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Browsing by Author "Konig, Heiko"
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Item Classic and targeted anti-leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications(Wiley, 2020-05-25) Chen, Fangli; Wu, Xue; Niculite, Cristina; Gilca, Marilena; Petrusca, Daniela; Rogozea, Adriana; Rice, Susan; Guo, Bin; Griffin, Shawn; Calin, George A.; Boswell, H. Scott; Konig, Heiko; Medicine, School of MedicineDespite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O2, ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.Item The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells(Nature, 2016) Chang, Emily; Ganguly, Sudipto; Rajkhowa, Trivikram; Gocke, Christopher D.; Levis, Mark; Konig, Heiko; Department of Medicine, IU School of MedicineEffective treatment regimens for elderly acute myeloid leukemia (AML) patients harboring internal tandem duplication mutations in the FMS-like tyrosine kinase-3 (FLT3) gene (FLT3/ITD) are lacking and represent a significant unmet need. Recent data on the effects of FLT3 tyrosine kinase inhibitors on FLT3/ITD+ AML showed promising clinical activity, including in elderly patients. DNA methyltransferase (DNMT) inhibitors such as decitabine (5-aza-2-deoxycytidine, DEC) and 5-azacitidine (AZA) demonstrated clinical benefit in AML, are well tolerated and are associated with minimal increases in FLT3 ligand, which can represent a potential resistance mechanism to FLT3 inhibitors. In addition, both FLT3 and DNMT inhibition are associated with the induction of terminal differentiation of myeloid blasts. Consequently, there is a strong theoretical rationale for combining FLT3 and DNMT inhibition for FLT3/ITD+ AML. We therefore sought to study the anti-leukemic effects of DEC, AZA and FLT3 inhibitors, either as single agents or in combination, on AML cell lines and primary cells derived from newly diagnosed and relapsed AML patients. Our studies indicate that combined treatment using FLT3 inhibition and hypomethylation confers synergistic anti-leukemic effects, including apoptosis, growth inhibition and differentiation. The simultaneous administration of AZA and FLT3 inhibition appears to be the most efficacious combination in this regard. These drugs may provide a novel therapeutic approach for FLT3/ITD+ AML, in particular for older patients.Item Combination of sorafenib, vorinostat and bortezomib for the treatment of poor-risk AML: report of two consecutive clinical trials(Elsevier, 2019-02) Sayar, Hamid; Cripe, Larry D.; Saliba, Antoine N.; Abu Zaid, Mohammad; Konig, Heiko; Boswell, H. Scott; Medicine, School of MedicineItem Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML(Impact Journals, 2017-12-25) Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry D.; Weisenbach, Jill; Sargent, Katie J.; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Boswell, H. Scott; Medicine, School of MedicineCo-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.Item Engineering Tools for Regulating Hypoxia in Tumour Models(Wiley, 2021) Kim, Min Hee; Green, Steven D.; Lin, Chien-Chi; Konig, Heiko; Biomedical Engineering, School of Engineering and TechnologyMajor advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain incurable due to the development of drug resistance, minimal residual disease (MRD) and disease relapse, highlighting an incomplete understanding of the mechanisms underlying these processes. In recent years, the impact of non-genetic factors on neoplastic transformations has increasingly been acknowledged, and growing evidence suggests that low oxygen (O2) levels (ie hypoxia) in the tumour microenvironment play a critical role in the development and treatment of cancer. As a result, there is a growing need to develop research tools capable of reproducing physiologically relevant O2 conditions encountered by cancer cells in their natural environments in order to gain in-depth insight into tumour cell metabolism and function. In this review, the authors highlight the importance of hypoxia in the pathogenesis of malignant diseases and provide an overview of novel engineering tools that have the potential to further drive this evolving, yet technically challenging, field of cancer research.Item Enzyme-immobilized hydrogels to create hypoxia for in vitro cancer cell culture(Elsevier, 2017-04) Dawes, Camron S.; Konig, Heiko; Lin, Chien-Chi; Department of Biomedical Engineering, School of Engineering and TechnologyHypoxia is a critical condition governing many aspects of cellular fate processes. The most common practice in hypoxic cell culture is to maintain cells in an incubator with controlled gas inlet (i.e., hypoxic chamber). Here, we describe the design and characterization of enzyme-immobilized hydrogels to create solution hypoxia under ambient conditions for in vitro cancer cell culture. Specifically, glucose oxidase (GOX) was acrylated and co-polymerized with poly(ethylene glycol)-diacrylate (PEGDA) through photopolymerization to form GOX-immobilized PEG-based hydrogels. We first evaluated the effect of soluble GOX on inducing solution hypoxia (O2 < 5%) and found that both unmodified and acrylated GOX could sustain hypoxia for at least 24 h even under ambient air condition with constant oxygen diffusion from the air-liquid interface. However, soluble GOX gradually lost its ability to sustain hypoxia after 