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Biomedical subjects

Grant McArthur

Publications and source records attributed to Grant McArthur.

7 recordsLinked to original sources
PubMed2006

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Adult↗
PubMed2004

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans.

NY-ESO-1 is a "cancer-testis" antigen expressed in many cancers. ISCOMATRIX is a saponin-based adjuvant that induces antibody and T cell responses. We performed a placebo-controlled clinical trial evaluating the safety and immunogenicity of recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant. Forty-six evaluable patients with resected NY-ESO-1-positive tumors received three doses of vaccine intramuscularly at monthly intervals. The vaccine was well tolerated. We observed high-titer antibody responses, strong delayed-type hypersensitivity reactions, and circulating CD8(+) and CD4(+) T cells specific for a broad range of NY-ESO-1 epitopes, including known and previously unknown epitopes. In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone. The vaccine is safe and highly potent immunologically.

Adjuvants, Immunologic↗
PubMed2004

Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor.

Biomarkers that indicate biological activity and/or efficacy are a potentially useful tool in the development of molecularly targeted therapeutics. It is useful, though challenging, to identify biomarkers during preclinical development in order to impact decision-making during early clinical development. SU11248 is an oral, selective multitargeted tyrosine kinase inhibitor currently in Phase II oncology clinical trials. It exhibits direct antitumor and antiangiogenic activity via inhibition of the receptor tyrosine kinases PDGFR, VEGFR, KIT and FLT3. To identify clinically translatable biomarkers of SU11248 activity, expression profiling was performed on Colo205 human xenograft tumors following treatment with SU11248. Over 100 transcripts changed in abundance in SU11248 as compared to vehicle-treated tumors. Nine candidate transcripts, chosen based on putative function, were also analysed and validated by TaqMan. One such potential biomarker, cadherin-11, was further evaluated at the protein level and was found to have increased expression in xenograft tumors after SU11248 treatment. Interestingly, cadherin-11 expression was also detected via immunohistochemical analysis of archived solid tumors, indicating the technical feasibility of translating this putative biomarker to clinical studies. Importantly, SU11248 treatment also resulted in increased expression of cadherin-11 protein in human tumor biopsies in three out of seven patients examined and confirms the feasibility of using transcriptional profiling of preclinical models to identify clinically translatable biomarkers.

Animals↗
PubMed2004

Molecularly targeted treatment for dermatofibrosarcoma protuberans.

Traditionally, treatment for dermatofibrosarcoma protuberans (DFSP), a rare cutaneous tumor that is locally aggressive, has been limited to wide surgical excision with negative margins. Although not usually metastatic, DFSP has significant potential for recurrence and interference in local structures. The pathogenesis of DFSP stems from a chromosomal rearrangement involving chromosomes 17 and 22, in which the collagen 1alpha1 gene is fused to the gene for platelet-derived growth factor (PDGF) B-chain. The resultant deregulated expression of PDGFB leads to continuous activation of the PDGF receptor beta (PDGFRbeta) protein-tyrosine kinase that promotes DFSP tumor cell growth. Imatinib is a potent and specific inhibitor of several protein-tyrosine kinases, including the PDGFRs. Preclinical investigations and clinical reports have shown the efficacy of imatinib in DFSP. Imatinib may provide an alternative for the treatment of unresectable or partially resectable tumors, thereby possibly improving the effectiveness of surgery.

Antineoplastic Agents↗
PubMed2003

Applications of positron emission tomography in the development of molecular targeted cancer therapeutics.

For molecular targeted cancer therapies to fulfill their promise in cancer treatment, innovative approaches are required to overcome significant obstacles that exist in the clinical development of these agents. Positron emission tomography (PET) is a functional imaging technology that allows rapid, repeated, noninvasive, in vivo assessment and quantification of many biological processes and in some cases molecular pathways targeted by these therapies. It is highly sensitive, with the capacity to detect subnanomolar concentrations of radiotracer and provides superior image resolution to conventional nuclear medicine imaging with gamma cameras. Novel PET radiotracers have been developed that allow visualisation of a variety of processes including tumour metabolism, cell proliferation, apoptosis, hypoxia and blood flow. Furthermore, specific molecular targets including cellular receptors can be identified using radiolabelled receptor ligands or specific monoclonal antibodies. Improvements in imaging technology leading to the development of small-animal PET scanners, with resolution capable of imaging commonly used mouse models of cancer, will enable PET to play an important role in preclinical proof-of-principle drug studies. Such improvements will also facilitate the validation of imaging protocols that can be readily translated to studies in humans. The greatest utility of PET in the development of molecular targeted therapeutics, however, lies in clinical studies, where PET may play a valuable role in a number of situations. These include selection of patients for therapy through noninvasive identification of the presence of specific molecular targets, pharmacokinetic studies with labelled drugs and pharmacodynamic evaluations of biological parameters to select the optimal biological dose, and assessment of response to therapies.

Animals↗