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4,531 results on '"Andreeff, Michael"'

1. A phase II trial of ipilimumab, nivolumab, or ipilimumab and nivolumab with or without azacitidine in relapsed or refractory myelodysplastic neoplasms

Author

Bouligny, Ian M., Montalban-Bravo, Guillermo, Sasaki, Koji, Daver, Naval, Jabbour, Elias, Alvarado, Yesid, DiNardo, Courtney D., Ravandi, Farhad, Borthakur, Gautam, Pemmaraju, Naveen, Kadia, Tapan, Masarova, Lucia, Takahashi, Koichi, Andreeff, Michael, Bazinet, Alexandre, Yang, Hui, Kanagal, Rashmi, Pierce, Sherry, Meyer, Meghan, Huang, Xuelin, and Garcia-Manero, Guillermo

Published
2024
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2. Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community

Author

Cuglievan, Branko, Kantarjian, Hagop, Rubnitz, Jeffrey E., Cooper, Todd M., Zwaan, C. Michel, Pollard, Jessica A., DiNardo, Courtney D., Kadia, Tapan M., Guest, Erin, Short, Nicholas J., McCall, David, Daver, Naval, Nunez, Cesar, Haddad, Fadi G., Garcia, Miriam, Bhalla, Kapil N., Maiti, Abhishek, Catueno, Samanta, Fiskus, Warren, Carter, Bing Z., Gibson, Amber, Roth, Michael, Khazal, Sajad, Tewari, Priti, Abbas, Hussein A., Bourgeois, Wallace, Andreeff, Michael, Shukla, Neerav N., Truong, Danh D., Connors, Jeremy, Ludwig, Joseph A., Stutterheim, Janine, Salzer, Elisabeth, Juul-Dam, Kristian L., Sasaki, Koji, Mahadeo, Kris M., Tasian, Sarah K., Borthakur, Gautam, Dickson, Samantha, Jain, Nitin, Jabbour, Elias, Meshinchi, Soheil, Garcia-Manero, Guillermo, Ravandi, Farhad, Stein, Eytan M., Kolb, E. Anders, and Issa, Ghayas C.

Published
2024
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5. Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial

Author

Konopleva, Marina Y., Dail, Monique, Daver, Naval G., Garcia, Jacqueline S., Jonas, Brian A., Yee, Karen W.L., Kelly, Kevin R., Vey, Norbert, Assouline, Sarit, Roboz, Gail J., Paolini, Stefania, Pollyea, Daniel A., Tafuri, Agostino, Brandwein, Joseph M., Pigneux, Arnaud, Powell, Bayard L., Fenaux, Pierre, Olin, Rebecca L., Visani, Giuseppe, Martinelli, Giovanni, Onishi, Maika, Wang, Jue, Huang, Weize, Dunshee, Diana R., Hamidi, Habib, Ott, Marion G., Hong, Wan-Jen, and Andreeff, Michael

Published
2024
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7. A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis

Author

Senapati, Jayastu, Muftuoglu, Muharrem, Ishizawa, Jo, Abbas, Hussein A., Loghavi, Sanam, Borthakur, Gautam, Yilmaz, Musa, Issa, Ghayas C., Dara, Samuel I., Basyal, Mahesh, Li, Li, Naqvi, Kiran, Pourebrahim, Rasoul, Jabbour, Elias J., Kornblau, Steven M., Short, Nicholas J., Pemmaraju, Naveen, Garcia-Manero, Guillermo, Ravandi, Farhad, Khoury, Joseph, Daver, Naval, Kantarjian, Hagop M., Andreeff, Michael, and DiNardo, Courtney D.

Published
2023
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10. Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy

Author

Ganan-Gomez, Irene, Yang, Hui, Ma, Feiyang, Montalban-Bravo, Guillermo, Thongon, Natthakan, Marchica, Valentina, Richard-Carpentier, Guillaume, Chien, Kelly, Manyam, Ganiraju, Wang, Feng, Alfonso, Ana, Chen, Shuaitong, Class, Caleb, Kanagal-Shamanna, Rashmi, Ingram, Justin P, Ogoti, Yamini, Rose, Ashley, Loghavi, Sanam, Lockyer, Pamela, Cambo, Benedetta, Muftuoglu, Muharrem, Schneider, Sarah, Adema, Vera, McLellan, Michael, Garza, John, Marchesini, Matteo, Giuliani, Nicola, Pellegrini, Matteo, Wang, Jing, Walker, Jason, Li, Ziyi, Takahashi, Koichi, Leverson, Joel D, Bueso-Ramos, Carlos, Andreeff, Michael, Clise-Dwyer, Karen, Garcia-Manero, Guillermo, and Colla, Simona

Subjects
Stem Cell Research, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research - Nonembryonic - Human, Hematology, Clinical Research, Orphan Drug, Regenerative Medicine, Cancer, 2.1 Biological and endogenous factors, Aetiology, Blood, Bridged Bicyclo Compounds, Heterocyclic, Hematopoietic Stem Cells, Humans, Myelodysplastic Syndromes, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Medical and Health Sciences, Immunology
Abstract

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.

