Abstract: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638 , CLIC5, SLC2A12, YAP1, MXRA5 , and SMAD6 . Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Abstract: Background: AML is the most common acute leukemia in adults. While most adults & lt; 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, Blood 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P & lt;0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, NEJM, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, Leukemia, 2004 and JCO 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, Ann Hem, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Robak et al Leuk Lymph, 2000; Wrzesień-Kuś et al, Eur J Haematol 2003; Wrzesień-Kuś et al, Ann Hematol, 2005; Wierzbowska et al, Eur J Haematol ,2008; Jaglal et al, Leuk Res, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. As midostaurin treatment has become approved and available the study was amended with an exclusion of FLT3-mutated patients. The trial schema is shown in Figure 1. The trial was initiated in July 2017 and 279 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1 Disclosures Wierzbowska: Janssen: Honoraria; Celgen/BMS: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Research Funding. Pluta:Angelini: Research Funding; Celgene/BMS: Honoraria. Libura:Novartis: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zaucha:Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Cellgene: Other: travel, accomodations, expenses; Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses. Robak:AstraZeneca: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Morphosys: Research Funding; UCB: Honoraria, Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; BioGene: Honoraria, Research Funding; Acerta: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Takeda: Consultancy. Lee:BMS: Consultancy; Helsinn: Other: Member -DSMB; AstraZeneca: Consultancy; Jazz: Consultancy; Roche Molecular Systems: Consultancy. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Roboz:Agios: Consultancy; Amphivena: Consultancy; Astex: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. OffLabel Disclosure: cladribine - in induction regimen in AML

Abstract: Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK‐2 plays a significant role by producing fructose‐2,6‐biphosphate; the most potent activator of the glycolysis rate‐limiting step performed by phosphofructokinase PFK‐1. Herein, the synthesis, biological evaluation and structure–activity relationship of novel inhibitors of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia‐induced isoform of PFK‐2, are reported. X‐ray crystallography and docking were instrumental in the design and optimisation of a series of N‐aryl 6‐aminoquinoxalines. The most potent representative, N ‐(4‐methanesulfonylpyridin‐3‐yl)‐8‐(3‐methyl‐1‐benzothiophen‐5‐yl)quinoxalin‐6‐amine, displayed an IC 50 of 14 n m for the target and an IC 50 of 0.49 μ m for fructose‐2,6‐biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.

Abstract: Adenosine is the key immunometabolite responsible for immune tolerance in tumors. It is present in normal tissue in low concentrations, having various physiological functions. In the tumor, its concentration increases rapidly, as a result of overexpression of enzymes producing adenosine, additionally enhanced by hypoxia and inflammation. Adenosine inhibits the biological functions of T lymphocytes infiltrating the cancer tissue by binding to the A2A receptor. The affinity to A2B receptor is believed to attenuate the response of dendritic cells and other parts of innate system. Thus blocking simultaneously the effects mediated by both receptor subtypes with dual inhibitor seems to be a viable approach to a single agent cancer immunotherapy or a combination with current immunotherapeutic agents. We have discovered a novel series of potent and selective A2A/A2B inhibitors. Best compounds present subnanomolar activity in both in vitro recombinant cellular model and in primary human cells. Our antagonists dose-dependently restore the adenosine agonist-impaired functional activity of CD4+ and CD8+ human T-lymphocytes (cytokine release assays). We observe also the relieve of adenosine-related suppression in NK cells cytotoxicity. Most importantly tested compounds present improved primary pharmacological profile in comparison to A2A inhibitors currently tested in clinical trials. Further validation in in vivo models showed efficacy standalone and in combination with checkpoint inhibitors. Citation Format: Michal Galezowski, Paulina Wegrzyn, Aneta Bobowska, Claude Commandeur, Katarzyna Dziedzic, Marcin Nowogrodzki, Alicja Obara, Joanna Szeremeta-Spisak, Anna Dzielak, Iwona Lozinska, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Mateusz Swirski, Adam Radzimierski, Magdalena Ziembik, Joanna Mierzwicka, Katarzyna Wojcik-Jaszczynska, Elzbieta Gocek, Karolina Grycuk, Aniela Golas, Olga Pierzchala, Julian Zachmann, Mateusz Nowak. Characterization of novel dual A2A/A2B adenosine receptor antagonists for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3770.

Abstract: Adenosine is important messenger molecule that is involved in signal transmission in central nervous, cardiovascular and immunological systems. The immunosuppressive role of adenosine attract attention of many researchers recently and reversal of that effect is addressed by several different approaches i.e.: inhibition of enzymes that are producing the adenosine in tumor microenvironment like CD39 and CD73 but also the antagonization of adenosine receptors mainly A2A and A2B subtypes. Here we present a novel series of unsurmountable, dual A2A/A2B antagonists that retain its nanomolar potency in tumor-like adenosine-rich environment. This advantageous profile comes mainly from long residence time in adenosine receptors which transfers into high receptor occupancy even after full clearance of the compound from plasma. We are demonstrating how our inhibitors restore adenosine depleted immune functionality in the series of functional in vitro assays in primary cells. This includes the cytokine release by activated CD4+ and CD8+ human T-lymphocytes (driven by A2A) and dendritic cells (driven by A2B). Most importantly presented compounds show improved in vivo pharmacological profile in comparison to adenosine inhibitors currently tested in clinical trials manifested by high inhibition of CREB phosphorylation in mouse model. Citation Format: Michal Galezowski, Paulina Węgrzyn, Aneta Bobowska, Katarzyna Dziedzic, Joanna Szeremeta-Spisak, Marcin Nowogrodzki, Grzegorz Satala, Alicja Obara, Iwona Lozinska-Raj, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Magdalena Zastawna, Grzegorz Statkiewicz, Maciej Rogacki, Magdalena Ziembik, Karolina Grycuk, Foteini Soukou, Kinga Michalik, Agnieszka Adamus, Karolina Wiatrowska, Natalia Lewandowska, Aniela Golas, Olga Haberkiewicz, Rod Porter, Krzysztof Brzozka, Mateusz Nowak. Novel dual A2A A2B adenosine receptor antagonists for cancer immunotherapy: in vitro and in vivo characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4135.