Author: McAllister, Andres ; Rigotti, Stefania ; Schürch, Christian M. ; Bachhav, Yogeshwar ; Ramachandra, Murali ; Aguet, Michel ; Murone, Maximilien ; Banz, Yara ; Radpour, Ramin ; Massière, Frédéric ; Riether, Carsten ; Huguenin, Anne-Laure ; Attinger, Antoine ; Sengupta, Saumitra ; Chessex, Anne Vaslin

AbstractAcute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34+ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497–510. ©2017 AACR.

01 Oct 2016·Molecular Cancer TherapeuticsQ2 · MEDICINE

Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases

Q2 · MEDICINE

Article

Author: Shetty, Shankar J. ; Rigotti, Stefania ; Ramachandra, Murali ; Vaslin Chessex, Anne ; Aguet, Michel ; Daginakatte, Girish ; Brienza, Silvano ; Bachhav, Yogeshwar ; Johnson, Faye M. ; Murone, Maximilien ; Sengupta, Saumitra ; McAllister, Andres ; Marappan, Sivapriya ; Nicholas, Courtney ; Dhodheri, Samiulla ; Traxler, Peter ; Zoete, Vincent ; Ramachandra, Raghuveer ; Lang, Marc ; Attinger, Antoine ; Michielin, Olivier

AbstractTumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non–small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334–43. ©2016 AACR.

100 Deals associated with Debio-0617B

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	Aurigene Oncology Ltd.	-
Neoplasms	Preclinical	-	Debiopharm International SA	-

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