Abstract 5203: Lineage-specific mechanisms regulating PDGFRα oncogenic activity in glioblastoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The highly heterogeneous nature of human tumors is a confounding feature which hinders understanding of the biology of cancer as well as design of effective therapies. Although a number of oncogenes and tumor suppressors, such as PI3K, Ras, TP53, CDKN2A, are frequently altrered across cancers of different origin, it is now apparent that cell lineage exerts a substantial effect on the distribution of genetic alterations in tumors. Consistent with the more recent notion that normal tissue stem cells or partially differentiated progenitor cells may serve as the cells of origin that undergo oncogenic transformation, it is conceivable to think that the cellular programs governing normal lineage development do also underlie the tumorigenic mechanisms. Therefore, the recognition of the tumor dependencies to oncogene functions in a lineage-specific context may offer more meaningful approaches for targeted cancer therapy. PDGF/PDGFRA signaling plays a particularly important role in the development of the brain, as a potent mitogen of oligodendrocyte precursor cells; it is also expressed in the type B neural stem cell population in the subventricular zone of adult brain. PDGF signaling has also been widely implicated in the formation of brain tumors. The Cancer Genome Atlas effort has revealed that overexpression and/or amplification of PDGFRA is the key feature of the proneural subtype of Glioblastomas (GBM), which constitutes 20-30% of all GBMs, occurs in younger patients and is extremely resistant to chemo- and radio-therapy. In proneural GBMs, PDGFRA expression clusters together with other proneural developmental genes such as Olig2 and Sox2. The targeting of PDGFRα has shown limited success in the setting of randomized clinical trials and in in vitro studies employing stable tumor cell lines. However, using a clinically relevant model, our data show that fresh patient-derived GBM stem like cells (Pt-GSLCs) belonging to the proneural subtype are particularly vulnerable to the inhibition of PDGFRα, both in vitro and in vivo, indicating a possible state of addiction to PDGFRα signaling. Interestingly, we observed that the neural transcription factor Olig2, might play a role in PDGFRα addiction. Inhibition of PDGFRα decreased phosphorylation of Olig2, while PDGFRα-inhibitor resistant lines upregulate the levels of Olig2 protein. Moreover Olig2 inhibition potentiates the effects of PDGFRα inhibition in proneural GBMs. Finally, PDGFRα and Olig2 inhibitors sensitize proneural GBM to radiation. These results provide an indication that oncogene deregulation may be “conditioned” by tumor lineage. We are now further investigating the lineage-specific mechanisms regulating addiction to PDGFRα of the proneural subtype of GBM with the hope to establish new pharmacological targets for the treatment of Glioblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5203. doi:1538-7445.AM2012-5203