tbuckley/cabot-search huggingface dataset:
Abstract 416: Regulation of osteosarcoma cell metastasis by FGFR and mTOR signaling
Authors: Arshiya Banu, Carolina Zandueta, Fernando Lecanda, Agamemnon E. Grigoriadis
Journal: Cancer Research (2020)

Abstract Osteosarcoma (OS) is the most common primary malignancy of the skeleton, occurring primarily in children and adolescents. Metastatic disease is the single most important prognostic factor with survival dropping to 15-20% in patients with lung metastases. We have recently demonstrated that high FGFR1 signaling in an oncogene-induced murine model of OS as well as in human OS samples contributes to the pathogenesis and metastasis of OS. Significantly, xenograft studies showed that genetic or pharmacological inhibition of FGFR1 decreased lung metastasis. We have identified the mTOR signaling pathway as a cooperating pathway with FGFR signaling in OS cells. Stimulation of murine and human OS cell lines with FGF2 showed an increase in both MAPK and pAkt/mTOR signaling and mTOR target genes that was inhibited by the FGFR inhibitor, PD173074. Colony growth in soft agar showed that inhibition of mTOR blocked FGF2-stimulated colony growth of OS cells and shRNA silencing of mTOR prevented FGF2-stimulated cell migration in wound/scratch assays. To confirm pathway cooperativity in vivo, we performed xenograft studies. Silencing of mTOR in FGFR1-expressing OS cells reduced tumor formation on a chick chorioallantoic membrane, with reduced pHistone-H3 expression. Orthotopic injection of OS cells demonstrated that small molecule inhibition of both FGFR1 and mTOR signaling (AZD4547 and AZD8055, respectively), showed greater inhibition of size and diameter of lung metastatic nodules than each inhibitor alone. This was associated with a decrease in the number of Ki67+ cells in lung metastases of FGFR/mTOR inhibitor-treated mice, whereas no changes in activated caspase-3 were detected. In a complementary in vivo model, tail vein injections of OS cells showed that combined FGFR/mTOR inhibition reduced cell seeding in the lungs, suggesting that FGFR/mTOR signaling are driving lung colonization independently of the primary tumor. Finally, preliminary studies indicate that long term growth of OS cells in the lung following tail vein injection may reveal a potential for OS cells to acquire chemoresistance to mTOR inhibition. The mechanisms are not yet known but are independent of the primary tumour. Taken together, our data suggest that combinatorial treatment significantly decreased lung metastasis of OS cells from primary xenografts. Ongoing analysis of activated FGFR and mTOR pathways in patient-derived tissue microarrays will enable patient stratification that will be useful in the clinical setting to exploit this as a potential anti-metastatic therapy in OS. Citation Format: Arshiya Banu, Carolina Zandueta, Fernando Lecanda, Agamemnon E. Grigoriadis. Regulation of osteosarcoma cell metastasis by FGFR and mTOR signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 416.
