<scp>SL</scp>‐401 and <scp>SL</scp>‐501, targeted therapeutics directed at the interleukin‐3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia

Frolova, Olga; Benito, Juliana; Brooks, Chris; Wang, Rui Yu; Korchin, Borys; Rowinsky, Eric K.; Cortes, Jorge; Kantarjian, Hagop M.; Andreeff, Michael; Frankel, Arthur E.; Konopleva, Marina

doi:10.1111/bjh.12978

Cited by 41 publications

(32 citation statements)

References 48 publications

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“…A recent study also demonstrated anti-CSC activity of SL-401 in advanced CML. 40 Together, our data suggests that SL-401 may target tumor-initiating stem-like cells and thereby abrogate development of drug-resistance in MM.…”

Section: Discussionmentioning

confidence: 66%

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

et al. 2017

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Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3 R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3 R-targeted therapeutic SL-401. In both in vitro and in vivo models of MM in its BM milieu, SL-401 decreases viability of pDCs, blocks pDC-induced MM cell growth, and synergistically enhances anti-MM activity of bortezomib and pomalidomide. Besides promoting pDC survival and MM cell growth, IL-3 also mediates progression of osteolytic bone disease in MM. Osteoclast (OCL) progenitor cells express IL-3 R, and we show that SL-401 abrogates monocyte-derived OCL formation and bone resorption. Finally, we show that SL-401 also decreases the viability of IL-3 R-expressing cancer stem-like cells in MM. Overall, our study provides the preclinical basis for clinical trials of SL-401 to block pDC-induced MM cell growth, inhibit osteoclastogenesis and target MM stem-like cell subpopulations to improve patient outcome in MM.

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Section: Discussionmentioning

confidence: 66%

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

et al. 2017

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“…132,133 Because activation of the Hedgehog signaling pathway could contribute to the development of leukemic stem cells, CMML patients can be included in a phase 1 study of a smoothened antagonist. 134 Finally, high expression of interleukin-3 receptor (CD123) in leukemic stem cells led exploration of the efficacy of SL-401, a diphtheria toxininterleukin-3 fusion protein, 135 in patients with hematological malignancies including CMML. Another characteristic feature of CMML is the frequent mutations of a splicing gene.…”

Section: Currently Explored Therapeutic Strategies In Cmml Patientsmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

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“…55 Increased expression of CD123/IL3Ra has subsequently been demonstrated in related malignancies, including MDS, chronic myeloid leukemia, and aggressive NHLs, among others. [56][57][58] The a subunit of IL-3R is a type I transmembrane glycoprotein (cytokine receptor superfamily) that co-dimers with CD131 (common b chain). Leukemic blasts seem to differentially express IL-3Ra compared with normal stem cells, 55 and this may relate to differential sensitivity to therapy.…”

Section: Novel Therapymentioning

confidence: 99%

Treatment of blastic plasmacytoid dendritic cell neoplasm

Sullivan

Rizzieri

2016

Hematology

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy with no defined standard of care. BPDCN presents most commonly with skin lesions with or without extramedullary organ involvement before leukemic dissemination. As a result of its clinical ambiguity, differentiating BPDCN from benign skin lesions or those of acute myeloid leukemia with leukemia cutis is challenging. BPDCN is most easily defined by the phenotype CD4 1 CD56 1 CD1231 lineage -MPO -, although many patients will present with variable expression of CD4, CD56, or alternate plasmacytoid markers, which compounds the difficulty in differentiating BPDCN from other myeloid or lymphoid malignancies. Chromosomal aberrations are frequent, and the mutational landscape of BPDCN is being rapidly characterized although no obvious molecular target for chemoimmunotherapy has been identified. Chemotherapy regimens developed for acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndrome have all been used to treat BPDCN. Relapse is frequent, and overall survival is quite poor. Allogeneic transplantation offers a chance at prolonged remission and possible cure for those who are eligible; unfortunately, relapse remains high ranging from 30% to 40%. Novel therapies such as SL-401, a diphtheria toxin conjugated to interleukin-3 (IL-3) is commonly overexpressed in BPDCN and other aggressive myeloid malignancies and has shown considerable promise in ongoing clinical trials. Future work with SL-401 will define its place in treating relapsed or refractory disease as well as its role as a first-line therapy or bridge to transplantation. Learning Objectives• To understand the clinical and laboratory approach for differentiating BPDCN from acute myeloid leukemia with cutaneous manifestations • To consider appropriate first-line and salvage treatments for BPDCN, including the utility of hematopoietic allogeneic stem cell transplantation and novel agents in various patient populations

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SL‐401 and SL‐501, targeted therapeutics directed at the interleukin‐3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia

Cited by 41 publications

References 48 publications

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

How I treat chronic myelomonocytic leukemia

Treatment of blastic plasmacytoid dendritic cell neoplasm

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