Abstract 3517: Changes in plasma components of β-oxidation as a pharmacodynamic (PD) biomarker of PI3K inhibition by GDC-0941, a potent, pan-inhibitor of Class I phosphatidyl-inositol-3-kinase (PI3K).
Authors: Ang Joo Ern , Pandher Rupinder , Asad Yasmin , Henley Alan , Valenti Melanie , Box Gary , de haven Brandon Alexis , Eccles Suzan , Workman Paul , de Bono Johann S. , Raynaud Florence I. 
Published: August 2014

Background: Potent pharmacologic agents that inhibit mediators of the PI3K pathway, such as GDC-0941, show promise in early phase clinical trials and their development could potentially be accelerated by the use of novel, minimally invasive PD biomarkers. We have previously described a consistent exometabolomic signature in preclinical animal models, involving components of β-oxidation, with perturbations of the PI3K pathway [1]. Changes in plasma level of β-oxidation components may therefore have potential as PD biomarkers of PI3K pathway activity.

Methods: Liquid chromatography-mass spectrometry (LC-MS) metabolomic profiling [2] was performed on plasma from PTEN knockout mice, as well as PTEN mutated U87MG xenograft-bearing and non-tumor-bearing NCr athymic mice treated with GDC-0941 or a chemotherapy agent, BCNU. The metabolomic candidate from preclinical studies was then clinically qualified using plasma from patients enrolled in a Phase I dose-escalation trial of GDC-0941 [3] using a targeted, quantitative and analytically-validated LC-MS assay [4]. The β-oxidation state (BOS) was estimated by taking the ratio of the sum of plasma acetylcarnitine and propionylcarnitine over carnitine.

Results: There was a consistent decrease in the BOS with PI3K pathway inhibition in both preclinical models: the median BOS was higher in the PTEN knockout mice (4.3; range 3.8-4.9) compared with wildtype littermates (2.8; 2.6-3.8) (p=0.02), while GDC-0941 treatment resulted in a dose-dependent decrease in the BOS in U87MG-bearing and non-tumor-bearing mice at 24h following administration. By contrast, there was no evidence of a statistically significant change in the BCNU-treated mice (p&gt;0.13).

In the Phase I clinical study, the mean intra-subject baseline variability of BOS was 13% (95%CI 8-18). In 29 patients treated with GDC0941 (7 at &lt;100 mg od; 22 at ≥100 mg od), there was a decrease in the BOS at 8h and 24h post-dose (median relative to baseline 0.57 and 0.66, respectively; p&lt;0.0001) which was dose-dependent (p=0.003). In 15 patients (treated at ≥330 mg od) with plasma samples taken at subsequent time points, the BOS returned to baseline levels following a protocol-mandated one-week off-drug period post-day 1 (day 8 versus day 1; p=0.39). With chronic dosing, the BOS level continued to decrease from day 8 on days 15 and 16 with respective median levels of 0.21, 0.17 and 0.11 (p&lt;0.001), indicating persistence of β-oxidation modulation.

Conclusions: This is the first proof-of-concept clinical qualification of a minimally invasive, potential PD biomarker of PI3K pathway modulation using a plasma metabolite index of β-oxidation. Further validation of this approach is planned.

Citation Format: Joo Ern Ang, Rupinder Pandher, Yasmin Asad, Alan Henley, Melanie Valenti, Gary Box, Alexis de haven Brandon, Suzan Eccles, Paul Workman, Johann S. de Bono, Florence I. Raynaud. Changes in plasma components of β-oxidation as a pharmacodynamic (PD) biomarker of PI3K inhibition by GDC-0941, a potent, pan-inhibitor of Class I phosphatidyl-inositol-3-kinase (PI3K). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3517. doi:10.1158/1538-7445.AM2013-3517