Brain glioma tumors, unequivocally glioblastoma multiforme (GBM), are among the most incurable forms of cancer. Such tumors are thought to arise from brain neural stem cells and progenitors that have undergone transformation into neoplasias. Neoplastic stem cells are thought to contribute to the recurrence of the glioma after chemotherapy and surgical resection. We found that activating transcription factor 5 (ATF5) is highly expressed in neural stem/progenitor cells, including cancer stem cells and GBMs. Blocking ATF5 function by dominant negative ATF5 (d/n-ATF5) or siRNA-ATF5 promotes apoptosis of glioma tumor cells, but not of non- neoplastic cells, both in vitro and in vivo. Currently, we synthesize recombinant cell penetrant d/n-ATF5 peptide that crosses the blood brain barrier, and enters into glioma cells, promoting their rapid death. The long-term objectives of our study will be to further test, as well as determine the apparent therapeutic index, of cell penetrant d/n-ATF5 toward tumor regression or full eradication in a pre-clinical approach by using different glioblastoma mouse models.
Our specific aims will be to 1) Define the most effective dosing schedule for delivery of the cell penetrant d/n-ATF5 that does not harm normal tissues;test efficacy in mouse glioma/glioblastoma models by creating brain tumors through de novo transformation of progenitors and by human GBM xenografts;determine whether treatment with the peptide can bring about long-term eradication of glioblastomas;and, in the case that tumors reappear after initial treatment, whether they can again be caused to regress by application of the d/n peptide. 2) To define the responsible molecular mechanistic pathways that mediate apoptotic actions of d/n-ATF5 in glioblastoma cells. To gain insight on these pathways will enlighten how neoplasm relies on ATF5 for survival that is not observed in non-transformed cells. Knowledge of the mechanistic routes will aid in predicting and circumventing off-target effects and will explain as well as promote avoidance of potential tumor resistance toward d/n-ATF5 therapy. Finally, synergy of d/n- ATF5 with other currently employed glioblastoma therapies will be more adequately addressed with awareness of such pathways.
Treatments for glioma tumors, especially glioblastoma, have a poor outcome. We discovered that activating transcription factor 5 (ATF5) plays a required role in the survival of gliomas, and that blocking ATF5's function prevents and eradicates this cancer both in culture and in living animals. We have developed and will further test here a novel therapeutic intervention that consists of systemically injecting a cell penetrant-ATF5 antagonist peptide that passes through the blood brain barrier and that enters and kills glioma cells without apparent harm to normal tissues. This approach has the potential to lead to a promising new and novel treatment for brain cancer.
|Cates, Charles C; Arias, Angelo D; Nakayama Wong, Lynn S et al. (2016) Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide. Oncotarget 7:12718-30|
|Karpel-Massler, Georg; Horst, Basil A; Shu, Chang et al. (2016) A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers. Clin Cancer Res 22:4698-711|