bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1320: NanoGhost: Harnessing the power of stem cell in an off-the-shelf novel targeted nano-delivery platform
Authors: Machluf Marcelle , Machluf Marcelle , Hamias Shani , Levii Lior , Kashtan Osnat Bohana 
Published: July 2021

Abstract
Mesenchymal stem cells (MSC) have been extensively investigated as cell carriers or cell therapies for treating a wide range of malignant and inflammatory diseases. In addition, recent studies show that MSCs' tropism to malignant and inflamed tissues as well as their immunomodulatory capacity, both are largely governed by direct cell-cell interactions facilitated by membrane-bound proteins. Never the less the translation of MSCs into broadly-applicable clinical applications may face obstacles due to MSCs' susceptibility to host-induced changes, limiting their ability to deliver a long-lasting effect. Based on this knowledge we developed a scalable technology for the production of nano-vesicles from the cell membrane of MSCs. These nano-vesicles, termed Nano-Ghosts (NGs), and our data demonstrate that these NGs can be used as a cancer targeted delivery platform, effectively loaded and used to selectively deliver diverse therapeutics including biological drugs, small molecules, and nucleic acids. In several preclinical cancer models (pancreatic, NSCLAC) we have shown selective NG targeting resulting in reduction in tumor growth and prolonged survival. In this study, we extend previous data and demonstrate the ability of NGs to penetrate the BBB in a two mice models for GBM demonstrating high and specific accumulation of NGs in the tumor while no off-target inn normal brain tissue nor filtrating organs. The lethal effect of drug carrying NGs was expanded by using cytotoxic ligand derived from CTLs (TRAIL) genetically engineered on the surface of the MSC-NGs, creating a new class of NGs termed immunotherapeutic NGs (iNGs). The membrane bound TRAIL enable the iNGs to inhibit significantly mice bearing melanoma tumors, without the need of a loaded drug. Our results, clearly demonstrate the translational potential of NGs, both as targeted carriers and as novel immunomodulatory biologics, for oncological and immunological applications.
Citation Format: Marcelle Machluf, Marcelle Machluf, Shani Hamias, Lior Levii, Osnat Bohana Kashtan. NanoGhost: Harnessing the power of stem cell in an off-the-shelf novel targeted nano-delivery platform [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 1320.
Abstract 1335: Dual MCT1/4 inhibition promotes anti-tumor immunity in triple-negative breast cancer
Authors: Goreczny Gregory James , Escobedo Jaime , Sandanayaka Vincent 
Published: July 2021

Abstract
Despite the recent FDA approval of Abraxane (nab-paclitaxel) and Atezolizumab (anti-PD-L1) for a subset of Triple-Negative Breast Cancer (TNBC) patients, there remains an unmet need to develop novel therapeutic strategies to effectively combat this disease. Nirogy Therapeutics has developed a first-in-class, orally bioavailable small molecule inhibitor targeting MonoCarboxylate Transporters (MCTs), specifically MCT1 and MCT4, which transport lactate into and out of the cell. MCT1/4 expression are upregulated in TNBC patients, and high MCT4 expression correlates with worse outcome. Although a MCT1-specific inhibitor is currently under investigation in clinical trials for some cancers that express only MCT1, primary resistance to these inhibitors occur via the upregulation of MCT4. Most cancers overexpress both MCT1 and MCT4. Thus, the need for dual MCT1/4 inhibitors (dMCTi) that block both MCT1 and MCT4 is crucial to effectively treat these patients. We have shown that our dMCTi compound, NGY-B, exhibits direct cytotoxicity against a panel of TNBC cell lines with various MCT1/4 expression patterns, and it inhibits lactate import through MCT1 and export through MCT4. Furthermore, NGY-B exhibited a significant tumor growth reduction in an MDA-MB-231 CDX mouse model of TNBC compared to the current standard-of-care chemotherapy. Using the syngeneic 4T1 mouse model of TNBC, we have shown that NGY-B also exhibited a significant reduction of tumor growth, indicating potential impact on anti-tumor immunity as well. Further analysis of the 4T1 model showed that NGY-B significantly enriched the CD8+ tumor infiltrating lymphocyte (TIL) population while exhibiting a concurrent reduction in the macrophage M2/M1 ratio, indicating preferred polarization to M1-phenotype. Also, we observed a significant reduction in granulocytic suppressor cells, gMDSCs in the tumor microenvironment (TME). Further work has demonstrated that NGY-B synergizes with immune checkpoint blockade to promote an anti-tumor immune response. By blocking lactate accumulation in the TME, our compound activates local immunity by overcoming lactate mediated immunosuppression in cytotoxic T-cells while suppressing inhibitory immune populations. Therefore, such a broader effect on multiple immune cells by NGY-B leads to overall immune activation in the TME. Our pre-clinical work shows that NGY-B intervenes two key hallmarks of caner; metabolism and immunity, providing us a novel therapeutic modality to combat TNBC.
Citation Format: Gregory James Goreczny, Jaime Escobedo, Vincent Sandanayaka. Dual MCT1/4 inhibition promotes anti-tumor immunity in triple-negative breast cancer [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 1335.
Abstract 1339: Investigations into rational combination approaches with ivosidenib in a mutant IDH1 acute myeloid leukemia patient-derived xenograft model
Authors: Hudson Christine , Narayanaswamy Rohini , Ronseaux Sebastien , Bowden Chris , Nicolay Brandon 
Published: July 2021

