Activity of GDC-0941, an inhibitor of phosphoinositol 3 kinase (PI3K), in gastrointestinal stromal tumor (GIST) xenograft and duration of response after discontinuation of treatment in combination with imatinib.

Floris, Giuseppe; Sciot, Raf; Woźniak, Agnieszka; Deroose, Christophe M.; Vermaelen, Peter; Dewaele, Barbara; Dębiec‐Rychter, Maria; Schöffski, Patrick

doi:10.1200/jco.2010.28.15_suppl.10020

Cited by 5 publications

(2 citation statements)

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“…In preclinical models, GDC-0941 leads to cell cycle arrest and apoptosis in human tumor cell lines as a single agent and in combination with other anticancer agents [98]. In xenografts of gastrointestinal stromal tumors, GDC-0941 added significantly to the anticancer effects of imatinib [99]. A Phase I single agent study reported in abstract suggested there was evidence of antitumor activity in 3 of 19 patients with advanced cancer.…”

Section: Gdc-0941mentioning

confidence: 96%

New phosphatidylinositol 3-kinase inhibitors for cancer

Bowles

Jimeno

2011

Expert Opinion on Investigational Drugs

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Section: Gdc-0941mentioning

confidence: 96%

New phosphatidylinositol 3-kinase inhibitors for cancer

Bowles

Jimeno

2011

Expert Opinion on Investigational Drugs

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“…We thank Lieve Ophalvens, Ulla Vanleeuw, Ann Van Santvoort and Vanessa Vanspauwen for their excellent technical assistance. Part of the results of the study have been presented at the annual meeting of the American Society of Clinical Oncology (Chicago, IL June 4 th - June 9 th 2010) (37). …”

mentioning

confidence: 99%

A Potent Combination of the Novel PI3K Inhibitor, GDC-0941, with Imatinib in Gastrointestinal Stromal Tumor Xenografts: Long-Lasting Responses after Treatment Withdrawal

Floris

Woźniak

Sciot

et al. 2013

Clinical Cancer Research

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Introduction Oncogenic signaling in gastrointestinal stromal tumors (GIST) is sustained via PI3K/AKT pathway. We used a panel of six GIST xenograft models to assess efficacy of GDC-0941 as single agent or in combination with imatinib (IMA). Experimental design Nude mice (n=136) were grafted bilaterally with human GIST carrying divers KIT mutations. Mice were orally dosed over four weeks, grouped as follows: A) control; B) GDC-0941; C) IMA and D) GDC+IMA treatments. Xenografts re-growth after treatment discontinuation was assessed in group C and D for additional four weeks. Tumor response was assessed by volume measurements, micro-PET imaging, histopathology and immunoblotting. Moreover genomic alterations in PTEN/PI3K/AKT pathway were evaluated. Results In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cells proliferation but did not induce apoptosis. Under GDC+IMA, profound tumor regression, superior to either treatment alone, was observed. This effect was associated with the best histologic response, a nearly complete proliferation arrest and increased apoptosis. Tumor re-growth assays confirmed superior activity of GDC+IMA over IMA; in three out of six models tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDC+IMA and PTEN loss, both on gene and protein levels, was found. Conclusion GDC+IMA has significant antitumor efficacy in GIST xenografts, inducing more substantial tumor regression, apoptosis and durable effects than IMA. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under IMA. Assessment of PTEN status may represent a useful predictive biomarker for patient selection.

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