Abstract 3662: FiTAc-seq: Fixed-Tissue ChIP-seq for H3K27Ac profiling and super-enhancer analysis on FFPE tissues
Authors: Alba Font-Tello, Nikolas Kesten, Yingtian Xie, Len Taing, Joaquim Bellmunt, Myles Brown, Paloma Cejas, Henry Long
Journal: Cancer Research (2020)

Abstract FiTAc-seq is an epigenetic method for profiling of active enhancers and promoters in FFPE clinical samples. The protocol is optimized to generate high-quality H3K27Ac ChIP-seq maps from FFPE macrodissected or cored tissues within 4 days. We previously developed FiT-seq, a modified ChIP-seq protocol for chromatin profiling in FFPE. FiT-seq produces high-quality chromatin profiles particularly for methylated histone marks but is not optimized to resolve H3K27Ac signal. To overcome this limitation, we have modified the tissue homogenization and sonication steps by replacing the proteinase K digestion applied in FiT-seq with extended heating at 65°C in more stringent detergent conditions and minimizing the sonication step. FiTAc-seq produces high-quality genome wide H3K27Ac profiles, and it is suitable to generate enhancer landscapes and super-enhancer annotation. We demonstrate FiTAc-seq applicability for a wide variety of human tumor types, including bladder cancers, breast cancer brain metastasis, melanomas, pancreatic neuroendocrine tumors and seminomas. The unsupervised hierarchical analyses of both enhancer and super-enhancer only H3K27Ac signal clearly identify clusters according to the different tumor types. Moreover, super-enhancer annotation shows lineage-specific transcription factors for the distinct tumor samples. We demonstrate that FiTAc-seq is a robust method suitable for the epigenetic interrogation of archived FFPE clinical samples. The results generated allow the identification of tissue-specific enhancer and SE landscapes, with potential immediate impact on ongoing basic and translational research. Citation Format: Alba Font-Tello, Nikolas Kesten, Yingtian Xie, Len Taing, Joaquim Bellmunt, Myles Brown, Paloma Cejas, Henry Long. FiTAc-seq: Fixed-Tissue ChIP-seq for H3K27Ac profiling and super-enhancer analysis on FFPE tissues [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3662.
Abstract 3453: Cancer Cell Line Factory: A systematic approach to create next-generation cancer model at scale
Authors: Yuen-Yi Tseng, Mushriq AI-Jazrawe, Rebecca Deasy, Paula Keskula, Grace Johnson, Andrew Hong, Priya Chatterji, Francisca Vasquez, Adam Bass, Barbara Van Hare, David Sandak, Keith Ligon, Jesse Boehm
Journal: Cancer Research (2020)

Abstract Precision cancer medicine is based on the ability to predict the dependencies of a given tumor from its molecular makeup. Despite successes in multiple common cancers, such prediction remains challenging for the majority of rare and understudied tumors given the absence of laboratory model systems in which to discover and/or validate therapeutic hypotheses. Here, we describe our efforts to address this challenge systematically with the ultimate goal of making it possible to learn how to predict ex vivo growth requirements for cancer samples based on technical, clinical and genomic properties of the starting tumor material. Over the last 5 years, we have processed nearly 2,000 tumor biospecimens and created over 375 genomically-confirmed patient-derived cell lines, organoids and neurosphere cultures, with &amp;gt;10% of these representing rare cancers. To make this possible, we have implemented three key workflows including (1) direct-to-patient sample sourcing, (2) a tissue cryopreservation and genomic credentialing system to ensure quality prior to model creation, and (3) a systematic empirical approach to screening rich medias and variations on organoid technologies ex vivo (HYBRID). We have begun performing genome-wide CRISPR viability screens in these cultures as part of our larger activities to generate a systematic laboratory-based functional map of cancer dependencies (a ‘Cancer Dependency Map'). The novel organoid, spheroid and cell line models created as part of this effort are being made publically available to the scientific community. Looking ahead, as the barriers to culturing rare tumors are overcome, we expect that preclinical functional genomics data will be useful for difficult-to-treat tumors without existing molecularly guided standard-of-care regimens. Citation Format: Yuen-Yi Tseng, Mushriq AI-Jazrawe, Rebecca Deasy, Paula Keskula, Grace Johnson, Andrew Hong, Priya Chatterji, Francisca Vasquez, Adam Bass, Barbara Van Hare, David Sandak, Keith Ligon, Jesse Boehm. Cancer Cell Line Factory: A systematic approach to create next-generation cancer model at scale [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3453.
