, but resistance is likely to occur. This study aimed to investigate the potential synergistic effect of combining PG545 with ATR inhibition in OC. Proliferation and clonogenic assay showed that combination of PG545 with ATR shRNA or ATR inhibitor (ATRi; VE-822) synergistically decreased cell survival compared with single-agent treatments in two OC cell lines, OVCAR5 and OVCAR8 cells. PG545 monotherapy induced DNA damage, activated the ATR signaling pathways as well as the S and G2/M cell cycle checkpoints. The combination of PG545 and ATRi inhibited the phosphorylation of ATR and Chk1, induced γH2AX and lead to a marked increase in pan-nuclear γH2AX-positive cells. Moreover, ATRi diminished the cell cycle effects of PG545 and markedly enhanced PG545-induced apoptosis in OC cell lines. Taken together, our results indicate that the combination of PG545 with ATR inhibition may be promising options to be considered in future clinical trials of OC.
Citation Format: Yinan Xiao, Chaolin Deng, Ye Guan, Ling Jin, Upasana Ray, Prabhu Thirusangu, Julie Staub, Haotian Xu, Viji Shridhar. Synergistic cytotoxic effect of sulfated glycolipid PG545 in combination with ATR inhibition in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1046.
Abstract 1050: Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia
Authors: Chen Xiaoyue , Caenepeel Sean , Belmontes Brian , McElroy Patricia L. , Rex Karen , Osgood Tao , Hughes Paul 
Published: July 2021

Abstract
Acute Myeloid Leukemia (AML) is the most common and aggressive acute leukemia in adults, with a 25% 5-year survival rate. FLT3 is the most frequently mutated gene in AML. About 25% of AML patients harbor FLT3 internal tandem duplication (ITD) mutations, and about 8 % of patients harbor FLT3 tyrosine kinase domain (TKD) mutations. Both FLT3-ITD and FLT3-TKD mutations constitutively activate the protein, which causes poor survival. Gilteritinib is a highly potent and selective oral FLT3 inhibitor recently approved by the FDA. Although gilteritinib showed strong single agent activity in AML patients with FLT3 mutations, the development of gilteritinib resistance limits the long-term efficacy of this treatment, indicating that combination therapy may be advantageous for AML patients with FLT3 mutations. FLT3 mutations are known to be anti-apoptotic. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic protein, expressed in a large percentage of the AML patient population, plays a critical role in AML cell survival and drug resistance. AMG 176 is a potent, selective and orally bioavailable MCL-1 inhibitor, which induces rapid commitment to apoptosis in AML. Here we demonstrated that AMG 176 and gilteritinib combination treatment synergistically targeted FLT3-ITD mutated AML. A strong synergistic effect (Combination index &lt;0.2) was observed in two FLT3-ITD mutated AML cell lines treated with the AMG 176 plus gilteritinib combination. Increased Bcl-2-like protein 11 (BIM) expression and decreased BIM/MCL-1 interaction was observed under the combination treatment, coupled with a significant increase in apoptosis. In the MV4-11 AML xenograft model, mice treated with two cycles of AMG 176 (2 days on 5 days off) at 30 mg/kg or with 3 mg/kg gilteritinib daily showed 76% or 74% tumor growth inhibition respectively. A statistically significant increase in efficacy was observed in the combination treatment group, with 92.8% tumor regression, including 50% of mice being tumor free. No significant difference in body weight was found between groups. Our results show that AMG 176 plus gilteritinib treatment was effective and well tolerated in mouse models of AML, which supports further evaluation in a clinical setting.
Citation Format: Xiaoyue Chen, Sean Caenepeel, Brian Belmontes, Patricia L. McElroy, Karen Rex, Tao Osgood, Paul Hughes. Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1050.
Abstract 1054: Patient derived organoids demonstrate synergistic antitumor effect of senogenic and senolytic drug combination of Aurora kinase inhibitor and BCL2/xL inhibitor
Authors: Bharti Vijaya , Weiss Vivian , Shen Chengli , Chen Sheau Chiann , Blevins Ashlyn , Shattuck-Brandt Rebecca L. , Richmond Ann , Vilgelm Anna E. 
Published: July 2021