Abstract
Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) arise in roughly 6-10% of patients with acute myeloid leukemia (AML). These mutations lead to the production of the oncometabolite 2-hydroxyglutarate at concentrations shown to interfere with epigenetic control of gene expression, which prevents hematopoietic cell maturation. Ivosidenib (IVO; AG-120) is an oral, potent, targeted oral inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory AML patients and mIDH1 newly diagnosed (ND) AML in adults ≥ 75 years of age or with comorbidities precluding intensive induction chemotherapy.
Methods: Currently, IVO is being investigated in combination with azacitidine (AZA) in the actively enrolling phase 3 AGILE study (NCT03173248). To support this ongoing effort, studies were undertaken to explore the IVO + AZA combination in a mIDH1 AML patient-derived xenograft (PDX) model in vivo. These studies examined the timing of IVO + AZA treatment with respect to disease burden control and durability in mice inoculated with a disseminated mIDH1 AML PDX model, both as a frontline treatment as well as in a maintenance therapy setting following either venetoclax (VEN) + AZA, or VEN + AZA + IVO. In addition, the studies examined the utility of combining IVO + VEN as an alternative frontline treatment approach in the same preclinical mIDH1 AML PDX disseminated model.
Results: The IVO + AZA combination led to a &gt; 99% reduction in hCD45+ cells within the bone marrow and undetectable disease in the peripheral blood of 7/10 mice by Week 10. Similar results were observed with IVO + VEN treated animal bone marrow (99% reduction in hCD45+ cells) and undetectable disease was observed in 8/10 mice by week 10.
Conclusions: Each combination was well tolerated by the mice. The observed disease control with either combination in the animals was greater than any of the three single agents alone. Ongoing follow-up xenograft studies investigating the utility of the combinations with IVO as a maintenance therapy are still ongoing and outcomes will be presented.
Citation Format: Christine Hudson, Rohini Narayanaswamy, Sebastien Ronseaux, Chris Bowden, Brandon Nicolay. Investigations into rational combination approaches with ivosidenib in a mutant IDH1 acute myeloid leukemia patient-derived xenograft model [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 1339.
Abstract 1400: SWI/SNF chromatin remodeling complex regulation of YAP-dependent enhancers drives therapeutic resistance in triple-negative breast cancer
Authors: Li Yihao , Qiu Xintao , Liu Hui , Wang Xiaoqing , Geck Renee C. , Tewari Alok , Chow Kin-Hoe , Cejas Paloma , Nguyen Quang-Dé , Long Henry , Liu Shirley X. , Toker Alex , Brown Myles 
Published: July 2021

