Antitumor effects of bevacizumab in a microenvironment‐dependent human adult <scp>T</scp>‐cell leukemia/lymphoma mouse model

Mori, Fumiaki; Ishida, Takashi; Ito, Asahi; Sato, Fumihiko; Awata, Masaki; Narita, Takuma; Suzuki, Susumu; Yamada, Takanobu; Takino, Hisashi; Ri, Masaki; Kusumoto, Shigeru; Komatsu, Hirokazu; Hishizawa, Masakatsu; Imada, Kazunori; Takaori‐Kondo, Akifumi; Ueda, Ryuzo; Inagaki, Hiroshi; Iida, Shinsuke

doi:10.1111/ejh.12231

Cited by 6 publications

(4 citation statements)

References 41 publications

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“…In a fourth group, CHOP [cyclophosphamide (40 mg/kg), doxorubicin (3 3. mg/kg), and vincristine (0.5 mg/kg) were given intravenously; and prednisone (0.2 mg/kg) was given by oral gavage] was administered for 5 consecutive days 3 weeks after injection of the lymphoma cell line [49, 50]. Tumor progression was monitored every week until death or until the study was concluded at week 13.…”

Section: Methodsmentioning

confidence: 99%

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

et al. 2014

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NPM-ALK+ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK+ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK+ solid tumors. However, NPM-ALK+ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK+ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK+ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK+ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK+ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.

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Section: Methodsmentioning

confidence: 99%

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

et al. 2014

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“…[121][122][123] Furthermore, involvement of angiogenesis and fibroblast-derived osteopontin has been suggested in proliferation and survival, as well as possible roles of exosomes produced by ATL cells. [124][125][126] In this regard, a possible role of mutations of Notch1 signaling 70,87 appears to deserve further examination. Further studies are expected to understand the mechanisms underlying resistance and survival of ATL cells in vivo.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Watanabe

2017

Blood

144

117

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Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

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“…Moreover, patients also die because of CHOP-related complications that are not directly related to their lymphoma [49]. We have previously noticed that the utilization of CHOP at the standard dose used in mice with subcutaneous xenografts of non-NPM-ALK + T cell lymphoma [50, 51] was associated with pronounced toxicity that frequently caused early expiration of mice with systemic NPM-ALK + T cell lymphoma [26]. Therefore, in the current study, we resorted to treat a subgroup of mice with only 1/3 of the standard concentration of CHOP (CHOP1/3).…”

Section: Discussionmentioning

confidence: 99%

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma

George

Shi

et al. 2019

J Hematol Oncol

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Background Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK + ) T cell lymphoma is an aggressive neoplasm. NPM-ALK, an oncogenic tyrosine kinase, plays a critical role in this lymphoma. Recently, selective ALK inhibitors have emerged as a first-line therapy for this neoplasm. Unfortunately, ALK inhibitors were hindered by emergence of resistance and relapse. We have previously demonstrated that type I insulin-like growth factor receptor (IGF-IR) is commonly expressed and activated in this lymphoma. In addition, IGF-IR and NPM-ALK are physically associated and reciprocally enhance their phosphorylation/activation. Herein, we tested the hypothesis that combined inhibition of IGF-IR and NPM-ALK could significantly improve the effects of inhibiting each kinase alone. Methods We used clinically utilized inhibitors of IGF-IR (picropodophyllin; PPP) and ALK (ASP3026) to assess the in vitro cellular effects of combined treatment versus treatment using a single agent. Moreover, we used a systemic NPM-ALK + T cell lymphoma mouse model to analyze the in vivo effects of PPP and ASP3026 alone or in combination. Results Our data show that combined treatment with PPP and ASP3026 decreased the viability, proliferation, and anchorage-independent colony formation, and increased apoptosis of NPM-ALK + T cell lymphoma cells in vitro. The in vitro effects of combined treatment were synergistic and significantly more pronounced than the effects of PPP or ASP3026 alone. Biochemically, simultaneous antagonism of IGF-IR and ALK induced more pronounced decrease in pIGF-IR Y1135/1136 , pNPM-ALK Y646 , and pSTAT3 Y705 levels than antagonizing IGF-IR or ALK alone. Moreover, combined targeting of IGF-IR and NPM-ALK decreased significantly systemic lymphoma tumor growth and improved mice survival in vivo. Consistent with the in vitro results, the in vivo effects of the combined therapy were more pronounced than the effects of targeting IGF-IR or ALK alone. Conclusions Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK + T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed. Electronic supplementary material The online version of this article (10.1186/s13045-019-0768-8) contains supplementary material, which is available to authorized users.

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Antitumor effects of bevacizumab in a microenvironment‐dependent human adult T‐cell leukemia/lymphoma mouse model

Cited by 6 publications

References 41 publications

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma

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