Abstract 5542: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, enhances immune mediated tumor killing and induction of immunogenic cell death
Authors: Nicola Ferrari, George Ward, Joanne Munck, Simone Jueliger, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin John Sims
Journal: Cancer Research (2020)

Abstract Introduction: ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor receptor superfamily mediated cell death and enhance anti-tumor immune responses. Herein, we describe the profile of ASTX660 in a range of preclinical tumor models and evaluate ASTX660's ability to enhance immune mediated killing of tumor cells, both in vitro and in vivo. Methods: ASTX660 was tested in a panel of human and mouse tumor cell lines, assessing proliferation, apoptosis and immunogenic cell death (ICD). ASTX660 was tested alone or with recombinant Death Receptor ligands. Additionally, we used a novel co-culture system of tumor cell lines with anti-CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement along with induction of apoptosis and ICD markers were analysed by Western blotting and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilised to evaluate the efficacy of ASTX660 in the presence or absence of an effective immune response. Results: ASTX660 antagonised IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels and disruption of the XIAP:SMAC protein complex. In murine T cell lymphoma cell lines ASTX660 treatment was associated with an increase in apoptosis and ICD. In immunocompetent mice, administration of ASTX660 delivered a complete regression of BW5147 tumor growth which was not seen in mice deficient in T and B cells. To confirm human relevance, ASTX660 also enhanced anti-CD3 stimulated PBMC-dependent killing of tumour cell lines. Conclusion: The combination of the direct effects of ASTX660 on tumor cells and ASTX660 dependent effects on immune responses adds to the description of ASTX660's mode of action and our ongoing understanding of the clinical efficacy in T cell Lymphoma(1). Reference: A Hollebecque et al. 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Citation Format: Nicola Ferrari, George Ward, Joanne Munck, Simone Jueliger, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin John Sims. ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, enhances immune mediated tumor killing and induction of immunogenic cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5542.
Comparison of Clinical Features of COVID-19 vs Seasonal Influenza A and B in US Children
Authors: Xiaoyan Song, Meghan Delaney, Rahul K. Shah, Joseph M. Campos, David L. Wessel, Roberta L. DeBiasi
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Compared with seasonal influenza, the clinical features and epidemiologic characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus 2019 (COVID-19) in US children remain largely unknown. <h3>Objective</h3> To describe the similarities and differences in clinical features between COVID-19 and seasonal influenza in US children. <h3>Design, Setting, and Participants</h3> This retrospective cohort study included children who were diagnosed with laboratory-confirmed COVID-19 between March 25 and May 15, 2020, and children diagnosed with seasonal influenza between October 1, 2019, and June 6, 2020, at Children's National Hospital in the District of Columbia. <h3>Exposures</h3> COVID-19 or influenza A or B. <h3>Main Outcomes and Measures</h3> Rates of hospitalization, admission to the intensive care unit, and mechanical ventilator use and the association between underlying medical conditions, clinical symptoms, and COVID-19 vs seasonal influenza. <h3>Results</h3> The study included 315 patients diagnosed with COVID-19 (164 [52%] male; median age, 8.3 years [range, 0.03-35.6 years]) and 1402 patients diagnosed with seasonal influenza (743 [53%] male; median age, 3.9 years [range, 0.04-40.4 years]). Patients with COVID-19 and those with seasonal influenza had a similar hospitalization rate (54 [17%] vs 291 [21%],<i>P</i> = .15), intensive care unit admission rate (18 [6%] vs 98 [7%],<i>P</i> = .42), and use of mechanical ventilators (10 [3%] vs 27 [2%],<i>P</i> = .17). More patients hospitalized with COVID-19 than with seasonal influenza reported fever (41 [76%] vs 159 [55%],<i>P</i> = .005), diarrhea or vomiting (14 [26%] vs 36 [12%],<i>P</i> = .01), headache (6 [11%] vs 9 [3%],<i>P</i> = .01), body ache or myalgia (12 [22%] vs 20 [7%],<i>P</i> = .001), and chest pain (6 [11%] vs 9 [3%],<i>P</i> = .01). Differences between patients hospitalized with COVID-19 vs influenza who reported cough (24 [48%] vs 90 [31%],<i>P</i> = .05) and shortness of breath (16 [30%] vs 59 [20%],<i>P</i> = .13) were not statistically significant. <h3>Conclusions and Relevance</h3> In this cohort study of US children with COVID-19 or seasonal influenza, there was no difference in hospitalization rates, intensive care unit admission rates, and mechanical ventilator use between the 2 groups. More patients hospitalized with COVID-19 than with seasonal influenza reported clinical symptoms at the time of diagnosis.
