Targeting Complement 5a-Mediated Immunoregulation for Neurofibroma Therapy

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Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang/Ratner, Nancy Abstract Neurofibromatosis type 1 (NF1) is a common inherited human disorder affecting about 1:2500 individuals worldwide. About half of NF1 patients develop plexiform neurofibromas, benign but devastating peripheral nerve tumors; surgical removal is often impossible due to the integration of tumor in critical peripheral nerves. We found that MEK inhibition shrinks 70% of tumors in DhhCre;Nf1fl/fl neurofibroma-bearing mice. This result in a mouse model predicted success of a phase I/II clinical trial for children with NF1 and large inoperable plexiform neurofibroma, in which MEK inhibition using Selumetinib in showed unprecedented activity, with 70% of patients experiencing sustained partial responses. However, the maximal tumor volume decrease was 50%, and continued MEK inhibition was required for sustained response. Therefore, we searched for genes, proteins, and pathways that are not normalized by MEK inhibition. Based on our promising preliminary data, we will test the therapeutic effects of targeting the one of these, the C5a/C5aR pathway in plexiform neurofibroma. The work proposed in this application will test if C5a is a therapeutic target for plexiform neurofibromas, alone or in combination with MEK inhibition. We will measure PK and PD, and efficacy. Our multidisciplinary team includes world leaders in neurofibroma preclinical testing, an expert in volumetric measurement for neurofibroma, a biostatistician, and experts in the biology of the complement system who developed unique antagonists of C5aR, and NF1 clinicians.