lbw242 and Brain-Neoplasms

We tested the use of the small-molecule Inhibitor of Apoptosis Protein (IAP) inhibitor LBW242 in combination with the standard-of-care therapies of irradiation and temozolomide for malignant gliomas. In vitro assays demonstrated that LBW242 enhanced the cytotoxic activity of radiotherapy, and clonogenic assays showed that the combination therapy led to a synergistic anti-glioma effect in multiple cell lines. Neurosphere assays revealed that the combination of radiation and LBW242 led to a pro-apoptotic effect in these glioma-initiating cell-enriched assays, with a corresponding inhibition of primary tumor cell growth. Athymic mice bearing established human malignant glioma tumor xenografts treated with LBW242 plus radiation and temozolomide demonstrated a synergistic suppression of tumor growth. Taken together, these experiments show that the pro-apoptotic and anti-glioma effects of radiotherapy and chemotherapy can be enhanced by the addition of a small-molecule IAP inhibitor. These results are readily translatable to clinical trial and offer the potential for improved treatment outcomes for patients with glioma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Dacarbazine; Gamma Rays; Glioma; Humans; In Vitro Techniques; Inhibitor of Apoptosis Proteins; Mice; Mice, Nude; Oligopeptides; Radiation-Sensitizing Agents; Temozolomide; Xenograft Model Antitumor Assays

Multiple receptor tyrosine kinases (RTKs), including PDGFR, have been validated as therapeutic targets in glioblastoma multiforme (GBM), yet inhibitors of RTKs have had limited clinical success. As various antiapoptotic mechanisms render GBM cells resistant to chemo- and radiotherapy, we hypothesized that these antiapoptotic mechanisms also confer resistance to RTK inhibition. We found that in vitro inhibition of PDGFR in human GBM cells initiated the intrinsic pathway of apoptosis, as evidenced by mitochondrial outer membrane permeabilization, but downstream caspase activation was blocked by inhibitor of apoptosis proteins (IAPs). Consistent with this, inhibition of PDGFR combined with small molecule inactivation of IAPs induced apoptosis in human GBM cells in vitro and had synergistic antitumor effects in orthotopic mouse models of GBM and in primary human GBM neurospheres. These results demonstrate that concomitant inhibition of IAPs can overcome resistance to RTK inhibitors in human malignant GBM cells, and suggest that blockade of IAPs has the potential to improve treatment outcomes in patients with GBM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Glioblastoma; Humans; Imatinib Mesylate; Intercellular Signaling Peptides and Proteins; Mice; Models, Biological; Neurons; Oligopeptides; Piperazines; Pyrimidines