tbuckley/cabot-search huggingface dataset:
Abstract 5810: Fyn kinase negatively regulates telomere length in stem cells and cancer cells
Authors: Souren Paul, Thi My Le Le, Joohyun Ryu, Ki Beom Bae, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2020)

Abstract Telomere maintenance is on the critical biological process in stem cell, aging, and cancer. Cells maintain telomere either by Telomerase (TERT) dependent pathway or by alternative lengthening of telomere (ALT) pathway. Here we report a link between Fyn kinase expression and telomere length. Fyn deficient mouse and mouse embryonic stem cells (mESC) maintain a stable telomere length through activation of ALT pathway. Fyn deficient mice are also resistant to the aging process as compared to wild type mice. We uncover a novel molecular mechanism of telomere maintenance. Menin, an essential component of an MLL/SET1 histone methyltransferase (HMT) complex that specifically methylates 'Lys-4' of histone H3 (H3K4), is a potential phosphorylation target of Fyn. Phosphorylation of Menin facilitates SUMOylation and binding to Telomerase RNA Component (TERC). The telomere dysfunction is one pivotal reason for many genetic disorders, including telomere related diseases like dyskeratosis congenita (DC). Currently, there are no curative therapies for these diseases of telomere dysfunction. We knockout Fyn gene from DC mice model and also used 4-Amino-5-(4-chlorophenyl)-7-(dimethyl ethyl) pyrazolo[3,4-d]pyrimidine (PP2), a selective inhibitor of Fyn kinase. Our results demonstrate that Fyn could be a therapeutic target in telomere related diseases. Knockout of Fyn or inhibition of Fyn by using inhibitor improves DC phenotype in mice like bone marrow failure. Human iPSC generated from DC patient's skin fibroblast shows higher expression of p-Menin and maintains a stable telomere length when we inhibited Fyn. Citation Format: Souren Paul, Thi My Le Le, Joohyun Ryu, Ki Beom Bae, Ann M. Bode, Zigang Dong. Fyn kinase negatively regulates telomere length in stem cells and cancer 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 5810.
Abstract 5565: Skin-targeted combinatorial DNA immunization overcomes tumor resistance to PD1 therapy
Authors: Louis D. Falo
Journal: Cancer Research (2020)

Abstract Despite the remarkable treatment benefits associated with interventional checkpoint blockade for solid tumors, many patients ultimately progress on therapy. The development of novel strategies that can overcome resistance to checkpoint therapy remains a considerable unmet clinical need. In this context, we developed a novel tumor immunization strategy that is multifunctional and combines co-delivery of plasmid DNA encoding antigen and molecules driving immunostimulatory function and antigen targeting. Specifically, we targeted expression of plasmid DNA encoding the stress response transcription factor XBP1 and the melanoma-associated antigen TRP2 fused to heat shock protein HSP70. Transient skin-localized expression promotes a pro-immunogenic skin microenvironment and the induction, recruitment, and maintenance of Type-1 cytotoxic CD8 T cells (Tc1), including Tc1 T-cell infiltrates within the tumor microenvironment (TME), and tumor regression in a PD1-resistant mouse melanoma model. These data suggest a novel therapeutic strategy in which combined effects of localized XBP1 and HSP70 antigen conjugation establishes a PD1-responsive TME for effective and durable treatment of PD1-resistant cancers. Citation Format: Louis D. Falo. Skin-targeted combinatorial DNA immunization overcomes tumor resistance to PD1 therapy [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 5565.