Abstract
The management of metastatic melanoma continues to be challenging, despite of evolving treatments such as immune checkpoint blockade and inhibitors of mutated BRAF. New therapies that work via immune and BRAF-independent mechanisms are urgently required for tumors that are unresponsive to currently available treatments. Here we hypothesized that combination of Aurora Kinase inhibitor (AURKAi) alisertib (senescence inducer) with a drug that selectively kills senescent cells, such as BCL2/xL inhibitor (BCLi) navitoclax (senolytic), will induce apoptosis in melanoma cells. Patient derived organoids (PDOs) were used to test anti- tumor effect of AURKAi and BCLi combination treatment. H&E staining of PDOs and their matched original tumors revealed similar histology. Fourteen out of ninety PDOs were highly sensitive to AURKAi and BCLi combination treatment exhibiting robust induction of cell death. NextGen DNA sequencing indicated that all sensitive PDOs retained wild type TP53, while resistant tumors had mutations in this gene. Knockout or knockdown of TP53 abrogated AURKAi and BCLi-induced cell death in melanoma cells, suggesting that transcription factor p53 encoded by TP53 is a key mediator of drug response. Addition of BCLi to AURKAi activated proapoptotic p53 targets BAX, NOXA and induced cleavage of PARP and Caspases 3, 7, and 8. Electron microscopy revealed morphological signs of apoptosis in combination-treated cells, including cell blebbing, apoptotic bodies, and nuclear fragmentation. This suggests that BCLi shifts cell fate decision in AURKAi-treated cells towards apoptosis. In conclusion, combination treatment with AURKAi and BCl2i induced p53-dependent apoptosis. Preclinical evaluation of this drug combination in PDO model demonstrated robust efficacy against melanomas with wild type p53. Since p53 mutations are relatively rare in melanoma, combination of AURKAi and BCLi presents promising therapeutic option for this deadly disease.
Keywords: Apoptosis, melanoma, patient-derived organoids, aurora kinase, bcl-2
Citation Format: Vijaya Bharti, Vivian Weiss, Chengli Shen, Sheau Chiann Chen, Ashlyn Blevins, Rebecca L. Shattuck-Brandt, Ann Richmond, Anna E. Vilgelm. Patient derived organoids demonstrate synergistic antitumor effect of senogenic and senolytic drug combination of Aurora kinase inhibitor and BCL2/xL inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1054.
Abstract 1067: PDK-1 targeting with SNS-510 in sarcoma
Authors: Musi Elgilda , Taverna Pietro , Schwartz Gary K. 
Published: July 2021

Abstract
Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have limited treatment options some of which include surgery, chemotherapy and radiation. 3-phosphoinositide dependent protein kinase 1 (PDK1) is overexpressed in many cancers, suggesting a role for PDK1 in cancer progression. In addition, PDK1 has been identified as a key modifier of acquired resistance to CDK4/6 inhibitors. In order to interrogate this in sarcoma, we elected to test SNS-510 a potent, orally bioavailable PDK1 inhibitor against a broad range of sarcoma cell lines (leiomyosarcoma, dedifferentiated liposarcoma, Ewing's sarcoma, osteosarcoma, chondrosarcoma and synovial sarcoma) as well as dedifferentiated liposarcoma cell lines with acquired resistance to ribociclib, which are also cross resistant to palbociclib. All the cell lines expressed PDK1 and, as measured by WST-8 cell proliferation assay, nearly all the cell lines were sensitive to the drug, with IC50s generally between 250 to 500nM. Leiomyosarcoma cell lines (SK-LMS, SK-UT1, SK-UT1b) were seen to be most sensitive to SNS-510 with IC50s determined to be between 50-100nM. In contrast, synovial sarcoma cell lines (SYO-1 and HSSY-II) exhibited relative resistance to SNS-510 with IC50s determined to be &gt; 500nM. As assessed by western blot, SNS-510 exhibited a dose dependent inhibition of the PDK-1/RSK2/AKT pathway with inhibition of p-RSK2(244), p-AKT(308), and pS6(235/236). SNS-510 induced a dose-dependent G1 cell cycle arrest. This was associated with inhibition of p-RB(780) and suppression of cyclin D1 and cyclin E1. The exception to this was the synovial cell lines for which there was no inhibition of p-RB despite inhibition of p-RSK, p-AKT and p-S6. When combined with palbociclib in both the CDK4/6 sensitive (LS141 and DDLS) and CDK4/6 resistant liposarcoma cells (RES.LS141 and RES.DDLS), we observed enhanced inhibition of proliferation with a synergistic effect, as defined by the Chou-Talalay method. These results would suggest a role for PDK-1 targeting with SNS-510 in sarcoma and consideration of combination strategies, especially with CDK4/6 inhibitors in both CDK4/6 sensitive and resistant dedifferentiated liposarcoma.
Citation Format: Elgilda Musi, Pietro Taverna, Gary K. Schwartz. PDK-1 targeting with SNS-510 in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1067.