Editors' ChoiceCancer

Identifying and targeting residual leukemic cells

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Science Translational Medicine  19 Sep 2018:
Vol. 10, Issue 459, eaav0339
DOI: 10.1126/scitranslmed.aav0339

Abstract

Targeting leukemia regenerating cells following chemotherapy can prevent relapse of the disease.

Historically, lymphoma and leukemia were the first cancers treated with chemotherapy (nitrogen mustards and antifolates). Today, high-dose combination chemotherapy is still the standard of care for leukemia, due to frequent curative responses in patients. Unfortunately, in acute myelogenous leukemia (AML), despite high remission rates, the patient’s disease often recurs or relapses, leaving limited treatment options. What causes this leukemic regrowth following chemotherapy treatment?

Previous work suggested that the leukemic stem cells, identified by cell surface markings (CD34+ CD38) and a defined molecular profile, preferentially resist chemotherapy and enable the regrowth of the leukemia. A recent publication by Boyd et al. effectively showed that the leukemic stem cell population was depleted upon chemotherapy (cytarabine) treatment. However, quiescent leukemic stem cells (LSC) entered the cell cycle in both patient samples and patient-derived xenografts treated with chemotherapy. Through interrogating patient remission and relapse in patient-derived xenografts, they identified residual cells that they termed “leukemic regenerating cells” (LRCs). Using transcriptomic analysis, they found that the LRCs had a molecular profile distinct from LSCs, were only found in vivo and not in cultured primary cells, and enabled regrowth of the leukemia. Importantly, the authors identified a series of therapeutic targets that were up-regulated in the “LRC-state,” including fibroblast growth factor receptor 2 (FGFR2) and dopamine receptor D2 (DRD2). Combining chemotherapy and a DRD2 antagonist (thioridazine) prevented the regrowth of the leukemia in patient-derived xenografts. Last, the authors also showed that LRCs are present in patient samples following treatment with chemotherapy and that presence of this molecular signature correlated with patient relapse.

Important questions arise in relation to timing of treatments from this work, including whether the targeted agents should be added in combination with the chemotherapy or if they could be more effective if added sequentially, after chemotherapy, when the LRCs are present. It will be interesting to investigate if LRCs are identified following treatment with targeted agents (such as ABT-199/venetoclax), or whether they just occur following chemotherapy treatment. Lastly, as the LRCs only develop in vivo, whether there is a microenvironment component essential to their development has yet to be elucidated. Future studies will help address these questions and determine if the actionable targets identified on the LRCs improve patient survival in clinical trials.

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