Abstract 157: Pervasive promoter hypermethylation of silenced <i>TERT</i> alleles in human cancers
Authors: Mindy K. Graham, David Esopi, Jacqueline A. Brosnan-Cashman, Anuj Gupta, Angelo De Marzo, William G. Nelson, Christopher M. Heaphy, Alan K. Meeker, Sarah J. Wheelan, Srinivasan Yegnasubramanian
Journal: Cancer Research (2020)

Abstract In cancers, the epigenetic regulation of telomerase expression is not fully characterized, with multiple conflicting reports. In particular, the role of DNA methylation of cytosine residues in the control of TERT expression remains unclear. Here, we have carried out the most comprehensive characterization of TERT promoter methylation using ultra-deep bisulfite sequencing spanning more than 310 CpGs within and surrounding the core TERT promoter in 96 different cell lines, including primary, immortalized, and cancer cell types, as well as in control and reference samples. In general, we observed that immortalized and cancer cell lines were hypermethylated in a region upstream of the recurrent G228A and G250A TERT promoter mutations, while non-malignant primary cells were comparatively hypomethylated in this region. Notably, in cancers, the hypermethylated alleles were associated with repressed expression while remaining unmethylated alleles were enriched with the open chromatin marks, H3K4me3 and H3K27ac. Furthermore, the hypomethylated alleles of the TERT promoter were responsible for the observed TERT expression in cancer. This association of hypomethylated alleles with active expression and hypermethylated alleles with repressed expression is particularly evident in cancers harboring TERT promoter mutations, and cancers displaying allele-specific expression. Reporter assays confirmed that DNA methylation of the TERT promoter greatly suppressed reporter expression in heterologous TERT promoter-reporter constructs. Overall, our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to the attenuation of TERT activation in cancer cells. Citation Format: Mindy K. Graham, David Esopi, Jacqueline A. Brosnan-Cashman, Anuj Gupta, Angelo De Marzo, William G. Nelson, Christopher M. Heaphy, Alan K. Meeker, Sarah J. Wheelan, Srinivasan Yegnasubramanian. Pervasive promoter hypermethylation of silenced TERT alleles in human cancers [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 157.
Abstract 1237: Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (<i>mirvetuximab soravtansine</i>) in high-grade serous ovarian cancer
Authors: Anca Chelariu-Raicu, Elaine Stur, Cristina Ivan, Robert L. Coleman, Anil K. Sood, Wen Yunfei
Journal: Cancer Research (2020)

Abstract Objective: Autophagic cell death is an important mechanism induced by blocking folate receptor (FRα) in inhibiting tumor growth. Here, our objective is to examine the biological effects of IMGN853 (mirvetuximab soravtansine) in preclinical models of ovarian cancer and to identify potential combination therapies. Methods: In vitro, immunoblotting, assays for cell viability, proliferation and cell cycle by fluorescence-activated cell sorting (FACS) were performed in an array of high grade serous carcinoma (HGSC) cell lines. Autophagy flux and activities of autophagy factors were also determined. In vivo, metastasis mouse models were used for testing the therapeutic efficacy of IMGN853 monotherapy or in combination with olaparib or cisplatin. Potential synergy with these drugs was assessed using in vitro assays. The resulting tumors were subjected to immunohistochemistry and reverse phase protein arrays (RPPA). Results: Data from the Cancer Genome Atlas Data (TCGA) revealed that FRα copy-number alterations was significantly correlated with shorter disease-free survival in patients with HGSC. Autophagy marker LC3 was upregulated following monotherapy with IMGN853 as well as in combination of IMGN853 with olaparib or cisplatin in HGSC cell lines such as OVCA8 and OVCA432, which express high-level of FRα. Experiments using metastatic HGSC models showed that IMGN853 monotherapy reduced tumor growth (30% change); the combination of IMGN853 and olaparib was superior to olaparib monotherapy (24% change; p 0.0033). Integrated analysis on RPPA revealed increased expression of ABL1 and PEA15 in the groups treated with IMGN853 monotherapy or in combination with olaparib. We further found reduced FRα expression and increased caspase 3 expression in IMGN853 groups compared with control. Conclusion: Our results point to sustained autophagy in FRα positive cells as a mechanism of effect of IMGN853. These findings could have implications for clinical development of anti-FRα therapies, especially in combination with other drugs such as olaparib. Citation Format: Anca Chelariu-Raicu, Elaine Stur, Cristina Ivan, Robert L. Coleman, Anil K. Sood, Wen Yunfei. Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (mirvetuximab soravtansine) in high-grade serous ovarian cancer [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 1237.
Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium
Authors: Elsa Solà, Elisa Pose, Daniela Campion, Salvatore Piano, Olivier Roux, Macarena Simon-Talero, Frank Uschner, Koos de Wit, Giacomo Zaccherini, Carlo Alessandria, Ulrich Beuers, Paolo Caraceni, Claire Francoz, Rajeshwar P. Mookerjee, Jonel Trebicka, Victor Vargas, Miquel Serra, Ferran Torres, Sara Montagnese, Aleksander Krag, Ruben Hernaez, Marko Korenjak, Hugh Watson, Juan G. Abraldes, Patrick S. Kamath, Pere Ginès, F. Durand, M. Bernardi, C. Solé, J. Pich, I. Graupera, L. Napoleone, C. Jiménez, A. Juanola, E. Avitabile, A. Ma, N. Fabrellas, M. Carol, E. Palacio, M. Aban, T. Lanzillotti, G. Nicolao, M.T. Chiappa, V. Esnault, A. Forner, S. Graf-Dirmeier, J. Helder, M. Lopez, M. Cervera, M. Pérez-Guasch
Journal: Journal of Hepatology (2020)

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.
Abstract 558: M6123, a selective FGFR1 antagonist, demonstrates anti-tumor activity as monotherapy and in combination with chemotherapy in mesothelioma models
Authors: Christina Esdar, Edith Ross, Michael Sanderson, Astrid Zimmermann
Journal: Cancer Research (2020)

Abstract Malignant pleural mesothelioma is an aggressive, asbestos-related cancer most commonly arising from the mesothelial cells lining the pleural cavity surrounding the lung. Despite the poor prognosis and increasing incidence of this disease, the combination of pemetrexed with cisplatin currently remains the only available treatment option to patients. Molecular characterization of mesothelioma tumors indicates a potential dependency on autocrine FGF-FGFR signaling. Based on this information, the therapeutic activity of M6123, a potent and selective, monovalent antagonist of FGFR1, was investigated in preclinical mesothelioma models in vitro and in vivo. In a panel of mesothelioma cell lines, M6123 mediated cellular growth reduction was clearly correlated with the level of endogenous FGF2 ligand. M6123 monotherapy significantly inhibited FGFR1 signal transduction and tumor growth in a cell line derived mesothelioma model. Furthermore, combination benefit was observed for M6123 with standard of care (SoC) chemotherapy. In a panel of nine mesothelioma patient derived xenograft (PDX) models, 66% (6/9) were sensitive to the combination of M6123 plus pemetrexed/cisplatin compared to 33% (3/9) for chemotherapy alone. The expression of a focused set of FGF-FGFR pathway genes was examined in PDX models to elucidate potential predictive biomarkers of sensitivity to M6123. Sprouty homolog 2 (SPRY2), a negative regulator of FGFR1 signaling, was upregulated in non-sensitive PDX models, whilst positive regulators of FGFR1 signaling including the ligand FGF5, the coreceptor FGFRL1 (FGFR5) and the downstream transcription factor ELK3 were elevated in sensitive models. In summary, M6123 showed favorable anti-tumor activity in preclinical models of mesothelioma, in particular in combination with standard of care chemotherapy. Further preclinical testing is warranted to confirm a predictive biomarker signature for selection of mesothelioma patients that may benefit from addition of M6123. Citation Format: Christina Esdar, Edith Ross, Michael Sanderson, Astrid Zimmermann. M6123, a selective FGFR1 antagonist, demonstrates anti-tumor activity as monotherapy and in combination with chemotherapy in mesothelioma models [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 558.
Abstract 1722: Nanoparticle pro-drug to overcome the stromal barrier in pancreatic ductal adenocarcinoma
Authors: Rami Alzhrani, Samaresh Sau, Amro Aboukameel, Hashem Alsaab, Asfar Azmi, Arun Iyer
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third-highest cause of cancer-related death in the United States. The heterogenicity of the PDAC is a major challenge in the success of anti-PDAC therapy. PDAC is comprised of &amp;gt;90 % dense desmoplastic tumor stroma that impedes the delivery of drugs into the core of the tumor, resulting development of drug resistance. Thus, we developed a nanoparticle pro-drug to overcome the stromal barrier of PDAC. We utilized nanoengineering to target dual CD44 and c-Met biomarkers that have a significant role in developing drug resistance on PDAC. Western blot analysis in various PDAC cell lines, such as PANC-1, AsPc-1, and BxPc3 revealed a high abundance of CD44 and cMet, strongly supporting our hypothesis. Therefore, targeting the CD44 and c-Met biomarker and selectively delivering anti-PDAC drug is a smart strategy to improve the anti-PDAC outcome. We developed dual CD44/c-Met targeted nanoparticle, called D44M that can efficiently penetrate the core of tumor as well as home into CD44 and cMet biomarker. We evaluated tumor selectivity of the near infrared (NIR) fluorescent dye conjugated D44M, D44M-NIR in the orthotopic PDAC model. The biodistribution of D44M-NIR in orthotopic animal model proved superior tumor penetration of D44M-NIR with 7-fold higher than the control NIR dye treatment. Moreover, D44M-NIR treated showed minimum liver accumulation, suggesting an outstanding approach of overcoming nanoparticle mediated liver toxicity. Finally, the D44M was chemically conjugated with gemcitabine (GEM), namely D44M-GEM pro-drug that showed excellent PDAC killing. The PDAC cell killing study of D44M-GEM in combination with Everolimus revealed high synergistic combination effect with CI value of 0.2-0.5. The anti-PDAC therapy in ASPC-1 xenograft model demonstrated significant tumor growth inhibition for treatment of D44M-GEM and D44M-GEM+Everolimus as compared to control. Supported with data, our work provides a perspective towards the implementation of nanotherapeutic to overcome the bottleneck barrier of therapeutic delivery and efficacy of PDAC management. Citation Format: Rami Alzhrani, Samaresh Sau, Amro Aboukameel, Hashem Alsaab, Asfar Azmi, Arun Iyer. Nanoparticle pro-drug to overcome the stromal barrier in pancreatic ductal adenocarcinoma [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 1722.
Abstract 665: Discovery and preclinical characterization of PQR626: A potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of tuberous sclerosis complex
Authors: Chiara Borsari, Erhan Keles, Denise Rageot, Anna Melone, Thomas Bohnacker, Lucinda Kate Batchelor, Martina De Pascale, Paul Hebeisen, Petra Hillmann, Doriano Fabbro, Matthias Wymann
Journal: Cancer Research (2020)

Abstract Mechanistic target of rapamycin (mTOR), a key player in cell proliferation, growth and survival, is overactivated in tumors and neurological disorders.[1] Rapalogs have recently been explored to alleviate epileptic seizures in Tuberous Sclerosis Complex (TSC).[2] Herein, we combined pharmacophore features of PQR620[3], the first-in-class brain penetrant ATP-competitive mTOR kinase inhibitor showing efficacy in a TSC mouse model, and PQR617[4], a potent, highly selective mTOR inhibitor. An extensive chemical exploration of the morpholine ring led to the discovery of PQR626, a highly potent, selective, brain penetrant inhibitor of mTORC1/2 kinase. In male Sprague Dawley rats and female C57BL/6J mice, PQR626 displayed an excellent brain penetration compared to everolimus, which possessed a limited ability to cross the blood-brain-barrier (brain/plasma levels ~ 1.4:1 vs 1:92). An additional pharmacokinetic comparative study with everolimus and AZD2014 confirmed the