Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Leyton, Julius; Smith, Graham; Lees, Mark; Perumal, Meg; Nguyen, Quang-Dé; Aigbirhio, Franklin I.; Golovko, Oksana; He, Quimin; Workman, Paul; Aboagye, Eric O.

doi:10.1158/1535-7163.mct-08-0264

Cited by 41 publications

(32 citation statements)

References 25 publications

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“…This observation is supported by a past study showing that a oral administration of PD0325901 was shown to suppress tumor growth by inhibition of ERK1/2 activation in HT116 (KRAS mutation) xenograft. 25 These results indicate that decreased ERK1/2 phosphorylation plays an important role in the inhibition of oxaliplatin-induced neuropathy and tumor growth by PD0325901.…”

Section: Discussionmentioning

confidence: 76%

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PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

Tsubaki

Takeda

Tani

et al. 2014

Intl Journal of Cancer

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Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/ extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.Oxaliplatin, a third-generation organoplatinum compound, has become the principal chemotherapy agent used in combination with 5-fluorouracil and leucovorin against colorectal cancer in both adjuvant and palliative therapy.1 However, neuropathy associated with oxaliplatin use is the predominant reason for dose modification, treatment schedule extension and termination of therapy.2 Oxaliplatin induces two different forms of neuropathy.3 A dose-limiting sensory neuropathy occurs at a cumulative dose above 540-850 mg/m 2 and may develop gradually following oxaliplatin treatment. 4A transient, acute syndrome consisting of cold-induced paraesthesia, dysesthesia or pain in the hands, feet, face and perioral regions appears in 80% of patients during the first or second cycle. 4 Current therapeutic options for alleviating neuropathy are mainly limited to drugs approved for other pain conditions, and none of the current agents proven to provide relief. 5 As chemotherapy becomes more effective, the number of cancer survivors is likely to increase, and neuropathy will become an important factor affecting their quality of life. Thus, it is of critical importance to elucidate the mechanism of oxaliplatin-induced neuropathy and consequently develop effective treatment strategies for this debilitating syndrome.Temperature-activated transient receptor potential (TRP) ion channels play important roles in pain sensation. Two particular TRP channels, TRPM8 and TRPA1, have been linked to the sensation of cold. Recently, i...

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Section: Discussionmentioning

confidence: 76%

“…The mice were maintained in a pathogen-free environment at 25 C under controlled lighting (12-hr light/12-hr dark cycle) and allowed free access to water and food pellets.…”

Section: Micementioning

confidence: 99%

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

Tsubaki

Takeda

Tani

et al. 2014

Intl Journal of Cancer

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“…5B). This indicates that D4-FCH can be used to detect treatment response even under conditions where large changes in tumor size reduction are not seen (31). To understand the biomarker changes, we examined the intrinsic cellular effect of PD0325901 on D4-FCH-phosphocholine formation by treating exponentially growing HCT116 cells in culture with PD0325901 for 24 h and measuring the 60 min uptake of D4-FCH in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…Both tumor-bearing (BALB/c nude mice) and non-tumor-bearing (BALB/c mice) animals were used. Human melanoma, SKMEL-28, and human colon, HCT116, tumors were grown in BALB/c nu/nu mice (Harlan) as reported previously (31). Tumor dimensions were measured continuously using a caliper and tumor volumes were calculated by the equation: volume = (p / 6) Â a Â b Â c, where a, b, and c represent three orthogonal axes of the tumor.…”

Section: Radiopharmaceuticalsmentioning

confidence: 99%

[18F]Fluoromethyl-[1,2-2H4]-Choline: A Novel Radiotracer for Imaging Choline Metabolism in Tumors by Positron Emission Tomography

et al. 2009

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18 F]fluoromethylcholine, respectively (P = 0.04). D4-FCH was also found to be a useful response biomarker. Treatment with the mitogenic extracellular kinase inhibitor PD0325901 resulted in a reduction in tumor radiotracer uptake that occurred in parallel with reductions in choline kinase A expression. In conclusion, D4-FCH is a very promising metabolically stable radiotracer for imaging choline metabolism in tumors.

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“…Similarly, Shapiro et al reported that PMR was attained in 6 of 15 (40%) evaluable patients treated with a combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941 in a dose-escalation trial (22). 18 F-fluoro-39-deoxy-39-L-fluorothymidine PET to investigate inhibition of proliferation by the MEK inhibitor PD0325901 has also been investigated (23,24). Although several other studies have confirmed the utility of PET in clinical trials, to our knowledge, this was the first study for which 18 F-FDG PET was used in a systematic and consistent manner over 2 phase I clinical trials with a view to comparing 2 compounds with similar mechanisms of action and guiding the most appropriate dose schedule to take forward into phase II.…”

Section: Discussionmentioning

confidence: 99%

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

et al. 2012

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Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with 18 F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients. Methods: 18 F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mmdiameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellularsignal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds. Results: Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. 18 F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in 18 F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P 5 0.052). Furthermore, a more pronounced relationship was seen between the change in 18 F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. 18 F-FDG was able to identify early nonresponding patients with a 97% negative predictive value. Conclusion: These data exemplify the role of 18 F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment.

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Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Cited by 41 publications

References 25 publications

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

[18F]Fluoromethyl-[1,2-2H4]-Choline: A Novel Radiotracer for Imaging Choline Metabolism in Tumors by Positron Emission Tomography

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

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Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Cited by 41 publications

References 25 publications

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

[18F]Fluoromethyl-[1,2-2H4]-Choline: A Novel Radiotracer for Imaging Choline Metabolism in Tumors by Positron Emission Tomography

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by 18F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

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Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials