Precision Medicine in Neurosurgery

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

Precision medicine in cancer has led to significant advances in cancer research. As we look to the future, improving technologies for molecular analyses, drug delivery, intraoperative guidance, and others will continue to expand the scope of precision medicine.
So far, applications in precision medicine have been limited in neurosurgery, but there is significant potential for use across neurosurgical specialties, including cerebrovascular neurosurgery, trauma, functional neurosurgery, epilepsy, and pediatrics.
Precision medicine in neurosurgery is both feasible and useful in the clinical setting, as highlighted by the example of its use in pediatric neuro-oncology.

Introduction

Although there has been a renewed wave of interest in personalized medicine, it is and has always been an integral part of the practice of neurological surgery. All neurosurgical cases may be considered personalized because the surgeon must consider the individual nuances of each case and must understand each patient’s unique anatomy. This may also be said of physicians in general, given the evaluation, counseling, and care for patients as individuals. However, with the improvement and development of new technologies, personalized and precision medicine have the potential to augment this and to improve treatments.

In 2016 President Obama instituted the $215 million dollar Precision Medicine Initiative, which included $130 million for the National Institutes of Health to form and study an “All of Us” voluntary national research cohort; $70 million for the National Cancer Institute to identify genomic drivers and target them in cancer treatment; $10 million for the US Food and Drug Administration (FDA) to create databases; and $5 million for the Office of the National Coordinator for Health Information Technology to support privacy and secure exchange of data. Here, precision medicine refers to the more general approach of creating more granular classifications of disease to which therapies can be targeted, rather than targeting individual patient alterations. Although this investment is focused on genomics and cancer, these techniques can be applied to many areas of neurosurgery. Furthermore, the resulting information and technologies can also be used to drive progress in personalized neurosurgical approaches in addition to the current standard of care. In this chapter, we will review the roots of precision medicine in oncology, examine applications across various neurosurgical specialties, then use precision medicine in pediatric neuro-oncology as a model for clinical integration.

Cancer

Ever since the discovery of DNA, there has been an allure to unlocking the secrets of the human genome. With the completion of the Human Genome Project in 2003 and the closely following 50,000-fold drop in sequencing cost, the possibility seems closer than ever, but also farther, owing to increasing recognition of its multifactorial etiology. Behind this dramatic price drop was the invention of next-generation sequencing (NGS). NGS, or massively parallel sequencing, works by sequencing many short reads using polymerase chain reaction (PCR)–based amplification in parallel, followed by alignment to a reference genome.

One major area of promise for whole-genome and whole-exome sequencing is its applications in cancer. Because cancer tends to be extremely heterogeneous between individuals and within the tumor itself, understanding its unique features is critical to successful therapy and improving outcomes. Furthermore, because samples are often accessible during resection or biopsy, molecular profiling is becoming more routine. In some cases, understanding underlying genetic alterations, such as the BCR-ABL fusion, has led to resounding success (e.g., the development of imatinib for chronic myelogenous leukemia). In neuro-oncology, there have been promising results from inhibition of BRAF ^V600E (and other targeted therapies) in BRAF ^V600E -mutant gliomas. ^, Unfortunately, targeting one lesion is rarely enough owing to tumor evolution. ^, For more about molecular biology and genomics, see Chapter 61 .

Beyond the genetic level, there are often interacting alterations at the epigenetic (epigenome), transcriptional (transcriptome), protein (proteome), posttranslational (e.g., phosphoproteome), protein-protein (interactome), and chemical (metabolome) levels. There are also complex interactions within the tumor microenvironment, including those with infiltrating myeloid cells, lymphocytes, vasculature, and stroma, as well as with systemic factors, such as the immune system and the gut microbiome. This interplay between tumor-intrinsic and tumor-extrinsic factors is critically important, particularly with an increasing focus on the design and application of immunotherapies for cancer. ^, Nevertheless, with the rapidly progressing pace of technology, we are also making progress in understanding these factors.

Clinical Application

Although NGS has led to significant advances in research, it is still emerging in its clinical applications. Comprehensive profiling remains expensive on an individual level, and analysis remains resource intensive and lacking in standardization. Some centers have reported promising results from NGS approaches, ^, but often the equipment, personnel, and training requirements preclude this for small centers, even when limited to one technology. Furthermore, there is still a significant lack in the areas of clinical research, infrastructure, and insurance coverage, which are necessary for expansion. As these issues are slowly resolved and technologies continue to improve and decrease in cost, we expect increasing adoption to occur.

Currently, more accessible options include Sanger sequencing and microarrays. Sanger sequencing is the “first-generation” sequencing technology that preceded NGS and was used to complete the Human Genome Project. It uses chain termination to quickly provide a high-fidelity sequence of small regions, although it requires high variant allele frequency for detection and does not provide information about copy number. It is best used for identifying de novo alterations in known genes. Meanwhile, microarrays can be used to detect selected panel of alterations and are often commonly used for precision medicine clinically. This is a reasonable approach at this time and has the benefit of translating research findings using NGS to the clinic at a lower cost.

To expand the therapeutic repertoire, several clinical trials have been designed with new strategies, such as the “umbrella” or “basket” strategies. Umbrella trials test multiple targeted therapies within tumor types; basket trials test one targeted therapy against a particular alteration across tumor types. The phase 2 NCI-MATCH clinical trial is currently recruiting patients across many cancers, including glioma, to examine whether a panel of drugs will benefit patients with certain genetic abnormalities. Trials with “ n -of-1” methodology have also been proposed and performed, though there is dissention over the validity of the method. New and rigorous trial designs are needed to accelerate progress for the newly stratified populations.

Drug Discovery and Selection

In line with the reasoning behind precision medicine clinical trials, recently the FDA has begun approving drugs for specific alterations, rather than tumor types, including pembrolizumab for cancers that have a high level of microsatellite instability or are mismatch repair deficient and larotrectinib for cancers with TRK fusion. Precision medicine has also changed drug discovery by making identifying putative targets relatively inconsequential. Combined with improving capabilities for synthesizing new antibodies and small-molecule inhibitors against these targets, targeting specific alterations is becoming increasingly accessible. Correlations between gene expression and polymorphisms with response to drugs may also facilitate treatment selection for individual patients when there are multiple options. The bottleneck has shifted from finding targets to validating their biologic significance. This is partially addressed by personalized drug screens, in which patient tumor models, such as organoids, humanized mouse models, or neural systems on a chip, are exposed to a panel of drugs to determine what therapies might work best.

Nanoparticles and Drug Delivery

Even when a targeted therapy is successfully identified, a significant challenge in treating central nervous system (CNS) malignancies is the problem of drug delivery across the blood-brain barrier. To counter this, nanoparticles have been developed, including liposomes, nanoparticle albumin-bound technology, polymeric nanoparticles, magnetic nanoparticles, and molecular-targeted nanoparticles. They may accumulate by means of the enhanced permeability and retention (EPR) effect, whereby large molecules accumulate in the tumor microenvironment owing to abnormal vasculature and reduced lymphatic drainage, but generally require further targeting for intracellular uptake. For example, polymeric nanoparticles have been developed to recognize platelet-derived growth factor receptor β (PDGFR-β) on glioblastoma cells and deliver dactolisib.

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