Adolfo A. Ferrando, MD, PhD
- Associate Professor of Pediatrics
- Associate Professor of Pathology and Cell Biology (in the Institute for Cancer Genetics)
- Associate Director for Shared Resources, Herbert Irving Comprehensive Cancer Center
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Enormous progress has been made in the treatment of ALL, raising the cure rate to more than 80 percent in children. However, there remains a subset of patients whose leukemia comes back, posing a clinical challenge to their physicians. Adolfo Ferrando, MD, PhD is a researcher whose investigations are exploring the molecular mechanisms underlying the growth of ALL, particularly leukemias that develop resistance to chemotherapy drugs.
His team in at the Institute for Cancer Genetics identified a protein called NOTCH1 as a major driver of ALL that develops from white blood cells, called T cells (T-ALL). Drugs that inhibit NOTCH suppress leukemia cell growth, but cause intestinal toxicity. Dr. Ferrando and his team defined the mechanism of action of NOTCH inhibitors and identified a drug combination that maximizes their anticancer effects while minimizing intestinal side effects. The findings moved the development of NOTCH inhibitors into clinical trials for the treatment of patients with high-risk T-ALL. In addition, his team has also learned that a protein called AKT1 may interact with NOTCH1 and promote the resistance of leukemia cells to a class of drugs central in the treatment of ALL, called glucocorticoids. AKT1 is in a pathway called the PI3 kinase pathway, and there are many drugs in development now that target these molecules. It is hoped that inhibiting AKT1 could reverse the resistance of leukemia cells to glucocorticoids.
Recently much of the efforts in the Ferrando lab are directed to determine how and why some leukemia cells escape the damaging effects of chemotherapy. The researchers identified a gene called NT5C2 which, when mutated, activates other genes that help leukemia cells clear themselves of chemotherapy drugs, enabling them to continue to survive and grow. This genetic mutation may serve as a target for new therapies that could work by inactivating mutant NT5C2, restoring the sensitivity of leukemia cells to anticancer drugs.
Dr. Ferrando has served PI or co-Investigator on several previous grants funded by the NIH, the Leukemia and Lymphoma Society and other private foundations. He has built a highly trained and well-coordinated team with specific expertise in genomics, bioinformatics, protein biochemistry, genetically manipulated mouse models of leukemia and experimental therapeutics. His labÃ¢â‚¬â„¢s research projects have produced numerous peer-reviewed publications, including Nature, Nature Medicine, Nature Genetics, Cancer Cell, and Cancer Discovery. He has been recognized for his contributions to the field with several awards, including the Pershing Square Sohn Prize in Cancer Research and induction into the American Society of Clinical Investigation membership.
- Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL. Wendorff AA, Quinn SA, Rashkovan M, Madubata CJ, Ambesi-Impiombato A, Litzow MR, Tallman MS, Paietta E, Paganin M, Basso G, Gastier-Foster JM, Loh ML, Rabadan R, Van Vlierberghe P, Ferrando AA. Cancer Discov. 2019. PMID: 30567843. DOI: 10.1158/2159-8290.CD-18-1005
- GATA3-Controlled Nucleosome Eviction Drives MYC Enhancer Activity in T-cell Development and Leukemia. Belver L, Yang AY, Albero R, Herranz D, Brundu FG, Quinn SA, Pérez-Durán P, Álvarez S, Gianni F, Rashkovan M, Gurung D, Rocha PP, Raviram R, Reglero C, Cortés JR, Cooke AJ, Wendorff AA, Cordó V, Meijerink JP, Rabadan R, Ferrando AA. Cancer Discov. 2019. PMID: 31519704. DOI: 10.1158/2159-8290.CD-19-0471.
- Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Kourtis N, Lazaris C, Hockemeyer K, BalandrÃ¡n JC, Jimenez AR, Mullenders J, Gong Y, Trimarchi T, Bhatt K, Hu H, Shrestha L, Ambesi-Impiombato A, Kelliher M, Paietta E, Chiosis G, Guzman ML, Ferrando AA, Tsirigos A, Aifantis I. Nat Med. 2018. PMID: 30038221. DOI: 10.1038/s41591-018-0105-8.
- Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia. Dieck CL, Tzoneva G, Forouhar F, Carpenter Z, Ambesi-Impiombato A, Sánchez-Martín M, Kirschner-Schwabe R, Lew S, Seetharaman J, Tong L, Ferrando AA. Cancer Cell. 2018. PMID: 29990496. DOI: 10.1016/j.ccell.2018.06.003.
- Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia. Tzoneva G, Dieck CL, Oshima K, Ambesi-Impiombato A, Sánchez-Martín M, Madubata CJ, Khiabanian H, Yu J, Waanders E, Iacobucci I, Sulis ML, Kato M, Koh K, Paganin M, Basso G, Gastier-Foster JM, Loh ML, Kirschner-Schwabe R, Mullighan CG, Rabadan R, Ferrando AA. Nature. 2018. PMID: 29342136. DOI: 10.1038/nature25186.
- Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martín M, Belver L, Tosello V, Xu L, Wendorff AA, Castillo M, Haydu JE, Márquez J, Matés JM, Kung AL, Rayport S, Cordon-Cardo C, DeBerardinis RJ, Ferrando AA. Nat Med. 2015. PMID: 26390244. DOI: 10.1038/nm.3955.
- Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Palomero T, Couronné L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, Carpenter Z, Abate F, Allegretta M, Haydu JE, Jiang X, Lossos IS, Nicolas C, Balbin M, Bastard C, Bhagat G, Piris MA, Campo E, Bernard OA, Rabadan R, Ferrando AA. Nat Genet. 2014. PMID: 24413734. DOI: 10.1038/ng.2873.
- A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, Xu L, Castillo-Martin M, Llobet-Navás D, Cordon-Cardo C, Clappier E, Soulier J, Ferrando AA. Nat Med. 2014. PMID: 25194570. DOI: 10.1038/nm.3665.
- Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M, Paietta E, Racevskis J, Rowe JM, Tallman MS, Paganin M, Basso G, Hof J, Kirschner-Schwabe R, Palomero T, Rabadan R, Ferrando A. Nat Med. 2013. PMID: 23377281. DOI: 10.1038/nm.3078.
- Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, Sanchez-Martin M, Perez-Garcia A, Rigo I, Castillo M, Indraccolo S, Cross JR, de Stanchina E, Paietta E, Racevskis J, Rowe JM, Tallman MS, Basso G, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. Cancer Cell. 2013. PMID: 24291004. DOI: 10.1016/j.ccr.2013.10.022.
- Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Della Gatta G, Palomero T, Perez-Garcia A, Ambesi-Impiombato A, Bansal M, Carpenter ZW, De Keersmaecker K, Sole X, Xu L, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Meijerink JP, Califano A, Ferrando AA. Nat Med. 2012. PMID: 22366949. DOI: 10.1038/nm.2610.
- PHF6 mutations in T-cell acute lymphoblastic leukemia. Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, Taghon T, Zuurbier L, Cauwelier B, Harrison CJ, Schwab C, Pisecker M, Strehl S, Langerak AW, Gecz J, Sonneveld E, Pieters R, Paietta E, Rowe JM, Wiernik PH, Benoit Y, Soulier J, Poppe B, Yao X, Cordon-Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando A. Nat Genet. 2010. PMID: 20228800. DOI: 10.1038/ng.542.
- The TLX1 oncogene drives aneuploidy in T cell transformation. De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cavé H, Dastugue N, Raimondi S, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. Nat Med. 2010. PMID: 20972433. DOI: 10.1038/nm.2246.
- Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, Sulis ML, Barnes K, Sawai C, Homminga I, Meijerink J, Aifantis I, Basso G, Cordon-Cardo C, Ai W, Ferrando A. Nat Med. 2009. PMID: 19098907. DOI: 10.1038/nm.1900.
- Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zúñiga-Pflücker JC, Dominguez M, Ferrando AA. Nat Med. 2007. PMID: 17873882. DOI: 10.1038/nm1636.