title: Targeting of the Hedgehog pathway in myeloid malignancies: still a worthy chase?
abstract: Deregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic intervention. Although initial haematological interest focused on the therapeutic targeting of this pathway in chronic myeloid leukaemia), small molecule inhibitors targeting the Hh pathway are now being tested in a range of other myeloid disorders, including myelofibrosis, myelodysplasia and acute myeloid leukaemia. In this review we will evaluate the rationale for targeting of the Hh pathway in myeloid diseases and discuss the novel agents that have entered the clinical arena. We will discuss pre-clinical models, emerging clinical trial data, and suggest how these targeted therapies may address current unmet medical needs. Finally, we will explore potential limitations of these therapies due to the emergence of secondary resistance mechanisms and speculate on future developments within this arena.
authors.affiliation: Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Alesia A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.affiliation: Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.|Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Donal P
authors.initials: DP
authors.lastname: McLornan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins
keywords: Hedgehog; cell signalling; myeloid leukaemia; pathways; smoothened