Published
2022

13. Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells

Author

Carter, Bing Z., Mak, Po Yee, Muftuoglu, Muharrem, Tao, Wenjing, Ke, Baozhen, Pei, Jingqi, Bedoy, Andrea D., Ostermann, Lauren B., Nishida, Yuki, Isgandarova, Sevinj, Sobieski, Mary, Nguyen, Nghi, Powell, Reid T., Martinez-Moczygemba, Margarita, Stephan, Clifford, Basyal, Mahesh, Pemmaraju, Naveen, Boettcher, Steffen, Ebert, Benjamin L., Shpall, Elizabeth J., Wallner, Barbara, Morgan, Robert A., Karras, Georgios I., Moll, Ute M., and Andreeff, Michael

Published
2023
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14. A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia

Author

Shen, Xi, Wang, Rui, Kim, Moon Jong, Hu, Qianghua, Hsu, Chih-Chao, Yao, Jun, Klages-Mundt, Naeh, Tian, Yanyan, Lynn, Erica, Brewer, Thomas F, Zhang, Yilei, Arun, Banu, Gan, Boyi, Andreeff, Michael, Takeda, Shunichi, Chen, Junjie, Park, Jae-Il, Shi, Xiaobing, Chang, Christopher J, Jung, Sung Yun, Qin, Jun, and Li, Lei

Subjects
Biological Sciences, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Hematology, Rare Diseases, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Cell Differentiation, Cellular Reprogramming, DNA Damage, DNA Repair, Fanconi Anemia, Formaldehyde, Gene Expression Regulation, Developmental, Genomic Instability, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, K562 Cells, Transcription, Genetic, DNA damage, Fanconi anemia, bone marrow failure, differentiation, formaldehyde, hematopoiesis, transcription reprogramming, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

Published
2020

16. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML

Author

Issa, Ghayas C., Bidikian, Aram, Venugopal, Sangeetha, Konopleva, Marina, DiNardo, Courtney D., Kadia, Tapan M., Borthakur, Gautam, Jabbour, Elias, Pemmaraju, Naveen, Yilmaz, Musa, Short, Nicholas J., Maiti, Abhishek, Sasaki, Koji, Masarova, Lucia, Pierce, Sherry, Takahashi, Koichi, Tang, Guilin, Loghavi, Sanam, Patel, Keyur, Andreeff, Michael, Bhalla, Kapil, Garcia-Manero, Guillermo, Ravandi, Farhad, Kantarjian, Hagop, and Daver, Naval

Published
2023
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17. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial

Author

Daver, Naval G., Dail, Monique, Garcia, Jacqueline S., Jonas, Brian A., Yee, Karen W. L., Kelly, Kevin R., Vey, Norbert, Assouline, Sarit, Roboz, Gail J., Paolini, Stefania, Pollyea, Daniel A., Tafuri, Agostino, Brandwein, Joseph M., Pigneux, Arnaud, Powell, Bayard L., Fenaux, Pierre, Olin, Rebecca L., Visani, Giuseppe, Martinelli, Giovanni, Onishi, Maika, Wang, Jue, Huang, Weize, Green, Cherie, Ott, Marion G., Hong, Wan-Jen, Konopleva, Marina Y., and Andreeff, Michael

Published
2023
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19. Undetectable Measurable Residual Disease is Associated with Improved Outcomes in AML Irrespective of Treatment Intensity

Author

Bazinet, Alexandre, Kadia, Tapan, Short, Nicholas J., Borthakur, Gautam, Wang, Sa A., Wang, Wei, Loghavi, Sanam, Jorgensen, Jeffrey, Patel, Keyur, DiNardo, Courtney, Daver, Naval, Alvarado, Yesid, Haddad, Fadi G., Pierce, Sherry, Gonzalez, Graciela Nogueras, Maiti, Abhishek, Sasaki, Koji, Yilmaz, Musa, Thompson, Philip, Wierda, William, Garcia-Manero, Guillermo, Andreeff, Michael, Jabbour, Elias, Konopleva, Marina, Huang, Xuelin, Kantarjian, Hagop, and Ravandi, Farhad

Published
2023
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20. TP53 Y220C mutations in patients with myeloid malignancies

Author

Gener-Ricos, Georgina, primary, Bewersdorf, Jan P., additional, Loghavi, Sanam, additional, Bataller, Alex, additional, Goldberg, Aaron D., additional, Famulare, Christopher, additional, Takahashi, Koichi, additional, Issa, Ghayas C., additional, Borthakur, Gautam, additional, Kadia, Tapan M., additional, Short, Nicholas J., additional, Senapati, Jayastu, additional, Carter, Bing Z., additional, Patel, Keyur P., additional, Kantarjian, Hagop, additional, Andreeff, Michael, additional, Stein, Eytan M., additional, and DiNardo, Courtney D., additional

