Research Interest

Experimental therapeutics in paediatric high grade glioma

Paediatric high grade glioma, like the disease in adults, is in clear need of novel therapeutic strategies. These tumours continue to have a dismal clinical outcome, with a median overall survival for patients with supratentorial glioblastoma of 11 months. Current standard of care is still questionable, with the Stupp protocol for adult cases of radiotherapy plus temozolomide commonly used despite an absence of published data demonstrating a clearly beneficial therapeutic effect. Novel, molecularly targeted agents have demonstrated little efficacy in early phase clinical trials, a problem exacerbated by concerns over drug delivery coupled with an incomplete knowledge of the importance of the specific target in the childhood setting.

Our lab has been using information derived from the genomic profiling of paediatric high grade glioma to guide new initiatives in preclinical drug development specific to the childhood disease. Using specific in vitro and in vivo models of paediatric glioma, we are evaluating small molecule inhibitors of numerous targets identified as amplified/overexpressed in patient samples, including the receptor tyrosine kinases EGFR, PDGFRA and IGF1R, either alone or combination.

In addition, we have been working with Professor Paul Workman, Division of Cancer Therapeutics, to investigate novel compounds developed at the Institute aimed at downstream signalling molecules and support networks routinely abrogated in human cancer, and have been linking the in vitro and in vivo efficacy to what we know about the molecular pathology of the disease. Such joint projects have included studying clinically relevant inhibitors of PI3-kinase and the HSP90 molecular chaperone, either alone, or in combination with other targeted therapeutics as well as temozolomide.

Finally we have been utilising the high throughput screening system implemented in the laboratory of Professor Alan Ashworth, Division of Breast Cancer Research, in order to compare the differential sensitivity to a large panel of targeted agents of paediatric versus adult high grade glioma cell lines, as well as derive novel strategies of synthetic lethality by screening these compounds in isogenic pairs of cell lines harbouring specific genetic alterations identified by our molecular profiling programme.

Selected recent publications

1. Bielen A, Perryman L, Box G, Valenti M, de Haven Brandon A, Martins V, Jury SA, Popov S, Gowan S, Jeay S, Raynaud F, Hofmann F, Hargrave D, Eccles SA and Jones C (submitted) “Enhanced efficacy of IGF1R inhibition in paediatric glioblastoma by combinatorial targeting of PDGFRalpha/beta”

2. Gaspar N, Marshall L, Perryman L, Bax DA, Little SE, Viana-Pereira M, Vassal G, Pearson AJ, Reis RM, Hargrave D, Workman P and Jones C (2010) “MGMT-independent temozolomide resistance in paediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature” Cancer Res 70:9243-9252

3. Gaspar N, Sharp SY, Eccles SA, Gowan S, Popov S, Jones C, Pearson ADJ, Vassal G and Workman P (2010) “Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and paediatric glioblastoma” Mol Cancer Ther 9:1219-1233

Bax DA*, Gaspar N*, Little SE, Marshall L, Perryman L, Regairaz M, Viana-Pereira M, Vuononvirta, R, Sharp SY, Reis-Filho JS, Stávale JN, Al-Sarraj S,  Vassal G, Pearson ADJ, Hargrave D, Ellison DW, Workman P and Jones C (2009) “EGFRvIII deletion mutations in paediatric high grade glioma and response to targeted therapy in paediatric glioma cell lines” Clin Cancer Res 15:5753-5761