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A small molecule IAP inhibitor sensitises medulloblastoma cells to radiation therapy and cytotoxic chemotherapy in vitro and in vivo

Keating, Joanna and Haber, Michelle and Zawel, Leigh and Ziegler, David (2010) A small molecule IAP inhibitor sensitises medulloblastoma cells to radiation therapy and cytotoxic chemotherapy in vitro and in vivo. Molecular cancer Therapeutics.

Abstract

Novel strategies for treating medulloblastoma are urgently needed. Despite intensive treatment one quarter of patients ultimately succumb to their disease. Radiation therapy is a critical component of current treatment strategies but often results in devastating long-term effects, particularly in younger patients. Strategies to sensitise medulloblastoma cells to the effects of radiation therapy have been proposed as a mechanism to both decrease toxicity and enhance efficacy. The Inhibitor of Apoptosis Proteins (IAPs) represent the last molecular barrier to programmed cell death. They have been shown to be over-expressed in medulloblastoma and to correlate with poor patient outcomes. We hypothesized that targeting the IAPs in conjunction with conventional cytotoxic therapies would overcome treatment resistance, increase levels of apoptosis and significantly enhance their anti-tumor activity.

We have previously shown that small molecule IAP inhibitor LBW242 penetrates the blood brain barrier and has a significant anti-tumour effect in intracerebral tumours such as high grade gliomas. We therefore sought to test LBW242 in medulloblastoma in combination with the standard-of-care therapies of irradiation and cytotoxic chemotherapy. In vitro experiments demonstrated that administration of LBW242 in combination with radiotherapy and chemotherapy led to both caspase 8 and 9 activation resulting in direct activation of both the intrinsic and extrinsic apoptotic pathways. Annexin staining showed that this ultimately led to medulloblastoma cell death and clonogenic assays showed that the combination therapy led to a synergistic anti-medulloblastoma effect in multiple cell lines. Athymic mice bearing established human medulloblastoma tumor xenografts treated with LBW242 plus cisplatinum demonstrated a profound and synergistic suppression of tumor growth in the in vivo setting.
Taken together these experiments show that the pro-apoptotic and anti-tumour effects of radiotherapy and chemotherapy can be enhanced by the addition of a small molecule, orally bioavailable IAP inhibitor. These results are readily translatable to clinical trial, and offer the potential for improved treatment outcomes for medulloblastoma patients.

Item Type: Article
Keywords: LBW242
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2310

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