MEK Inhibitors and Other Medical Therapies for Benign Peripheral Nerve Sheath Tumors

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic tumor predisposition condition [1]. It is caused by the haploinsufficiency of the NF1 gene, which results in overactivation of the Ras pathway. As a consequence of this, people with NF1 develop multiple tumor and non-tumor manifestations, including histologically benign, borderline, and malignant peripheral nerve sheath tumors (MPNST). Plexiform neurofibromas (PNF) are histologically benign complex tumors, which can extend across the length of a nerve and involve multiple fascicles and branches. These tumors can result in substantial clinical morbidities, including pain, disfigurement, neurologic and motor dysfunction, as well as airway compromise and vision loss [2, 3]. Surgical management of PNF is challenging, and indications for surgery depend on several considerations. Importantly, complete surgical resection of PNF is frequently not feasible, and regrowth of tumors after surgery has been observed [4]. Therefore, there has been an unmet need for the development of effective medical treatments for PNF. Multiple agents targeting Ras pathway activation in adult cancers including malignant melanoma have been in development, some of which have received regulatory approval [5]. Capitalizing on the availability of Ras pathway targeting agents for other conditions, a series of clinical trials have been performed over the past 20 years with the goal of identifying agents that slow the progression of PNF or cause tumor shrinkage [6]. Recently, selumetinib, an inhibitor of the mitogen-activated protein kinase kinase (MEK) downstream of Ras, has demonstrated clinical benefit for inoperable PNF in children and received regulatory approval in many countries [7, 8]. In this chapter, we review the development of medical treatments for PNF and the current experience with MEK inhibitors (MEKi) for histologically benign NF1 peripheral nerve sheath tumors, and describe considerations for future clinical trials.