EG-011 / E2DG, Oncology Institute of Southern Switzerland - LARVOL DELTA

Pharmacological activation of WASp potentiates macrophage phagocytosis and enhances ibrutinib efficacy against mouse models of brain tumors. (PubMed, Sci Transl Med) - "Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit."

Journal • Preclinical • Brain Cancer • CNS Lymphoma • Glioblastoma • Hematological Malignancies • Immunology • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Primary Immunodeficiency • Solid Tumor • BTK

A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers. (PubMed, Haematologica) - "Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form...Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization."

Journal • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Multiple Myeloma • Oncology • Primary Immunodeficiency

The first-in-class WASP activator EG-011 is active in lymphoma and multiple myeloma cell lines resistant to FDA approved compounds (AACR-NCI-EORTC 2022) - "The anti-tumor activity of EG-011 was maintained in the resistant cell line derived from the MZL VL51 with secondary resistance to ibrutinib (IC50: 500 nM in both parental and resistant), while it was higher in the MZL model with resistance to PI3Kdelta inhibitor derived from VL51 (IC50: 100 nM). The copanlisib-resistant MZL VL51 (IC50: 2 μM) and Karpas1718 idelalisib-resistant (5 nM) showed a slightly decreased sensitivity to EG-011 (Karpas1718 parental, IC50: 1 nM)...A 4-fold increase in sensitivity was observed in both RPMI-8266 bortezomib resistant and in RPMI-8266 carfilzomib resistant cells compared to parental (IC50: 2.5 vs 10 μM for both models). Conclusions. These data indicate that the first-in-class WASP activator EG-011 was active also after acquisition of resistance to different FDA approved agents such as PI3K, BTK and proteasome inhibitors in MZL and MM models."

FDA event • Preclinical • Hematological Malignancies • Leukemia • Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Oncology