Frank Eckerdt
Northwestern University, USA
Title: Rationale for combinatorial approaches including PI3K-p110alpha targeting in brain cancer stem cells
Biography
Biography: Frank Eckerdt
Abstract
Glioblastoma (GBM) and Medulloblastoma (MB) are deadly brain tumors in adults and children, respectively. Most patients still succumb to these diseases due to relapse, which is caused by a subpopulation of therapy resistant brain cancer stem cells (CSCs). The PI3K pathway promotes cancer cell survival and might stimulate chemotherapy resistance in solid tumors. We employed analysis of gene expression data and found that expression of PIK3CA (p110alpha) correlates with stem cell markers in MB and GBM patient samples, respectively, suggesting important roles in CSCs. Using 3-D neurosphere cultures, we show that the PI3K/AKT pathway is activated in stem-like cancer cells and inhibition of PI3K blocked kinase signaling and neurosphere growth in these CSCs. Of all class I PI3K catalytic isoforms, only knockdown of p110alpha disrupted cancer stem cell frequencies, indicating a pivotal role for this isoform in CSCs. Inhibition of the PI3K pathway in combination with inhibitors targeting protein kinases known to be important for survival signaling enhanced these antineoplastic effects in CSCs. In summary, the p110alpha isoform is a promising target for MB and GBM. The striking effects on stem-like cancer cells and neurospheres is particularly interesting as it suggests enhanced vulnerability of the therapy-resistant, tumor-initiating CSC population to PI3K-p110alpha inhibition in MB and GBM.