Therapy for myeloproliferative neoplasms: when, which agent, and how?

Geyer, Holly; Mesa, Ruben A.

doi:10.1182/blood-2014-05-577635

Cited by 94 publications

(81 citation statements)

References 60 publications

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“…JAK3 is exclusively expressed in cells of the lymphoid lineage and plays important roles in the immune system [41], while the other three isoforms are ubiquitously expressed and regulate a range of physiological functions [42]. Although small-molecule kinase inhibitors against JAKs are potential agents for the treatment of autoimmune and neoplastic disorders [43], the development of isoform-selective JAK inhibitors is challenging due to the high sequence similarity among the four JAK kinases [7].…”

Section: Approved Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

FDA-approved small-molecule kinase inhibitors

Nielsen

Clausen

2015

Trends in Pharmacological Sciences

824

739

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Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. To date, the US FDA has approved 28 small-molecule kinase inhibitors, half of which were approved in the past 3 years. While the clinical data of these approved molecules are widely presented and structure-activity relationship (SAR) has been reported for individual molecules, an updated review that analyzes all approved molecules and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-molecule kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.

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Section: Approved Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

FDA-approved small-molecule kinase inhibitors

Nielsen

Clausen

2015

Trends in Pharmacological Sciences

824

739

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“…Myeloproliferative neoplasms (MPNs) represent a heterogeneous group of clonal diseases with a common propensity to progress to acute leukemia (1–4). Essential Thrombocythemia (ET), Polycythemia Vera (PV), Primary Myelofibrosis (MF), and mixed myelodysplastic/myeloproliferative neoplasms such as Chronic Myelomonocytic Leukemia (CMMoL) are all clonal neoplasms derived from aberrant early hematopoietic precursors but have varied clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms

Pratz

Koh

Patel

et al. 2016

Clinical Cancer Research

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Purpose DNA repair defects have been previously reported in myeloproliferative neoplasms (MPNs). Inhibitors of poly(ADP-ribose) polymerase (PARP) have shown activity in solid tumors with defects in homologous recombination (HR). The present study was performed to assess MPN sensitivity to PARP inhibitors ex vivo. Experimental Design HR pathway integrity in circulating myeloid cells was evaluated by assessing formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. Results Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared to normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia or unspecified myelodysplastic/MPN overlap syndromes. Conclusions Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared to normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted.

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“…Unfortunately, the conventional drug therapies do not provide survival benefits to patients with myelofibrosis or change the natural course of disease progression. Additionally, they offer only modest response rates to myelofibrosis-related symptoms [44]. …”

Section: Clinical Intervention For Myelofibrosismentioning

confidence: 99%

Identity of Gli1+ cells in the bone marrow

Sena

Prazeres

Santos

et al. 2017

Experimental Hematology

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Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study by using state-of-the-art techniques including in vivo lineage-tracing provides evidence that Gli1+ cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1+ cells rescues bone marrow failure and abolishes myelofibrosis. This work brings a new central cellular target for bone marrow fibrosis. The emerging knowledge from this research will be important for the treatment of several malignant and non-malignant disorders.

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Therapy for myeloproliferative neoplasms: when, which agent, and how?

Cited by 94 publications

References 60 publications

FDA-approved small-molecule kinase inhibitors

FDA-approved small-molecule kinase inhibitors

Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms

Identity of Gli1+ cells in the bone marrow

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