Abstract
Outcomes for patients with triple negative breast cancer (TNBC) remain poor despite significant advances in the treatment of other breast cancer subtypes. We report an epigenetic mechanism leading to the adaptive resistance of TNBC to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodeling leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenografts (PDX) models. Treatment-induced YAP/TEAD accessible chromatin was observed in a subpopulation of PDX cells by single cell analysis of accessible chromatin. Thus, combinatorial therapies based on the YAP and mTORC1 dependent feedback loop have the potential to improve the efficacy of FGFR inhibitors in TNBC.
Citation Format: Yihao Li, Xintao Qiu, Hui Liu, Xiaoqing Wang, Renee C. Geck, Alok Tewari, Kin-Hoe Chow, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X. Liu, Alex Toker, Myles Brown. SWI/SNF chromatin remodeling complex regulation of YAP-dependent enhancers drives therapeutic resistance in triple-negative breast cancer [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 1400.
Abstract 1434: Uncovering the mechanism of adaptive resistance to RET inhibitors in RET rearranged thyroid cancer
Authors: Raman Renuka , Villefranc Jacques , Ullmann Timothy , Thiesmeyer Jessica , Anelli Viviana , Pauli Chantal , Bareja Rohan , Eng Kenneth Wha , Dorsaint Princesca , Wilkes David , Beg Shaham , Shaw Reid , Churchill Michael , Gumpeni Naveen , Scognamiglio Theresa , Rubin Mark , Grandori Carla , Mosquera Juan , Mosquera Juan , Mosquera Juan , Dephoure Noah , Sboner Andrea , Elemento Olivier , Houvras Yariv 
Published: July 2021

Abstract
Kinase inhibitors are a critical tool for cancer treatment, but their efficacy is limited by resistance mechanisms. In thyroid and lung cancer RET gene rearrangements result in constitutive MAPK pathway activation and drive malignancy. While treatment with new selective RET inhibitors has been associated with significant clinical responses, a majority of patients experience a partial response or disease stabilization as their best clinical outcome. Resistance to RET inhibitors has emerged as a clinical problem requiring new treatment strategies. Using a combination of drug screening, proteomic, and biochemical profiling we identified a strategy to overcome adaptive resistance to RET inhibitors in human thyroid cancer cell lines and vertebrate animal models. The identification of alternative signaling pathways that reactivates ERK signaling as a mechanism of resistance to RET inhibitors provides an opportunity to anticipate resistance to selective RET inhibitors and use combination therapy that leads to more significant and durable anti-tumor responses in patients with RET rearranged cancers.
Citation Format: Renuka Raman, Jacques Villefranc, Timothy Ullmann, Jessica Thiesmeyer, Viviana Anelli, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David Wilkes, Shaham Beg, Reid Shaw, Michael Churchill, Naveen Gumpeni, Theresa Scognamiglio, Mark Rubin, Carla Grandori, Juan Mosquera, Juan Mosquera, Juan Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras. Uncovering the mechanism of adaptive resistance to RET inhibitors in RET rearranged thyroid cancer [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 1434.
Abstract 1448: Combination therapy of anti-sense oligonucleotide targeting TGF-beta2 (TASO) and IL-2 (Proleukin) has anti-cancer effect in solid cancer
Authors: Park Jun-Eui , Koo Jihye , Lee Hong-Kyu , Kim Tae Hun 
Published: July 2021