24 h due to the loss of enzyme activity over time. On the other hand, GOX-immobilized hydrogels were able to create hypoxia within the hydrogel for at least 120 h, potentially due to enhanced protein stabilization by enzyme ‘PEGylation’ and immobilization. As a proof-of-concept, this GOX-immobilized hydrogel system was used to create hypoxia for in vitro culture of Molm14 (acute myeloid leukemia (AML) cell line) and Huh7 (hepatocellular carcinoma (HCC) cell line). Cells cultured in the presence of GOX-immobilized hydrogels remained viable for at least 24 h. The expression of hypoxia associated genes, including carbonic anhydrase 9 (CA9) and lysyl oxidase (LOX), were significantly upregulated in cells cultured with GOX-immobilized hydrogels. These results have demonstrated the potential of using enzyme-immobilized hydrogels to create hypoxic environment for in vitro cancer cell culture.Item Immunotherapeutic Concepts to Target Acute Myeloid Leukemia: Focusing on the Role of Monoclonal Antibodies, Hypomethylating Agents and the Leukemic Microenvironment(MDPI, 2017-07-31) Gbolahan, Olumide Babajide; Zeidan, Amer M.; Stahl, Maximilian; Abu Zaid, Mohammad; Farag, Sherif; Paczesny, Sophie; Konig, Heiko; Medicine, School of MedicineIntensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML) treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment. More effective and less toxic therapies therefore represent an unmet need in the management of AML, a disease for which therapeutic progress has been traditionally slow when compared to other cancers. Several studies have shown that leukemic blasts elicit immune responses that could be exploited for the development of novel treatment concepts. To this end, early phase studies of immune-based therapies in AML have delivered encouraging results and demonstrated safety and feasibility. In this review, we discuss opportunities for immunotherapeutic interventions to enhance the potential to achieve a cure in AML, thereby focusing on the role of monoclonal antibodies, hypomethylating agents and the leukemic microenvironment.Item Pharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions(Wiley, 2021-12) Chen, Fangli; Licarete, Emilia; Wu, Xue; Petrusca, Daniela; Maguire, Callista; Jacobsen, Max; Colter, Austyn; Sandusky, George E.; Czader, Magdalena; Capitano, Maegan L.; Ropa, James P.; Boswell, H. Scott; Carta, Fabrizio; Supuran, Claudiu T.; Parkin, Brian; Fishel, Melissa L.; Konig, Heiko; Pathology and Laboratory Medicine, School of MedicineAcute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O2 )-deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and CD33 have been established in recent years, survival rates remain unsatisfactory, which indicates that other, yet unrecognized, mechanisms influence the ability of AML cells to escape cell death and to proliferate in hypoxic environments. Our data illustrates that Carbonic Anhydrases IX and XII (CA IX/XII) are critical for leukaemic cell survival in the O2 -deprived milieu. CA IX and XII function as transmembrane proteins that mediate intracellular pH under low O2 conditions. Because maintaining a neutral pH represents a key survival mechanism for tumour cells in O2 -deprived settings, we sought to elucidate the role of dual CA IX/XII inhibition as a novel strategy to eliminate AML cells under hypoxic conditions. Our findings demonstrate that the dual CA IX/XII inhibitor FC531 may prove to be of value as an adjunct to chemotherapy for the treatment of AML.Item Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS(Nature Publishing Group, 2020-09-21) Wu, Xue; Niculite, Cristina M.; Preda, Mihai Bogdan; Rossi, Annalisa; Tebaldi, Toma; Butoi, Elena; White, Mattie K.; Tudoran, Oana M.; Petrusca, Daniela N.; Jannasch, Amber S.; Bone, William P.; Zong, Xingyue; Fang, Fang; Burlacu, Alexandrina; Paulsen, Michelle T.; Hancock, Brad A.; Sandusky, George E.; Mitra, Sumegha; Fishel, Melissa L.; Buechlein, Aaron; Ivan, Cristina; Oikonomopoulos, Spyros; Gorospe, Myriam; Mosley, Amber; Radovich, Milan; Davé, Utpal P.; Ragoussis, Jiannis; Nephew, Kenneth P.; Mari, Bernard; McIntyre, Alan; Konig, Heiko; Ljungman, Mats; Cousminer, Diana L.; Macchi, Paolo; Ivan, Mircea; Medicine, School of MedicineWe hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.Item Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts(Elsevier, 2020-06-18) Zeidan, Amer M.; Boddu, Prajwal C.; Patnaik, Mrinal M.; Bewersdorf, Jan Philipp; Stahl, Maximilian; Rampal, Raajit K.; Shallis, Rory; Steensma, David P.; Savona, Michael R.; Sekeres, Mikkael A.; Roboz, Gail J.; DeAngelo, Daniel J.; Schuh, Andre C.; Padron, Eric; Zeidner, Joshua F.; Walter, Roland B.; Onida, Francesco; Fathi, Amir; DeZern, Amy; Hobbs, Gabriela; Stein, Eytan M.; Vyas, Paresh; Wei, Andrew H.; Bowen, David T.; Montesinos, Pau; Griffiths, Elizabeth A.; Verma, Amit K.; Keyzner, Alla; Bar-Natan, Michal; Navada, Shyamala C.; Kremyanskaya, Marina; Goldberg, Aaron D.; Al-Kali, Aref; Heaney, Mark L.; Nazha, Aziz; Salman, Huda; Luger, Selina; Pratz, Keith W.; Konig, Heiko; Komrokji, Rami; Deininger, Michael; Cirici, Blanca Xicoy; Bhatt, Vijaya Raj; Silverman, Lewis R.; Erba, Harry P.; Fenaux, Pierre; Platzbecker, Uwe; Santini, Valeria; Wang, Eunice S.; Tallman, Martin S.; Stone, Richard M.; Mascarenhas, John; Medicine, School of MedicineThe ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.