Therapeutic Advances in Neuro-Oncology

In recent years, there have been important advances in understanding the biology and molecular pathogenesis of brain tumors and improvement in their classification. This special issue of Neurotherapeutics focuses on the most recent Therapeutic Advances in Neuro-Oncology. We are very grateful to the international group of experts who have contributed to the outstanding articles.

More than ever, the 2021 WHO Classification of Tumors of the Central Nervous System (CNS) incorporates molecular features into CNS tumor classification [1] and is the subject of the first article by Smith et al. [2]. The upgraded classification for gliomas, in particular, begs the question–how should we think about pathogenesis, treatment, and management in light of these changes? For example, a tumor previously classified as a glioblastoma (GBM) might now be reclassified as glioblastoma, IDH-wildtype or astrocytoma, IDH-mutant, WHO grade 4. Both are aggressive WHO grade 4 gliomas but exhibit very different molecular profiles and tumor drivers, and we may ultimately learn that they should be treated differently. The next two articles focus on updates in the management of IDH-wildtype GBMs (by Melhem et al.) [3] and IDH-mutant gliomas (by Miller) [4]. Medulloblastoma is another aggressive CNS tumor that is now subclassified by its molecular features and is the subject of the next article in this series by Lazow et al. [5]. Rounding out the focus on genetics, Prabhumallikarjun et al. review nervous system tumors arising in cancer predisposition syndromes [6].

We move from primary CNS tumors to secondary CNS tumors with the next two articles, focused on brain metastases (by Singh et al.) [7] and leptomeningeal metastases (by Wilcox et al.) [8]. Historically, CNS metastases were associated with poor prognosis and limited treatment options, mostly comprised of local therapies such as surgery and radiation therapy. However, novel-targeted therapies and immunotherapies with CNS activity have improved the outcomes for a subset of patients with CNS metastases.

The next section focuses on experimental strategies in brain tumors and their potential therapeutic implications. Despite the disappointing studies of immune checkpoint inhibitors as monotherapy in GBM to date [9–11], we remain hopeful of a possible benefit to immunotherapy in the CNS given the success of ipilimumab and nivolumab in melanoma brain metastases [12]. Bunse et al discuss clinical and translational advances in glioma immunotherapy [13] while Shoaf and Desjardins explore oncolytic viral therapy [14]. Increasing evidence points to the role of neuro-glial synapses in driving glioma progression and is the subject of the next article by Yang et al. [15]– better understanding of these brain tumor networks may offer novel therapeutic strategies.

Despite the wealth of preclinical knowledge about CNS tumors, we have made few advances in improving the survival of patients with CNS tumors. Traditional drug development has relied on inefficient methods requiring significant time and effort. Our final two articles ponder ways to improve clinical trial design and response assessment. Saraf et al. [16] discuss the pros and cons of novel clinical trial concepts such as master protocol trials, response-based adaptive randomization, and platform trial infrastructures. Ellingson et al. introduce us to the concept of quantifying therapeutic response using control systems theory [17].