Published
2024
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22. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1–2 study

Author

Bazinet, Alexandre, Darbaniyan, Faezeh, Jabbour, Elias, Montalban-Bravo, Guillermo, Ohanian, Maro, Chien, Kelly, Kadia, Tapan, Takahashi, Koichi, Masarova, Lucia, Short, Nicholas, Alvarado, Yesid, Yilmaz, Musa, Ravandi, Farhad, Andreeff, Michael, Kanagal-Shamanna, Rashmi, Ganan-Gomez, Irene, Colla, Simona, Qiao, Wei, Huang, Xuelin, McCue, Deborah, Mirabella, Bailey, Kantarjian, Hagop, and Garcia-Manero, Guillermo

Published
2022
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26. Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

Author

Baran, Natalia, Lodi, Alessia, Dhungana, Yogesh, Herbrich, Shelley, Collins, Meghan, Sweeney, Shannon, Pandey, Renu, Skwarska, Anna, Patel, Shraddha, Tremblay, Mathieu, Kuruvilla, Vinitha Mary, Cavazos, Antonio, Kaplan, Mecit, Warmoes, Marc O., Veiga, Diogo Troggian, Furudate, Ken, Rojas-Sutterin, Shanti, Haman, Andre, Gareau, Yves, Marinier, Anne, Ma, Helen, Harutyunyan, Karine, Daher, May, Garcia, Luciana Melo, Al-Atrash, Gheath, Piya, Sujan, Ruvolo, Vivian, Yang, Wentao, Shanmugavelandy, Sriram Saravanan, Feng, Ningping, Gay, Jason, Du, Di, Yang, Jun J., Hoff, Fieke W., Kaminski, Marcin, Tomczak, Katarzyna, Eric Davis, R., Herranz, Daniel, Ferrando, Adolfo, Jabbour, Elias J., Emilia Di Francesco, M., Teachey, David T., Horton, Terzah M., Kornblau, Steven, Rezvani, Katayoun, Sauvageau, Guy, Gagea, Mihai, Andreeff, Michael, Takahashi, Koichi, Marszalek, Joseph R., Lorenzi, Philip L., Yu, Jiyang, Tiziani, Stefano, Hoang, Trang, and Konopleva, Marina

Published
2022
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27. Correction: Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Author

Zhang, Qi, Riley-Gillis, Bridget, Han, Lina, Jia, Yannan, Lodi, Alessia, Zhang, Haijiao, Ganesan, Saravanan, Pan, Rongqing, Konoplev, Sergej N., Sweeney, Shannon R., Ryan, Jeremy A., Jitkova, Yulia, Dunner, Jr, Kenneth, Grosskurth, Shaun E., Vijay, Priyanka, Ghosh, Sujana, Lu, Charles, Ma, Wencai, Kurtz, Stephen, Ruvolo, Vivian R., Ma, Helen, Weng, Connie C., Ramage, Cassandra L., Baran, Natalia, Shi, Ce, Cai, Tianyu, Davis, Richard Eric, Battula, Venkata L., Mi, Yingchang, Wang, Jing, DiNardo, Courtney D., Andreeff, Michael, Tyner, Jeffery W., Schimmer, Aaron, Letai, Anthony, Padua, Rose Ann, Bueso-Ramos, Carlos E., Tiziani, Stefano, Leverson, Joel, Popovic, Relja, and Konopleva, Marina

Published
2022
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28. Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Author

Zhang, Qi, Riley-Gillis, Bridget, Han, Lina, Jia, Yannan, Lodi, Alessia, Zhang, Haijiao, Ganesan, Saravanan, Pan, Rongqing, Konoplev, Sergej N., Sweeney, Shannon R., Ryan, Jeremy A., Jitkova, Yulia, Dunner, Jr, Kenneth, Grosskurth, Shaun E., Vijay, Priyanka, Ghosh, Sujana, Lu, Charles, Ma, Wencai, Kurtz, Stephen, Ruvolo, Vivian R., Ma, Helen, Weng, Connie C., Ramage, Cassandra L., Baran, Natalia, Shi, Ce, Cai, Tianyu, Davis, Richard Eric, Battula, Venkata L., Mi, Yingchang, Wang, Jing, DiNardo, Courtney D., Andreeff, Michael, Tyner, Jeffery W., Schimmer, Aaron, Letai, Anthony, Padua, Rose Ann, Bueso-Ramos, Carlos E., Tiziani, Stefano, Leverson, Joel, Popovic, Relja, and Konopleva, Marina

Published
2022
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30. The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and aurora kinases.

