A Nanoparticle Carrying the p53 Gene Targets Tumors Including Cancer Stem Cells, Sensitizes Glioblastoma to Chemotherapy and Improves Survival

Abstract

Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O6-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM.

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…14 While the killing of cancer cells by p53 does not require a fully functional immune system, p53 can push cancer cells toward apoptotic death and tends to sensitize tumors to conventional therapeutic modalities (chemotherapy and radiotherapy) that result in DNA damage. 26 Indeed, we have shown that the restoration of p53 function via SGT-53, a tumor-targeted nanomedicine, could inhibit tumor growth and sensitize xenografts of human tumors in nude mice lacking T cells to both chemotherapy 27,28 and radiotherapy. 29 Nonetheless, it has become clear that p53 also participates in various aspects of immune modulation in cancer.…”

“…Indeed, in human tumor cell lines, we have observed that SGT-53 can push cells harboring either wtp53 or mutated p53 readily into apoptotic death. 27,28 …”

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53^{wild type} Neuroendocrine Tumor Cell Line GOT1

“…Expression of p53 wild type has been reported to downregulate MGMT in glioblastoma [54][55][56][57] . Increasing the expression of p53 [58] or PUMA [98] has been reported to sensitize glioblastoma cells to temozolomide. A Western blot analysis of the expression level of MGMT in the BON1, NCI-H727, and GOT1 NET cell lines demonstrated that there was no detectable level of MGMT expression ( Fig.…”

“…In human glioblastoma cells, the MDM2 inhibitor ISA27 and temozolomide have been reported to exert synergistic antiproliferative effects [53] , while expression of p53 wild type downregulates MGMT expression in glioblastoma [54][55][56][57] and sensitizes glioblastoma cells to temozolomide [58] . Therefore, we aimed to investigate whether there are additive effects of co-incubation with temozolomide and the MDM2 inhibitor NVP-CGM097 on the expression profile of MGMT.…”

Targeting glioblastoma cancer stem cells: the next great hope?

“…By using a systemically administered nanoparticle carrying the p53 gene, Kim et al targeted GBM cells, including CSCs. 72 They reported that the combination of the nanoparticle-carrying p53 and temozolomide increased the antitumor efficacy of temozolomide and enhanced survival benefits in a mouse model of highly temozolomide-resistant GBM.…”