Presenting Author:

Frank Eckerdt, Ph.D.

Principal Investigator:

Leonidas Platanias, M.D.

Department:

Medicine

Keywords:

medullobalstoma, brain cancer stem cells, neurospheres, PI3 kinase, MNK, targeted therapy

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B54 - Basic Science

Dual PI3K-p110alpha and MNK Targeting in Medulloblastoma Cancer Stem Cells

Medulloblastoma (MB) is the most common malignant pediatric brain tumor and about one third of patients still succumb to the disease due to relapse and leptomeningeal dissemination. As relapse is caused by a subpopulation of therapy resistant MB cancer stem cells (CSCs), we sought to investigate PI3K and MNK survival signaling in MB CSCs. Gene expression data revealed that expression of PIK3CA (p110alpha) and MKNK1 (MNK1) correlate with stem cell markers such as NES, KLF4, POU5F1 and SOX2 in MB patient samples, suggesting important roles in CSCs. Using 3-D neurosphere cultures, we show that both PI3K/AKT and MNK/eIF4E pathways are activated in MB stem-like cancer cells and inhibition of PI3K and MNK blocked kinase signaling and neurosphere growth in these CSCs. Of all class I PI3K catalytic isoforms, only knockdown of p110alpha disrupted MB stem cell frequencies, indicating a pivotal role for this isoform in CSCs. Importantly, MNK inhibition substantially enhanced this blockade of CSC function, indicating the PI3K-p110alpha and MNK pathways cooperate to promote survival of MB CSCs. Growth of both flank and intracerebellar tumors was significantly inhibited after combined targeting of PI3K-p110alpha and MNK. Treated tumors showed decreased expression of the stem cell marker nestin, reduced mitotic index and increased apoptosis. Combined targeting of PI3K-p110alpha and MNK increased survival in the intracerebellar mouse model. In summary, the p110alpha isoform is a promising target for MB in vitro and in vivo. The striking effects of concomitant MNK inhibition on stem-like cancer cells, neurospheres and tumors is particularly interesting as it suggests enhanced vulnerability of the therapy-resistant, tumor-initiating CSC population to PI3K-p110alpha inhibition in medulloblastoma.