The Future of Neuro-Oncology

Terry Burns
Melanie Hayden-Gephart

The neurosurgery training philosophy upholds high expectations for scholarly activity. We require academic programs to contribute to and train our residents in clinical and basic science research, and for good reason. Many malignant neuro-oncological conditions have remained untreatable, or with only marginal improvement in outcomes, over the last several decades. For pediatric brain tumors, improved survival has been achieved only by accepting the price of permanently stunted cognition from radiation and chemotherapy. Fortunately, both for our patients and our own desire to advance the field of neurosurgery, we practice at a time of exponential growth in neuroscience and cancer biology. Paradigm shifts in the management of malignant brain tumors are on the horizon as monumental advances in core basics sciences are channeled to tackle these devastating conditions. We anticipate that the next half-century of scientific discovery will see unprecedented innovation in both the surgical and adjuvant treatment of malignant brain tumors.

Operative methods will continue to build on recent approach advancements (endoscopic assistance), with trends towards decreased invasiveness (sterotactic guided laser thermal ablation) and decreased morbidity (diffusion tensor imaging for white matter tracks). Augmenting nature’s biodiversity will enable improved surgical accuracy and precision through fluorescent targeting and guided resection of tumors. Chlorotoxin, derived from scorpion venom,<sup>1</sup> and engineered cystineknot peptides (knottins), already employed by nature from spider venom to squash plants,<sup>2</sup> will be modified to further improve intraoperative fluorescent-guided resection of intraparenchymal tumors profiled intraoperatively via mass spectroscopy.<sup>3</sup>

Transport vesicles steered by engineered peptides and nanoparticles will accompany tumor-tropic stem cells as vehicles to shuttle therapeutic payloads specifically across the otherwise impenetrable blood-brain barrier. Consequently, many pharmaceuticals previously unsuitable for CNS malignancies due to systemic toxicity or blockage by the bloodbrain or blood-tumor barrier may prove quite versatile.

In addition to transport facilitation of drugs, we will be able to activate therapy by light (optogenetics), stereotactic radiosurgery, and/ or focused ultrasound. Harnessing nature’s biologic innovation will continue to unveil potential for anti-cancer therapy in the same way that studying bacteria in soil may allow for the development of new antibacterials.<sup>4</sup> The immune system’s innate ability to regulate cells will be tailored to target infiltrating and malignant tumors—for example, by targeting CD47.<sup>5</sup> Although malignant brain tumors take hold in part by subverting brain microglia into tumor-supportive cells, new strategies to reinvigorate microglial function may help the brain defend against diverse diseases ranging from Alzheimer’s disease<sup>6</sup> to glioblastoma.<sup>7</sup>

Genetics has revolutionized the scientific and medical understanding of and approaches to brain tumors. Over the next decades, tumors will be defined not only by their appearance on pathology slides, but also through a routine mutation identification algorithm which will guide operative intervention (outcome-based), medication selection (mutation-specific chemotherapeutics), and radiation (sensitization, timing). This genetic targeting will occur not just at the time of diagnosis but throughout the treatment course through a minimally invasive profiling of the genetic heterogeneity of the malignant brain tumor.

We have already defined the profound heterogeneity of brain tumors at singlecell resolution. Undoubtedly, this innate heterogeneity will contribute to therapeutic failures with molecular therapies—even the “best” single molecular sandbag may not long restrain a heterogeneous flood of tumorinduced alterations. Likely, an upcoming era of molecular polytherapies will be guided by lineage analysis from numerous tumor cells, analyzed on a single-cell basis from each patient. Such tailored molecular cocktails based on a “genome-centric” model will achieve robust effect with minimized side effects by simultaneously targeting (1) upstream initiators of the malignant lineage tree; (2) identified alterations enabling cell-autonomous replication; (3) predicted downstream mutations identified from a vast international database of tumor lineages trees. Indeed, future trials will evaluate the algorithms used to determine the optimal patient-specific cocktails, rather than the individual drugs themselves.

Recent advances in sequencing tumor DNA as circulating tumor markers may make obsolete standard operative procedures such as invasive tumor biopsies. Recently, sequencing fetal-cell-free DNA from a peripheral blood sample of the mother has supplanted amniocentesis to detect Down Syndrome.<sup>8</sup> Similar techniques, applied to tumor-cell-free DNA, have allowed for the tracking of response for treatment of systemic tumors, and brain tumor mutations detectable within cerebral spinal fluid.<sup>9</sup> The application of next-generation sequencing techniques as a research and diagnostic tool will allow for the tracking of brain tumor mutations as they vary with recurrence and progression of disease, suggesting novel therapies and improving outcomes.

While traditional anti-cancer therapies have focused on anti-proliferative therapies of chemotherapy and radiation, the essentially zero percent cure rate for glioblastoma illustrates the failure of this approach. Slowly dividing quiescent tumor stem cells invariably survive to re-initiate the tumor PMID.<sup>10</sup> Recent advances in stem cell biology have yielded important insights and offer great hope for advancing our management of brain tumors.

First, mechanisms regulating stem cell maintenance and quiescence are increasingly understood. While radiation and chemotherapy will serve a diminishing role in the future, their efficacy will be augmented by concomitant use of agents to tumor stem cell quiescence, thereby rendering them susceptible to ablation. Second, as epitomized by induced pluripotent stem (iPS) cells, stem cell maintenance and function are dictated by epigenetic state. While tumor subgroups are already classified in part by their patterns of gene methylation, future therapies will seek to epigenetically reprogram malignant cells in situ to promote non-malignant behavior and enhance response to therapy.<sup>11</sup> Third, tumors fundamentally result from accumulated genetic damage. Enhanced DNA repair mechanisms and telomere maintenance programs are upregulated in stem cells. Epitomizing this fact, germ cells—the “ultimate” stem cells—successfully pass on a pristine genetic code from generation to generation throughout a species’ existence. In the future, mechanisms employed by germ cells to maintain genetic integrity will be harnessed not only to retard the development of additional tumor mutations and heterogeneity, but to forestall the very process of tumorgenesis from endogenous progenitor cells.

Finally, we speculate that a 2065 version of glioma “salvage therapy” will employ highly virulent CNS-tropic self-replicating viruses to simply and unequivocally ablate any and all neuro-ectoderm-derived cells if and whenever they should enter cell cycle. Such an aggressive approach would be a fitting counter to an aggressive disease such as glioblastoma. Although cognitive impacts should result from loss of endogenous neural stem cells and oligodendrocyte progenitor cells, these will be circumvented by either transplant-mediated replacement, in a (i.e., in a manner analogous) manner analogous to bone marrow transplantation, or through regeneration via in situ reprogramming of post-mitotic glia.<sup>12</sup> Critically, such neo-“salvage” approaches will avoid the constellation of premature brain aging, neuro- inflammation, and neurodegenerative-like symptoms induced by the genomic and mitochondrial DNA damage following irradiation and chemotherapy.<sup>13, 14</sup>

The next generations of neurosurgeons will have ever-increasing capacity to safely treat and cure patients with malignant brain tumors. Neurosurgeon-scientists are a critical part of the innovation equation, developing and applying new techniques in collaboration with committed researchers. Our academic commitment in the training of our residents ensures neurosurgeons remain at the center of this conversation for the benefit of our patients and specialty. Modifying nature’s design is just one potential method for applying scientific discovery to advance the field of neuro-oncology.


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