Abstract 3321: Immunogenic clearance sensitizes cold tumor to PD-1 blockade by enhancing quantity and quality of CD8+ T cells
Authors: Gi-Hoon Nam, Yoonjeong Choi, In-San Kim
Journal: Cancer Research (2020)

Abstract The effective immune response against cancer requires stepwise events from the release of tumor antigens to T cells' exhibiting cytotoxic effects in the tumor microenvironment (TME). Immunogenic clearance reveals intrinsic tumor antigenicity with immunogenic cell death of the tumor cells and increases priming of T cells with increased phagocytosis activity of professional antigen-presenting cells (pAPCs), therefore, overcome the failure in immune surveillance of cancer caused by immunological ignorance. Here, we investigated the potential strategy to induce immunogenic clearance with immunogenic cell death (ICD) inducers and phagocytosis enhancer. Using anthracyclines, one of the renowned ICD inducers and fasudil, rho-kinase (ROCK) inhibitors that increases phagocytosis activity, reinforced cross-presentation of dendritic cells and cross-priming of CD8+ T cells in secondary lymphoid organ contributes to consecutive infiltration of CD8+ T cells in TME. Inducing the CD8+ T cell immune response, this strategy could surmount the resistance to immune checkpoint blockade of the immunologically cold tumor where little infiltrated T cells exist in the tumor site, which leads not just increased tumor-specific CD8+ T cells, but prolonged survival accompanied with the formation of sustainable CD8+ T cell memory. Citation Format: Gi-Hoon Nam, Yoonjeong Choi, In-San Kim. Immunogenic clearance sensitizes cold tumor to PD-1 blockade by enhancing quantity and quality of CD8+ T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3321.
Abstract 5407: Novel imipridone combination therapies targeting oncohistone H3K27M mutant diffuse midline glioma (DMG)
Authors: Robyn Borsuk, Lanlan Zhou, Rishi Lulla, Wafik El-Deiry
Journal: Cancer Research (2020)

Abstract Malignant glioma including diffuse midline glioma (DMG) is the leading cause of cancer related death in children. Recent advances in sequencing have identified the oncohistone H3K27M mutation in ~80% of pediatric DMG, which represents a target for new therapeutics. ONC201 is a first-in-class small molecule which upregulates TNF-related apoptosis inducing ligand (TRAIL) and its proapoptotic receptor DR5, independent of p53, selecting for apoptosis/growth arrest of many different tumor types including H3K27M mutant DMG. While single agent ONC201 along with RT is currently being tested in clinical trials for newly diagnosed and refractory DMG, there is an urgent need to evaluate ONC201 and other imipridone analogs in combination with other agents. Patient derived H3K27M mutant DMG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SU-DIPG-36, and SF8628), were grown in culture and exposed to imipridones (ONC201, ONC206 and ONC212) alone, and in combination with other chemotherapeutic agents that have demonstrated pre-clinical activity against DMG (HDAC inhibitors and etoposide). Response to treatment was determined by Cell Titer-Glo cell viability assays as well as Western Immunoblotting for evidence of apoptosis and integrated stress response (ISR) activation. All H3K27M-mutant DMG cell lines tested to date exhibit a dose-dependent response to imipridone therapy. Mean IC50 values were significantly lower with the imipridone analogs ONC206 (0.11 µM) and ONC212 (0.03 µM) as compared to ONC201 (1.46 µM) when used as a single agent. ONC206 and ONC212 were associated with robust induction of apoptosis evidenced by increased expression of cleaved PARP, and ISR by increased expression ATF4. In the SU-DIPG-IV cell line, combination studies of ONC201 and panobinostat demonstrated a synergistic effect of both agents, as calculated by CompuSyn software. Combination indices below one were observed at concentrations of 0.003 - 0.05 µM of panobinostat with ONC201 at 0.156 - 5 µM, with the best combination index of 0.22. We similarly observed synergy between either ONC201 or ONC206 with Etoposide. Additional combination testing and synergy analysis is ongoing and will be presented. Our findings suggest that H3K27M DMG cells demonstrate increased sensitivity to imipridones ONC206 and ONC212 as single agents and combinational strategies with HDAC inhibitors and etoposide, and provide insights into novel therapies for further clinical testing. Citation Format: Robyn Borsuk, Lanlan Zhou, Rishi Lulla, Wafik El-Deiry. Novel imipridone combination therapies targeting oncohistone H3K27M mutant diffuse midline glioma (DMG) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5407.
