Status and Recommendations for Incorporating Biomarkers for Cutaneous Neurofibromas Into Clinical Research

Abstract

Objective: To summarize existing biomarker data for cutaneous neurofibroma (cNF) and to inform the incorporation of biomarkers into clinical trial design for cNFs.

Methods: The cNF working group, a subgroup of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) consortium, was formed to review and inform clinical trial design for cNFs. Between June 2018 and February 2020, the cNF working group performed a review of existing data on genetic biomarkers for cNFs in the setting of neurofibromatosis type 1. We also reviewed criteria for successful biomarker application in the clinic. The group then held a series of meetings to develop a consensus report.

Results: Our systematic literature review of existing data revealed a lack of validated biomarkers for cNFs. In our report, we summarize the existing signaling, genomic, transcriptomic, histopathologic, and proteomic data relevant to cNF. Finally, we make recommendations for incorporating exploratory aims for predictive biomarkers into clinical trials through biobanking samples.

Conclusion: These recommendations are intended to provide both researchers and clinicians with best practices for clinical trial design to aid in the identification of clinically validated biomarkers for cNF.

Figure 1. Diagram of Ras and mTOR Pathways in NF1 and Targeted Intervention With MEK and mTOR Inhibitors

mTOR = mammalian target of rapamycin; NF1 = neurofibromin type 1; PI3K = phosphoinositide 3-kinase.

Figure 2. Activation of the Ras and mTOR Pathways in Human Cutaneous Neurofibromas

Immunohistochemistry demonstrates elevated phospho-ERK1/2 (brown), a downstream kinase of the Ras pathway, and phospho-S6, a ribosomal protein downstream of the mammalian target of rapamycin (mTOR) pathway, in resected human cutaneous neurofibromas.