Author

Yu, Guopan, Zhang, Weiguo, Basyal, Mahesh, Nishida, Yuki, Mizumo, Hideaki, Ly, Charlie, Zhang, Hongying, Rice, William G., and Andreeff, Michael

Subjects
AURORA kinases, ACUTE myeloid leukemia, PROTEIN-tyrosine kinases, BRUTON tyrosine kinase, DRUG resistance
Abstract

Despite the development of several Fms-like tyrosine kinase 3 (FLT3) inhibitors that have improved outcomes in patients with FLT3-mutant acute myeloid leukemia (AML), drug resistance is frequently observed, which may be associated with the activation of additional pro-survival pathways, such as those regulated by BTK, aurora kinases (AuroK), and potentially others, in addition to acquired tyrosine kinase domain (TKD) mutations of FLT3 gene. FLT3 may not always be a driver mutation. We evaluated the anti-leukemia efficacy of the novel multi-kinase inhibitor CG-806, which targets FLT3 and other kinases, to circumvent drug resistance and target FLT3 wild-type (WT) cells. The anti-leukemia activity of CG-806 was investigated by measuring apoptosis induction and analyzing the cell cycle using flow cytometry in vitro. CG-806 demonstrated superior anti-leukemia efficacy compared to commercially available FLT3 inhibitors, both in vitro and in vivo, regardless of FLT3 mutational status. The mechanism of action of CG-806 may involve its broad inhibitory profile against FLT3, BTK, and AuroK. In FLT3 mutant cells, CG-806 induced G1 phase blockage, whereas in FLT3 WT cells, it resulted in G2/M phase arrest. Targeting FLT3 and Bcl-2 and/or Mcl-1 simultaneously results in a synergistic pro-apoptotic effect in FLT3 mutant leukemia cells. The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemic efficacy regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291). KEY POINTS: The multi-kinase inhibitor CG-806 exerts superior anti-leukemic activity in AML, regardless of its FLT3 status. CG-806 triggered G1 arrest in FLT3 mutated cells and G2/M arrest in FLT3 WT cells through the suppression of FLT3/BTK and aurora kinases. Concomitantly targeting FLT3 and Bcl-2 and/or Mcl-1 exerted synergistic pro-apoptotic effects on both FLT3 WT and mutated AML cells. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Combination of dasatinib and venetoclax in newly diagnosed chronic phase chronic myeloid leukemia

Author

Jabbour, Elias, primary, Haddad, Fadi G., additional, Sasaki, Koji, additional, Carter, Bing Z., additional, Alvarado, Yesid, additional, Nasnas, Cedric, additional, Nasr, Lewis, additional, Masarova, Lucia, additional, Daver, Naval, additional, Pemmaraju, Naveen, additional, Short, Nicholas J., additional, Skinner, Jeffrey, additional, Kadia, Tapan, additional, Borthakur, Gautam, additional, Garcia‐Manero, Guillermo, additional, Ravandi, Farhad, additional, Issa, Ghayas C., additional, Andreeff, Michael, additional, and Kantarjian, Hagop, additional

Published
2024
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33. Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition

Author

Saito, Kaori, Zhang, Qi, Yang, Haeun, Yamatani, Kotoko, Ai, Tomohiko, Ruvolo, Vivian, Baran, Natalia, Cai, Tianyu, Ma, Helen, Jacamo, Rodrigo, Kuruvilla, Vinitha, Imoto, Junichi, Kinjo, Sonoko, Ikeo, Kazuho, Moriya, Kaori, Suzuki, Koya, Miida, Takashi, Kim, Yong-Mi, Vellano, Christopher P., Andreeff, Michael, Marszalek, Joseph R., Tabe, Yoko, and Konopleva, Marina

Published
2021
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36. Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia

Author

Maiti, Abhishek, DiNardo, Courtney D., Wang, Sa A., Jorgensen, Jeffrey, Kadia, Tapan M., Daver, Naval G., Short, Nicholas J., Yilmaz, Musa, Pemmaraju, Naveen, Borthakur, Gautam, Bose, Prithviraj, Issa, Ghayas C., Ferrajoli, Alessandra, Jabbour, Elias J., Jain, Nitin, Garcia-Manero, Guillermo, Ohanian, Maro, Takahashi, Koichi, Montalban-Bravo, Guillermo, Masarova, Lucia, Burger, Jan A., Thompson, Philip A., Verstovsek, Srdan, Sasaki, Koji, Andreeff, Michael, Rausch, Caitlin R., Montalbano, Kathryn S., Pierce, Sherry, Qiao, Wei, Ning, Jing, Kantarjian, Hagop M., Konopleva, Marina Y., and Ravandi, Farhad

Published
2021
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37. Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia.