Abstract 4064: Optimization of the transposon expression system for electroporation based gene delivery
Authors: Jian Chen, Youbang Chen
Journal: Cancer Research (2020)

Abstract Stable protein expression in therapeutic cells such as T cells and NK cells is important for long-lasting clinical effects in cell therapy such as CAR-T therapy. Stable protein expression can be achieved by the viral vector expression method, transposon based expression method and CRISPR/Cas9 mediated knock-in method. Transposon based expression method has the advantage of being relatively safe and cost-effective compared with other methods. However, in the actual application of the transposon systems such as the piggyBac (PB) system and the Sleeping Beauty (SB) system, it is quite challenging to achieve a high delivery efficiency and a high cell viability. We found that in addition to the choice of electroporation methodology, vector design and cell culture are two most important aspects that need to be optimized. Vector design dictates protein expression level as commonly anticipated, it also dictates the expression timing. We found that two distinct designs give two very different expression timing, one with initial high efficiency of expression which tapers down to about half, and another one with very low initial expression level and it goes up to a very high level after two weeks. We propose that the differential expression profiles of the vector systems can be applied to different circumstances to achieve better therapeutic effects. Citation Format: Jian Chen, Youbang Chen. Optimization of the transposon expression system for electroporation based gene delivery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4064.
Abstract LB-047: CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia
Authors: Katharine Umphred-Wilson, Stanley Adoro
Journal: Cancer Research (2020)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a very aggressive hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation is sustained by strong oncogenic drivers, notably NOTCH1 and MYC, whose activation is present in more than half of all T-ALL cases. However, although it is known that post-translational modifications, such as ubiquitination by the E3-ligase FBXW7, regulate NOTCH1 and MYC protein stability and activity, regulatory proteins involved in their stability remain unestablished. The Charged multivesicular body protein 5 (CHMP5), an accessory protein of the ESCRT (endosomal sorting complex required for transport) pathway, has been shown to regulate the stability of client proteins in thymocytes through the recruitment of de-ubiquitinating enzymes. Here, we report that CHMP5 protein is not only highly expressed in T-ALL cells, but also promotes the stability of transactivating intracellular NOTCH1 (ICN1) and MYC. We found that depletion of CHMP5 significantly reduced the abundance of ICN1 and MYC, and the transcription of their target genes in vitro, as well as suppressed the development of T-ALL in vivo in a murine model of NOTCH1 driven T-ALL. Additionally, loss of CHMP5 restored T-ALL cell susceptibility to chemotherapeutic agents, including glucocorticoids and gamma secretase inhibitors, resistance to which contributes to disease relapse in patients. We further reveal CHMP5 as an adaptor protein required to orchestrate T-ALL client protein deubiquitination and stability. Altogether, our data suggest that CHMP5 is a non-oncogenic dependency of T-ALL and its depletion may be an effective therapeutic strategy for T-ALL. Citation Format: Katharine Umphred-Wilson, Stanley Adoro. CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-047.