3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition

Solit, David B.; Santos, Elmer; Pratilas, Christine A.; Lobo, Jose; Moroz, Maxim A.; Cai, Sanjun; Blasberg, Ronald; Sebolt–Leopold, Judith S.; Larson, Steven M.; Rosen, Neal

doi:10.1158/0008-5472.can-07-2976

Cited by 56 publications

(45 citation statements)

References 16 publications

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“…Melanoma cells appear to repress cellular markers of the melanocytic lineage via activation of the MAPK pathway (24)(25)(26)(27). To some extent, this might reflect a normal developmental process used by melanocytic precursors for lineage determination.…”

Section: Discussionmentioning

confidence: 99%

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MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

Asundi

Lacap

Clark

et al. 2014

Molecular Cancer Therapeutics

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Therapies targeting the mitogen-activated protein (MAP) kinase pathway in melanoma have produced significant clinical responses; however, duration of response is limited by acquisition of drug resistance. Rational drug combinations may improve outcomes in this setting. We assessed the therapeutic combination of an antibody-drug conjugate (ADC) targeting the endothelin B receptor (EDNRB) with small-molecule inhibitors of the MAP kinase signaling pathway in melanoma. Cell lines and tumor models containing either mutant BRAF or NRAS, or wild-type for both, were exposed to small-molecule inhibitors of BRAF and MEK. Expression of EDNRB was analyzed and the therapeutic impact of combining the anti-EDNRB ADC with the BRAF and MEK inhibitors was assessed. Increased expression of EDNRB in response to inhibition of BRAF and/or MEK was observed and augmented the antitumor activity of the ADC. Enhanced target expression and ADC antitumor activity were realized irrespective of the response of the tumor model to the BRAF or MEK inhibitors alone and could be achieved in melanoma with mutant NRAS, BRAF, or neither mutation. Cells that acquired resistance to BRAF inhibition through long-term culture retained drug-induced elevated levels of EDNRB expression. Expression of EDNRB was not enhanced in normal human melanocytes by inhibition of BRAF and the combination of the ADC with MAPK inhibitors was well-tolerated in mice. The anti-EDNRB ADC combines well with BRAF and MEK inhibitors and could have therapeutic use in the majority of human melanoma cases. Mol Cancer Ther; 13(6); 1599-610. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

“…PMEL17 and EDNRB, are suppressed by MAPK signaling (24)(25)(26)(27). As the expression level of a cell surface target can affect the efficacy of an ADC, we evaluated the suitability of combining the anti-EDNRB ADC with the BRAF inhibitors PLX4032 (28) and G590945 and 2 chemically distinct MEK inhibitors GDC-0973 and GDC-0623.…”

Section: Xenograft Modelsmentioning

confidence: 99%

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

Asundi

Lacap

Clark

et al. 2014

Molecular Cancer Therapeutics

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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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“…However, nonspecific incorporation can be observed in proliferating macrophages in inflammatory lesions [8]. It also appears to predict outcome after chemotherapy [9], radiotherapy [10] as well as progression and overall survival of patients with brain tumors [11]. Moreover, in breast cancer [12] and in high-grade non-Hodgkin's lymphoma [13], early change in [ 18 F]FLT uptake, immediately after initiation of chemotherapy predicts tumor response to treatment.…”

Section: Introductionmentioning

confidence: 99%

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

et al. 2010

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3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition

Cited by 56 publications

References 16 publications

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

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

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

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3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition

Cited by 56 publications

References 16 publications

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

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

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

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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