Abstract
Background: TGF-Β (transforming growth factor-beta) is an essential cytokine for tumor proliferation and metastasis. The expression of TGF-Β correlates with malignancy of various cancers and involves immunosuppression and angiogenesis of a tumor. IL-2 is a major cytokine to proliferate T cells and NK cells which are major players of cancer immunity. However, the toxicity of high dose IL-2 limits its use in cancer therapy. Combination treatment of TGF-Β inhibitor and IL-2 would have an anti-tumor effect by immune cells through diminishing immunosuppression by TGF-Β and enforcement of immune cells by IL-2. Trabedersen is an anti-sense oligonucleotide targeting human TGF-Β mRNA. It is shown that Trabedersen is well tolerable in cancer patients and effective reagent to treat pancreatic cancer, melanoma, and glioblastoma. Proleukin is the only approved IL-2 reagent to treat Renal cell carcinoma and Melanoma.
Methods: Trabedersen and Proleukin activated human PBMC (Peripheral Blood Mononuclear Cell) are treated to several solid cancer cell lines, such as Breast cancer, Pancreatic cancer, Melanoma, Lung cancer, and Colon cancer to see the cytotoxicity effect of combination therapy of Trabedersen and Proleukin. NSG mouse (NOD Scid Gamma mouse, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) which are humanized by human PBMC engraftment and the tumor growth of Melanoma and TNBC (Triple Negative Breast Cancer cell) cell line are monitored.
Results: The combination treatment of Trabedersen and low dose Proleukin decreased cancer cell viability in vitro experiment in solid cancer cell lines. Melanoma and TNBC tumor growth was delayed in humanized NSG mouse model by Trabedersen and low dose IL-2 combination therapy and tumor growth delay was statistically significant to Trabedersen alone or IL-2 alone group. Tumor infiltrating lymphocyte population was increased in Trabedersen treated group and FoxP3+ regulatory T cell population in blood and tumor microenvironment was decreased by treatment of Trabedersen.
Conclusion: TGF-Β inhibitor (Trabedersen) and low dose IL-2 (Proleukin) combination treatment is expected to be an effective regimen in solid cancer treatment than individual treatment by alteration of tumor environment. Modulation of the dose of Proleukin expects to help reduce the toxicity of IL-2 and increase the anti-cancer effect by combination with Trabedersen.
Citation Format: Jun-Eui Park, Jihye Koo, Hong-Kyu Lee, Tae Hun Kim. Combination therapy of anti-sense oligonucleotide targeting TGF-beta2 (TASO) and IL-2 (Proleukin) has anti-cancer effect in solid cancer [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 1448.
Abstract 1460: The design and biological characterization of PTP4A-targeted chemodegraders
Authors: Hart Duncan J. , Rastelli Ettore J. , Mendelson Anna J. , Letai Christopher T. , Cornelison John Robert , Sharlow Elizabeth R. , Wipf Peter , Lazo John S. 
Published: July 2021

Abstract
The protein tyrosine phosphatase 4A (PTP4A) family members, PTP4A1, PTP4A2 or PTP4A3, are overexpressed in many cancers, and this overexpression is associated with a distinct disadvantage to overall patient survival. Genetic knockdown or deletion of PTP4A diminishes cancer cell migration, survival and tumorigenesis. We previously demonstrated that the small molecule JMS-053 or KVX-053 (7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-dione) functions as a selective, allosteric, and reversible pan-PTP4A, inhibitor. KVX-053 decreased ovarian cancer cell line spheroid viability, migration and in vivo tumor growth. We now report a conjugate of KVX-053 to an adamantyl moiety in an effort to design intracellular PTP4A chemodegraders. In addition to the linker length, we also modified the functional group attachments to the KVX-053 pharmacophore and the adamantly moiety. Significantly, several of these analogs retained potent in vitroinhibition of PTP4A3 enzymatic activity (IC50=100-750 nM), suggesting they could be dual-purpose PTP4A3 inhibitors, targeting both the catalytic activity and reducing intracellular protein concentration. Some of these KVX-053 analogs, including EJR-876-35 and EJR-887-35, exhibited enhanced cytotoxicity against human ovarian cancer, triple negative breast cancer or leukemia cell lines compared to the parent chemotype, KVX-053. Human ovarian cancer cells incubated with 1 micromolar EJR-887-35 exhibited a pronounced loss of PTP4A protein within 6 hours and the loss was sustained for at least 18 hours. These results support the further investigation of chemodegraders as specific first-in-class bifunctional PTP4A inhibitors directed against human cancers.
Citation Format: Duncan J. Hart, Ettore J. Rastelli, Anna J. Mendelson, Christopher T. Letai, John Robert Cornelison, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. The design and biological characterization of PTP4A-targeted chemodegraders [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 1460.
Abstract 1472: Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need
Authors: Neumüller Ralph A. , Wilding Birgit , Scharn Dirk , Böse Dietrich , Santoro Valeria , Gerlach Daniel , Ettmayer Peter , Gerstberger Thomas , Fuchs Julian , Treu Matthias , Zahn Stephan , Baum Anke , Chetta Paolo , Pearson Mark , McConnell Darryl B. , Kraut Norbert , Solca Flavio 
Published: July 2021

