作者: Erkner, Estelle ; Radszuweit, Pia ; Lengerke, Claudia ; Roti, Giovanni ; Keppeler, Hildegard ; Fischer, Jacqueline ; Schneidawind, Dominik ; Korkmaz, Fulya ; Schneidawind, Corina ; Fitzel, Rahel

MLL rearrangement (MLLr) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 MLL-AF4/-AF9 translocation model, the newly developed NOTCH1 inhibitor CAD204520 with less toxic side effects allowed us to unravel the impact of NOTCH1 as a pathogenic driver and potential therapeutic target in MLLr leukemia. RNA sequencing (RNA-seq) and RT-qPCR of our MLLr model and MLLr cell lines showed the NOTCH1 pathway was overexpressed and activated. Strikingly, we confirmed this elevated expression level in leukemia patients. We also demonstrated that CAD204520 treatment of MLLr cells significantly reduces NOTCH1 and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule. Accordingly, treatment with CAD204520 resulted in dose-dependent reduced proliferation and viability, increased apoptosis, and the induction of cell cycle arrest via the downregulation of MLL and NOTCH1 target genes. In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in MLLr leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings.

2020-06-01·Cell Chemical Biology1区 · 生物学

Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

1区 · 生物学

Article

作者: Dalby-Brown, William ; Vilella, Rocchina ; Mecucci, Cristina ; Patrizi, Laura ; Roti, Giovanni ; Heit, Sabine ; Sportoletti, Paolo ; Rompietti, Chiara ; Sorrentino, Claudia ; Gherli, Andrea ; Rizzi, Federica ; Montanaro, Anna ; Pagliaro, Luca ; Møller, Jesper V ; Marchesini, Matteo ; Kitara, Samuel ; Bublitz, Maike ; Baglione, Marilena ; Savi, Monia ; Bocchi, Leonardo ; Stegmaier, Kimberly ; Rastelli, Giorgia ; Aversa, Franco ; Olesen, Claus E ; La Starza, Roberta ; Loiacono, Caterina ; Stilli, Donatella ; Lund Winther, Anne-Marie

The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca²⁺ toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Uniquely among SERCA inhibitors, CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenografted model without causing cardiac toxicity. This study supports the development of SERCA inhibitors for Notch-dependent cancers and extends their application to cases with isolated mutations in the PEST degradation domain of NOTCH1, such as MCL or chronic lymphocytic leukemia (CLL).

International Journal of Molecular Sciences

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders

Article

作者: Zamponi, Raffaella ; Tartaglione, Isotta ; Vento, Federica ; Todaro, Giannalisa ; Cuneo, Antonio ; Montanaro, Anna ; Roti, Giovanni ; Simoncini, Elisa ; Scita, Matteo ; Moron Dalla Tor, Lucas ; Cerretani, Elisa ; Lorusso, Bruno ; Rigolin, Gian Matteo ; Sammarelli, Gabriella ; Silini, Enrico Maria ; Pagliaro, Luca ; Gherli, Andrea ; Quaini, Federico ; Giaimo, Mariateresa ; Russo, Filomena

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

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适应症	最高研发状态	国家/地区	公司	日期
急性淋巴细胞白血病	临床2期	意大利	University of Parma	2019-06-14
急性淋巴细胞白血病	临床2期	意大利	Università degli Studi di Perugia	2019-06-14
急性淋巴细胞白血病	临床2期	美国	Dana-Farber Cancer Institute, Inc.	2019-06-14
急性淋巴细胞白血病	临床2期	丹麦	CaDo Biotechnology IvS	2019-06-14
前体T淋巴细胞白血病淋巴瘤	临床前	丹麦	CaDo Biotechnology IvS	2019-06-14
前体T淋巴细胞白血病淋巴瘤	临床前	意大利	University of Parma	2019-06-14