Author

Han, Lina, Jorgensen, Jeffrey, Brooks, Chris, Shi, Ce, Zhang, Qi, Nogueras González, Graciela, Cavazos, Antonio, Pan, Rongqing, Mu, Hong, Wang, Sa, Zhou, Jin, Ai-Atrash, Gheath, Ciurea, Stefan, Rettig, Mike, DiPersio, John, Cortes, Jorge, Huang, Xuelin, Kantarjian, Hagop, Andreeff, Michael, Ravandi, Farhad, and Konopleva, Marina

Subjects
Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Flow Cytometry, Humans, Immunoconjugates, Interleukin-3 Receptor alpha Subunit, Leukemia, Myeloid, Acute, Mice, Neoplastic Stem Cells, Signal Transduction, Single-Chain Antibodies, Xenograft Model Antitumor Assays
Abstract

Purpose: The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34+CD123+ LSC-containing cells and antileukemia potency of a novel antibody conjugate SL-101 in targeting CD123+ LSCs.Experimental Methods and Results: In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34+CD123+ LSC-containing cells in remission was associated with persistent MRD and predicted shorter relapse-free survival in patients with poor-risk cytogenetics. Using flow cytometry, we explored the potential benefit of therapeutic targeting of CD34+CD38-CD123+ cells by SL-101, a novel antibody conjugate comprising an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A The antileukemia potency of SL-101 was determined by the expression levels of CD123 antigen in a panel of AML cell lines. Colony-forming assay established that SL-101 strongly and selectively suppressed the function of leukemic progenitors while sparing normal counterparts. The internalization, protein synthesis inhibition, and flow cytometry assays revealed the mechanisms underlying the cytotoxic activities of SL-101 involved rapid and efficient internalization of antibody, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL3-induced p-STAT5 and p-AKT signaling pathways. In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 in vitro was significantly impaired.Conclusions: Our data define the mechanisms by which SL-101 targets AML and warrant further investigation of the clinical application of SL-101 and other CD123-targeting strategies in AML. Clin Cancer Res; 23(13); 3385-95. ©2017 AACR.

Published
2017

38. Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.

Author

Sekihara, Kazumasa, Saitoh, Kaori, Han, Lina, Ciurea, Stefan, Yamamoto, Shinichi, Kikkawa, Mika, Kazuno, Saiko, Taka, Hikari, Kaga, Naoko, Arai, Hajime, Miida, Takashi, Andreeff, Michael, Konopleva, Marina, and Tabe, Yoko

Subjects
XPO1, mTORC1/2, mantle cell lymphoma, metabolism, selective inhibitor of nuclear export, Acrylates, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Cell Line, Tumor, Cell Proliferation, Cell Survival, Energy Metabolism, Humans, Karyopherins, Lymphoma, Mantle-Cell, Morpholines, Proteome, Proteomics, Pyrimidines, Receptors, Cytoplasmic and Nuclear, Signal Transduction, TOR Serine-Threonine Kinases, Triazoles, Exportin 1 Protein
Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, characterized by aberrant expression of growth-regulating and oncogenic effectors and requiring novel anticancer strategies. The nuclear transporter exportin-1 (XPO1) is highly expressed in MCL and is associated with its pathogenesis. mTOR signaling, a central regulator of cell metabolism, is frequently activated in MCL and is also an important therapeutic target in this cancer. This study investigated the antitumor effects and molecular/metabolic changes induced by the combination of the small-molecule selective inhibitor XPO1 inhibitor KPT-185 and the dual mTORC1/2 kinase inhibitor AZD-2014 on MCL cells. AZD-2014 enhanced the KPT-185-induced inhibition of cell growth and repression of cell viability. The combination of KPT-185 and AZD-2014 downregulated c-Myc and heat shock factor 1 (HSF1) with its target heat shock protein 70 (HSP70). As a consequence, the combination caused repression of ribosomal biogenesis demonstrated by iTRAQ proteomic analyses. Metabolite assay by CETOF-MS showed that AZD-2014 enhanced the KPT-185-induced repression of MCL cellular energy metabolism through the TCA (Krebs) cycle, and further repressed KPT-185-caused upregulation of glycolysis.Thus the simultaneous inhibition of XPO1 and mTOR signaling is a novel and promising strategy targeting prosurvival metabolism in MCL.

Published
2017

39. Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation.

Author

Gaballa, Sameh, Saliba, Rima, Oran, Betul, Brammer, Jonathan, Chen, Julianne, Rondon, Gabriela, Alousi, Amin, Kebriaei, Partow, Marin, David, Popat, Uday, Andersson, Borje, Shpall, Elizabeth, Jabbour, Elias, Daver, Naval, Andreeff, Michael, Ravandi, Farhad, Cortes, Jorge, Patel, Keyur, Champlin, Richard, and Ciurea, Stefan

Subjects
Adolescent, Adult, Aged, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Neoplasm, Residual, Polymerase Chain Reaction, Preoperative Period, Prognosis, Recurrence, Remission Induction, Retrospective Studies, Risk, Survival Analysis, Survival Rate, Young Adult, fms-Like Tyrosine Kinase 3
Abstract