Abstract
Activating mutations in ERBB2 receptors are tractable oncogenes in 2-3% of NSCLC patients for whom no approved targeted therapies are available. In this indication, oncogenic mutations in HER2 predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. We initiated a drug discovery program aiming at discovering novel HER2 selective inhibitors sparing EGFR WT activity. Focus was set on the most frequent HER2 mutation (ERBB2 A775 insYVMA), which is least sensitive to current compounds tested in clinical trials. Here, we report the identification and pharmacological characterization of novel selective HER2 exon 20 mutation TKIs that differ from currently tested TKIs such as poziotinib, TAK-788 or BDTX-189. We could demonstrate that selective inhibition of oncogenic HER2 signaling abrogates oncogenic signaling in in vitro models. Cell survival and proliferation was reduced, which translated into tumor regressions in preclinical CRISPR engineered xenotransplantation models of HER2 exon 20 mutants. The in vivo efficacy was confirmed in patient-derived tumor models. Our results suggest that HER2 exon 20 insertions can be effectively treated by a potent and highly selective HER2 inhibitor that spares EGFR wild type. These findings warrant the upcoming clinical testing in HER2 mutant NSCLC patients in order to effectively treat this aggressive type of cancer.
Citation Format: Ralph A. Neumüller, Birgit Wilding, Dirk Scharn, Dietrich Böse, Valeria Santoro, Daniel Gerlach, Peter Ettmayer, Thomas Gerstberger, Julian Fuchs, Matthias Treu, Stephan Zahn, Anke Baum, Paolo Chetta, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Flavio Solca. Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need [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 1472.
Abstract 1477: Co-targeting c-Met and c-Src pathways to inhibit metastatic cancer cell migration and invasion
Authors: Dai Yao , Siemann Dietmar W. 
Published: July 2021

Abstract
Overexpression of tyrosine kinases c-Src and c-Met has been shown to be highly associated with disease progression and poor clinical outcomes in many types of cancers. Although small molecule Src or Met inhibitors are being individually evaluated in clinical trials, patient data suggest that single treatment with any of these inhibitors only yield limited effects. One possibility is that redundant signaling pathways in tumor cells may allow tumor cell functions less interrupted upon inhibition of only one pathway. We therefore propose that c-Src and c-Met are two compensatory pathways that may cooperate to promote cancer metastasis. In order to delineate this hypothesis, we studied treatment effects of combining inhibitors targeting c-Src (dasatinib) and c-Met (ASLAN002) on multiple functional behaviors associated with tumor metastasis in c-Src and c-Met expressing metastatic cancer cells. Combination of Src- and Met-inhibitors was found to strongly inhibit cell colony formation by clonogenic survival assay. In a wound-healing assay, compared to either treatment alone, the combinatorial treatment exhibited greater suppression on cell motility. In addition, using a Matrigel-based Transwell assay, dasatinib plus ASLAN002 resulted in significant reduction of cell invasion in the presence or absence of HGF. Western blot analysis demonstrated that co-targeting Met and Src kinases lead to not only inhibition on c-Met and c-Src autophosphorylation but also multiple downstream kinases such as focal adhesion kinase (FAK), Akt and extracellular signal-regulated kinase (ERK). These data indicate that combined application of small molecule Src and Met inhibitors cause significant impairment on functional behaviors associated with cancer metastasis in vitro including survival, migration and invasion, suggesting that this combination intervention modality may serve as a potential anti-metastatic strategy that could be further tested in metastatic models in vivo.
Citation Format: Yao Dai, Dietmar W. Siemann. Co-targeting c-Met and c-Src pathways to inhibit metastatic cancer cell migration and invasion [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 1477.