The PI3K inhibitor GDC-0941 displays promisingin vitro and in vivoefficacy for targeted medulloblastoma therapy

Abstract

Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancer, also displays anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines. Loss in cell viability is accompanied by reduced phosphorylation of AKT, a downstream target of PI3K. Furthermore, we show that GDC-0941 attenuates the migratory capacity of medulloblastoma cells and targets subpopulations expressing the stem cell marker CD133. GDC-0941 also synergizes with the standard medulloblastoma chemotherapeutic etoposide. In an orthotopic xenograft model of the most aggressive human medulloblastoma variant we document that oral adminstration of GDC-0941 impairs tumor growth and significantly prolongs survival. These findings provide a rational to further investigate GDC-0941 alone and in combination with standard chemotherapeutics for medulloblastoma treatment.

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

“…Our studies and those of others have shown that Myc can confer metastatic phenotypes in medulloblastoma (6)(7)(8). Although mechanisms of Myc-mediated transformation in medulloblastoma remain largely unknown, multiple lines of data suggest Mycdriven medulloblastoma are dependent on PI3K/AKT signaling (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and point to the PI3K/AKT axis as a critical downstream effector of Myc in group 3 medulloblastoma (7,16,17). Activation of PI3K/AKT signaling has been shown to promote various oncogenic phenotypes in medulloblastoma including enhanced tumor growth, metastasis, and chemoresistance (14,(18)(19)(20)(21)(22).…”

“…To date, multiple studies have demonstrated that pharmacologic inhibitors of PI3K signaling have potent antineoplastic effects in medulloblastoma (7,13,14,16,17,19,36), and underscore the importance of PI3K signaling particularly in Myc-driven medulloblastoma. To effectively exploit PI3K/AKT signaling for medulloblastoma treatment, it would be important to delineate the extent of the Myc-PI3K/AKT signaling axis through identification of novel targetable effector and mediators of this pathway.…”

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[84] The highly specific pan-PI3K inhibitor GDC-0941 has recently been shown to have anti-migratory, anti-proliferative and proapoptotic effects in MB cell lines, showing synergy with the standard chemotherapeutic drug etoposide and good clinical tolerability. [85] Other elements of the PI3K/AKT pathway are also being considered as potential targets to inhibit cell proliferation and migration in GBM and MB. One example is AKT, which usually shows high levels of phosphorylation in these brain tumors.…”

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

“…Therefore, inhibiting this signaling pathway may facilitate chemotherapy treatments (7,8). Preclinical studies and early clinical trials indicate that the treatment of several cancers including breast (9), lung (10), medulloblastoma (11), and pancreatic cancer (6) could benefit from PI3K inhibitors. It is plausible that such targeted therapeutic approaches against the PI3K/AKT pathway can be used in patients with advanced bladder cancer, either as a single agent or in combination, to decrease drug resistance and augment the efficacy of chemotherapy.…”