In patients with AML with FMS-like tyrosine kinase 3 (FLT3) mutations, the significance of minimal residual disease (MRD) detected by PCR before allogeneic stem cell transplantation (SCT) on outcomes after transplant remains unclear. We identified 200 patients with FLT3-AML who underwent SCT at our institution. Disease status at transplant was: first or second complete remission (CR1/CR2, n = 119), high-risk CR (third or subsequent CR, marrow hypoplasia, or incomplete count recovery) (CR-HR, n = 31), and morphological evidence of active disease (AD, n = 50). The median follow-up was 27 months, and the 2-year overall and progression-free survival were 43% and 41%, respectively. Relapse was highest in the AD group (85%) and the CR-HR FLT3 MRD positive group (72%), followed by CR-HR FLT3 MRD negative (58%), CR1/CR2 FLT3 MRD positive (39%), and lowest in the CR1/CR2 FLT3 MRD negative group (23%). On multivariate analysis, independent factors influencing the risk of relapse were detectable morphological disease and FLT3 MRD by PCR pre-transplant. Factors that did not influence the relapse risk included: age, graft type, graft source, type of FLT3 mutation, or conditioning intensity. Morphologic and molecular remission status at the time of transplant were key predictors of disease relapse and survival in patients with FLT3-AML.

Published
2017

41. Menin inhibitors in pediatric acute leukemia:a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community

Author

Cuglievan, Branko, Kantarjian, Hagop, Rubnitz, Jeffrey E., Cooper, Todd M., Zwaan, C. Michel, Pollard, Jessica A., DiNardo, Courtney D., Kadia, Tapan M., Guest, Erin, Short, Nicholas J., Mccall, David, Daver, Naval, Nunez, Cesar, Haddad, Fadi G., Garcia, Miriam, Bhalla, Kapil N., Maiti, Abhishek, Catueno, Samanta, Fiskus, Warren, Carter, Bing Z., Gibson, Amber, Roth, Michael, Khazal, Sajad, Tewari, Priti, Abbas, Hussein A., Bourgeois, Wallace, Andreeff, Michael, Shukla, Neerav N., Truong, Danh D., Connors, Jeremy, Ludwig, Joseph A., Stutterheim, Janine, Salzer, Elisabeth, Juul-Dam, Kristian L., Sasaki, Koji, Mahadeo, Kris M., Tasian, Sarah K., Borthakur, Gautam, Dickson, Samantha, Jain, Nitin, Jabbour, Elias, Meshinchi, Soheil, Garcia-Manero, Guillermo, Ravandi, Farhad, Stein, Eytan M., Kolb, E. Anders, Issa, Ghayas C., Cuglievan, Branko, Kantarjian, Hagop, Rubnitz, Jeffrey E., Cooper, Todd M., Zwaan, C. Michel, Pollard, Jessica A., DiNardo, Courtney D., Kadia, Tapan M., Guest, Erin, Short, Nicholas J., Mccall, David, Daver, Naval, Nunez, Cesar, Haddad, Fadi G., Garcia, Miriam, Bhalla, Kapil N., Maiti, Abhishek, Catueno, Samanta, Fiskus, Warren, Carter, Bing Z., Gibson, Amber, Roth, Michael, Khazal, Sajad, Tewari, Priti, Abbas, Hussein A., Bourgeois, Wallace, Andreeff, Michael, Shukla, Neerav N., Truong, Danh D., Connors, Jeremy, Ludwig, Joseph A., Stutterheim, Janine, Salzer, Elisabeth, Juul-Dam, Kristian L., Sasaki, Koji, Mahadeo, Kris M., Tasian, Sarah K., Borthakur, Gautam, Dickson, Samantha, Jain, Nitin, Jabbour, Elias, Meshinchi, Soheil, Garcia-Manero, Guillermo, Ravandi, Farhad, Stein, Eytan M., Kolb, E. Anders, and Issa, Ghayas C.

Abstract

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

Published
2024

42. Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.

Author

DiNardo, Courtney D., Olin, Rebecca, Wang, Eunice S., Skikne, Barry, Rosenthal, Joseph, Kumar, Prasanna, Sumi, Hiroyuki, Hizukuri, Yoshiyuki, Hong, Ying, Patel, Parul, Seki, Takahiko, Duan, Tao, Lesegretain, Arnaud, and Andreeff, Michael

Subjects
MYELODYSPLASTIC syndromes, ACUTE myeloid leukemia, HEMATOLOGIC malignancies, MOUSE leukemia, POLYMERASE chain reaction
Abstract

Background: Mouse double minute‐2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. Methods: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high‐risk myelodysplastic syndromes. Results: Seventy‐four patients (monotherapy, n = 57; milademetan‐AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14–21 days of 28‐day cycles as monotherapy and on Days 5–14 in combination with AZA. Dose‐limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment‐emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre‐existing below standard detection frequency by droplet digital polymerase chain reaction. Interpretation: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal. [ABSTRACT FROM AUTHOR]

Published
2024
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43. Hypomethylating agent and venetoclax with FLT3 inhibitor “triplet” therapy in older/unfit patients with FLT3 mutated AML