superiority of PQR626 [brain/plasma levels: ~ 1:25 (AZD2014), ~ 1:61 (everolimus), ~ 1.8:1 (PQR626)]. PQR626 showed very good tolerability in mice (MTD 100-150 mg/kg). Efficacy studies, using mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1GFAPCKO mice), were performed in a dose-range finding study. PQR626 (50 mg/kg, BID - twice a day) showed a significant effect on survival and significantly prevented/decreased mortality as compared to the vehicle. On the basis of its favorable pharmacological parameters, excellent brain penetration, safety profile and efficacy in Tsc1GFAPCKO mice, PQR626 qualifies as a novel mTOR inhibitor with potential application in the treatment of epilepsy and neurological disorders. [1] Wymann M. P. and Schneiter R. Nat. Rev. Mol. Cell Biol. 2008, 9, 162-176. [2] Krueger D. A. et. al. Neurology 2016, 87, 2408-2415. [3] Rageot D. et. al. J Med Chem. 2018, 61 (22), 10084-10105. [4] Borsari C. et. al. J Med Chem. 2019, 62 (18), 8609-8630. Citation Format: Chiara Borsari, Erhan Keles, Denise Rageot, Anna Melone, Thomas Bohnacker, Lucinda Kate Batchelor, Martina De Pascale, Paul Hebeisen, Petra Hillmann, Doriano Fabbro, Matthias Wymann. Discovery and preclinical characterization of PQR626: A potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of tuberous sclerosis complex [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 665.
Abstract 5822: Targeting an immortalization mutation to control glioblastoma
Authors: Jayashree S. Iyer, Nanyun Tang, Shayesteh R. Ferdosi, Vijay Gokhale, Laurence H. Hurley, Harshil D. Dhruv, Michael E. Berens
Journal: Cancer Research (2020)

Abstract Glioblastoma multiforme (GBM), the most aggressive primary brain cancer, is a heterogeneous disease. Standard treatment of temozolomide and radiation therapy has remained unchanged for the past thirty years. However, over 80% of GBM tumors have a telomerase reverse transcriptase (TERT) promoter mutation, or TPM. Telomerase is an enzyme containing the catalytic subunit, telomerase reverse transcriptase (TERT), that mediates telomere elongation in the nucleus. In the absence of any effective molecular targeting therapy for GBM, the elucidation of oncogenic signaling of TERT could open new avenues in GBM treatment. Canonically, mutations of TERT, which result in TERT upregulation, maintain telomere length in the nucleus and promote indefinite proliferation of cancer cells. However, a non-canonical function of TERT in the mitochondria has recently been suggested. We screened GBM cell models against a novel small molecule inhibitor (RG1534, Reglagene Inc.) that interferes with the functionality of a mutated TERT promoter. RG1534 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. A dose dependent response was observed in glioma cell lines, resulting in a decrease in TERT mRNA expression. To validate this, TERT protein levels in glioma cells treated with RG1534 were measured and results showed a reduction in expression post treatment. More interestingly, RG1534 treatment leads to rapid induction of apoptosis in glioma cell line which does not correlate with the time course of the telomere shortening effect. Based on prior findings that mitochondrial TERT is involved in DNA damage, we conducted the fractionation of various glioma cell lines to measure the protein expression of TERT in subcellular compartments. We observed a higher expression of TERT in the mitochondria compared to the nucleus. This suggests that TERT may have non-canonical functions outside of telomeric elongation. In summary, our results demonstrate that non-canonical functions of TERT may play a critical role in glioma pathobiology and warrants further study. Citation Format: Jayashree S. Iyer, Nanyun Tang, Shayesteh R. Ferdosi, Vijay Gokhale, Laurence H. Hurley, Harshil D. Dhruv, Michael E. Berens. Targeting an immortalization mutation to control glioblastoma [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 5822.