18 F-FLT-PET for response evaluation of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with solid tumors

Abstract

Selumetinib (AZD6244, ARRY-142886) is a potent, selective, uncompetitive inhibitor of MEK 1 / 2, part of the RAF/MEK/ERK protein kinase signal cascade, which is responsible for tumor. This pilot study was used to explore if 18F-fluoro-l-thymidine (FLT), a thymidine analogue positron emission tomography (PET) tracer and a surrogate marker for proliferation, can be used as an early predictor of response for patients with solid cancers treated with Selumetinib. FLT-PET scans were performed in four patients at baseline and after 2 weeks of treatment with Selumetinib. FLT uptake in tumors was analyzed qualitatively and quantitatively by measuring standard uptake value (SUV) max in regions of interest (ROI). Results were compared to computed tomography (CT) scans (baseline and after 8 weeks), which were evaluated using the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. One patient with melanoma showed both a qualitative and quantitative decrease in FLT uptake associated with a decrease in sum of longest diameter of 12% RECIST on CT evaluation. Another patient who had colorectal carcinoma (CRC) showed a significant increase in FLT uptake with initially stable, but eventually progressive disease on CT. The other two patients (one with melanoma and one with CRC) showed no significant changes in FLT uptake, whereas CT evaluation showed progressive disease. This is the first report describing changes in FLT-PET in patients receiving Selumetinib. In two patients, changes in FLT uptake as early as after 2 weeks of treatment were consistent with CT results after 8 weeks. Biomarkers to predict and evaluate treatment the outcome of targeted therapies are highly warranted. These initial results need further investigation.

FLT-PET for early response evaluation of colorectal cancer patients with liver metastases: a prospective study

“…To the best of our knowledge, to date, the potential of FLT-PET for the early response evaluation of CRC during chemotherapy has been investigated in only three clinical studies with 2, 12 and 18 patients, respectively [17–19]. Just one of these studies used liver metastases as measurable outcome lesions [17], while none of them used the currently preferred treatment regimen, i.e.…”

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

“…98 18 F-FLT PET has not yet been utilized in a trial of a PI3K pathway inhibitor; however, it has been incorporated into a clinical trial of the MEK inhibitor AZD6244 (selumetinib) as a single agent. 105 In this pilot study, 18 F-FLT PET scans were performed in four patients at baseline and after two weeks of treatment with selumetinib. FLT uptake in tumor was compared to CT scans at baseline and eight weeks to evaluate the utility of 18 F-FLT PET as an early predictor of response.…”

“…In two patients, changes in FLT uptake as early as after two weeks of treatment were consistent with CT results after eight weeks. 105 Magnetic resonance spectroscopy. Cancer cells are known to reprogram their metabolism to facilitate tumor growth and survival by alteration of signaling pathways, which lead to alterations in glucose, glutamine, and lipid metabolism.…”

Mechanisms shaping the role of ERK1/2 in cellular sene scence (Review)

“…Extracellular signal-regulated protein kinase (ERK)1/2 is a mitogen-activated protein kinase (MAPK) family protein with typical cascade signaling characteristics and serves an important role in signal transduction pathways and the function of transcription factors, including activator protein-1, proto-oncogene c-Fos (c-Fos) and ETS domain-containing protein Elk-1 (Elk1) (9). The majority of research has focused on its regulatory effect on cell growth and differentiation (10–14); however, a number of previous studies demonstrated that ERK1/2 promotes cell senescence (15–17). Based on these characteristics, numerous small molecule MAPK/ERK kinase (MEK) inhibitors were examined in early-phase clinical trials, including PD098059, U0126, CI-1040, PD0325901 and AZD6244 (18); however, none of them were approved by The Food and Drug Administration due to adverse side effects or other toxic reactions (18).…”