Author

Yilmaz, Musa, Kantarjian, Hagop, Short, Nicholas J., Reville, Patrick, Konopleva, Marina, Kadia, Tapan, DiNardo, Courtney, Borthakur, Gautam, Pemmaraju, Naveen, Maiti, Abhishek, Jabbour, Elias, Jain, Nitin, Issa, Ghayas, Takahashi, Koichi, Sasaki, Koji, Ohanian, Maro, Pierce, Sherry, Tang, Guillin, Loghavi, Sanam, Patel, Keyur, Wang, Sa A., Garcia-Manero, Guillermo, Andreeff, Michael, Ravandi, Farhad, and Daver, Naval

Published
2022
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44. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia

Author

Short, Nicholas J., Montalban-Bravo, Guillermo, Hwang, Hyunsoo, Ning, Jing, Franquiz, Miguel J., Kanagal-Shamanna, Rashmi, Patel, Keyur P., DiNardo, Courtney D., Ravandi, Farhad, Garcia-Manero, Guillermo, Takahashi, Koichi, Konopleva, Marina, Daver, Naval, Issa, Ghayas C., Andreeff, Michael, Kantarjian, Hagop, and Kadia, Tapan M.

Published
2020
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45. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial

Author

DiNardo, Courtney D, Maiti, Abhishek, Rausch, Caitlin R, Pemmaraju, Naveen, Naqvi, Kiran, Daver, Naval G, Kadia, Tapan M, Borthakur, Gautam, Ohanian, Maro, Alvarado, Yesid, Issa, Ghayas C, Montalban-Bravo, Guillermo, Short, Nicholas J, Yilmaz, Musa, Bose, Prithviraj, Jabbour, Elias J, Takahashi, Koichi, Burger, Jan A, Garcia-Manero, Guillermo, Jain, Nitin, Kornblau, Steven M, Thompson, Philip A, Estrov, Zeev, Masarova, Lucia, Sasaki, Koji, Verstovsek, Srdan, Ferrajoli, Alessandra, Weirda, William G, Wang, Sa A, Konoplev, Sergej, Chen, Zhining, Pierce, Sherry A, Ning, Jing, Qiao, Wei, Ravandi, Farhad, Andreeff, Michael, Welch, John S, Kantarjian, Hagop M, and Konopleva, Marina Y

Published
2020
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46. MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells

Author

Zeng, Zhihong, Wang, Rui-Yu, Qiu, Yi Hua, Mak, Duncan H, Coombes, Kevin, Yoo, Suk Young, Zhang, Qi, Jessen, Katti, Liu, Yi, Rommel, Christian, Fruman, David A, Kantarjian, Hagop M, Kornblau, Steven M, Andreeff, Michael, and Konopleva, Marina

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Hematology, Pediatric Research Initiative, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Nonembryonic - Non-Human, Pediatric, Cancer, Pediatric Cancer, Childhood Leukemia, Rare Diseases, Acute Disease, Animals, Apoptosis, Benzoxazoles, Cell Line, Tumor, Cell Proliferation, Cell Survival, Humans, Leukemia, Myeloid, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplastic Stem Cells, Phosphorylation, Proto-Oncogene Proteins c-akt, Pyrimidines, Signal Transduction, TOR Serine-Threonine Kinases, U937 Cells, Xenograft Model Antitumor Assays, mTOR, AML, stem cells, CyTOF, therapy, Oncology and carcinogenesis
Abstract

mTOR activation leads to enhanced survival signaling in acute myeloid leukemia (AML) cells. The active-site mTOR inhibitors (asTORi) represent a promising new approach to targeting mTOR in AKT/mTOR signaling. MLN0128 is an orally-administered, second-generation asTORi, currently in clinical development. We examined the anti-leukemic effects and the mechanisms of action of MLN0128 in AML cell lines and primary samples, with a particular focus on its effect in AML stem/progenitor cells. MLN0128 inhibited cell proliferation and induced apoptosis in AML by attenuating the activity of mTOR complex 1 and 2. Using time-of-flight mass cytometry, we demonstrated that MLN0128 selectively targeted and functionally inhibited AML stem/progenitor cells with high AKT/mTOR signaling activity. Using the reverse-phase protein array technique, we measured expression and phosphorylation changes in response to MLN0128 in 151 proteins from 24 primary AML samples and identified several pro-survival pathways that antagonize MLN0128-induced cellular stress. A combined blockade of AKT/mTOR signaling and these pro-survival pathways facilitated AML cell killing. Our findings provide a rationale for the clinical use of MLN0128 to target AML and AML stem/progenitor cells, and support the use of combinatorial multi-targeted approaches in AML therapy.

Published
2016

47. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

Author

Townsend, Elizabeth C, Murakami, Mark A, Christodoulou, Alexandra, Christie, Amanda L, Köster, Johannes, DeSouza, Tiffany A, Morgan, Elizabeth A, Kallgren, Scott P, Liu, Huiyun, Wu, Shuo-Chieh, Plana, Olivia, Montero, Joan, Stevenson, Kristen E, Rao, Prakash, Vadhi, Raga, Andreeff, Michael, Armand, Philippe, Ballen, Karen K, Barzaghi-Rinaudo, Patrizia, Cahill, Sarah, Clark, Rachael A, Cooke, Vesselina G, Davids, Matthew S, DeAngelo, Daniel J, Dorfman, David M, Eaton, Hilary, Ebert, Benjamin L, Etchin, Julia, Firestone, Brant, Fisher, David C, Freedman, Arnold S, Galinsky, Ilene A, Gao, Hui, Garcia, Jacqueline S, Garnache-Ottou, Francine, Graubert, Timothy A, Gutierrez, Alejandro, Halilovic, Ensar, Harris, Marian H, Herbert, Zachary T, Horwitz, Steven M, Inghirami, Giorgio, Intlekofer, Andrew M, Ito, Moriko, Izraeli, Shai, Jacobsen, Eric D, Jacobson, Caron A, Jeay, Sébastien, Jeremias, Irmela, Kelliher, Michelle A, Koch, Raphael, Konopleva, Marina, Kopp, Nadja, Kornblau, Steven M, Kung, Andrew L, Kupper, Thomas S, LeBoeuf, Nicole R, LaCasce, Ann S, Lees, Emma, Li, Loretta S, Look, A Thomas, Murakami, Masato, Muschen, Markus, Neuberg, Donna, Ng, Samuel Y, Odejide, Oreofe O, Orkin, Stuart H, Paquette, Rachel R, Place, Andrew E, Roderick, Justine E, Ryan, Jeremy A, Sallan, Stephen E, Shoji, Brent, Silverman, Lewis B, Soiffer, Robert J, Steensma, David P, Stegmaier, Kimberly, Stone, Richard M, Tamburini, Jerome, Thorner, Aaron R, van Hummelen, Paul, Wadleigh, Martha, Wiesmann, Marion, Weng, Andrew P, Wuerthner, Jens U, Williams, David A, Wollison, Bruce M, Lane, Andrew A, Letai, Anthony, Bertagnolli, Monica M, Ritz, Jerome, Brown, Myles, Long, Henry, Aster, Jon C, Shipp, Margaret A, Griffin, James D, and Weinstock, David M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Clinical Trials and Supportive Activities, Orphan Drug, Clinical Research, Hematology, Cancer, Rare Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Good Health and Well Being, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Lineage, Female, Gene Expression Profiling, Genes, p53, Heterografts, Humans, Internet, Isoquinolines, Leukemia, Leukemia, Experimental, Lymphoma, Male, Mice, Mice, Inbred NOD, Molecular Targeted Therapy, Neoplasm Proteins, Neoplasm Transplantation, Phenotype, Piperazines, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proteome, Proto-Oncogene Proteins c-mdm2, Random Allocation, Randomized Controlled Trials as Topic, Research Design, Tissue Banks, Transcriptome, Xenograft Model Antitumor Assays, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.

Published
2016

48. Mitochondrial regulation of GPX4 inhibition–mediated ferroptosis in acute myeloid leukemia

Author

Akiyama, Hiroki, primary, Zhao, Ran, additional, Ostermann, Lauren B., additional, Li, Ziyi, additional, Tcheng, Matthew, additional, Yazdani, Samar J., additional, Moayed, Arman, additional, Pryor, Malcolm L., additional, Slngh, Sandeep, additional, Baran, Natalia, additional, Ayoub, Edward, additional, Nishida, Yuki, additional, Mak, Po Yee, additional, Ruvolo, Vivian R., additional, Carter, Bing Z., additional, Schimmer, Aaron D., additional, Andreeff, Michael, additional, and Ishizawa, Jo, additional

Published
2023
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49. Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias

Author

Nishida, Yuki, primary, Ishizawa, Jo, additional, Ayoub, Edward, additional, Montoya, Rafael Heinz, additional, Ostermann, Lauren B., additional, Muftuoglu, Muharrem, additional, Ruvolo, Vivian R, additional, Patsilevas, Tallie, additional, Scruggs, Darah A., additional, Khazaei, Shayaun, additional, Mak, Po Yee, additional, Tao, Wenjing, additional, Carter, Bing Z., additional, Boettcher, Steffen, additional, Ebert, Benjamin L., additional, Daver, Naval G., additional, Konopleva, Marina, additional, Seki, Takahiko, additional, Kojima, Kensuke, additional, and Andreeff, Michael, additional

Published
2023
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50. Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy

Author

Venugopal, Sangeetha, Takahashi, Koichi, Daver, Naval, Maiti, Abhishek, Borthakur, Gautam, Loghavi, Sanam, Short, Nicholas. J., Ohanian, Maro, Masarova, Lucia, Issa, Ghayas, Wang, Xuemei, Carlos, Bueso-Ramos, Yilmaz, Musa, Kadia, Tapan, Andreeff, Michael, Ravandi, Farhad, Konopleva, Marina, Kantarjian, Hagop M., and DiNardo, Courtney D.

Published
2022
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