Neurooncology is a specialized medical field dedicated to the study and treatment of tumors affecting the brain and spinal cord. While these tumors have historically presented significant challenges, recent years have seen considerable progress in understanding and managing these conditions. Advances across various aspects of care, from initial diagnosis to innovative therapies, offer renewed hope for patients.
Understanding Brain Tumor Biology
Understanding brain tumor biology involves unraveling their intricate genetic and molecular architecture. Researchers analyze specific mutations, gene expressions, and cellular pathways to understand how these tumors develop and progress. For instance, mutations in genes like TP53, a tumor suppressor, are frequently observed in glioblastoma and can activate pathways that promote uncontrolled cell growth, such as the PI3K/AKT pathway. Similarly, alterations or amplifications of the EGFR gene are common in glioblastoma and can drive cell division, tumor invasiveness, and resistance to chemotherapy.
The tumor microenvironment also plays a significant role, influencing how cancer cells behave and respond to treatment. This environment includes various cell types, such as immune cells and astrocytes, which can interact with tumor cells and promote their growth and survival. For example, a hypoxic (low oxygen) environment can activate pathways like HIF1α, which promotes angiogenesis and cell survival within the tumor.
Advancements in Diagnosis
Diagnosis of brain tumors has advanced, with less invasive and more informative techniques. Advanced imaging provides detailed insights into tumor structure and function. Functional MRI (fMRI) measures changes in blood flow to map brain activity, helping surgeons identify and preserve critical brain areas during tumor removal. Positron Emission Tomography (PET) scans detect metabolic parameters, offering a functional view of the tumor that can differentiate it from normal brain tissue.
Advanced diffusion tensor imaging (DTI) visualizes white matter tracts, revealing how tumors affect neural connections and aiding in surgical planning. Liquid biopsies are also emerging as a diagnostic tool. These minimally invasive tests analyze circulating tumor DNA (ctDNA) and RNA found in cerebrospinal fluid (CSF) or blood.
CSF, which surrounds the brain and spinal cord, can contain tumor-derived genetic material, offering a way to monitor tumor changes over time without repeated invasive biopsies. While brain tumor ctDNA does not readily enter the bloodstream due to the blood-brain barrier, CSF provides a more reliable source for detecting these genetic alterations. This approach provides information for diagnosis, molecular profiling, and tracking disease progression, especially for gliomas where traditional tissue biopsies are challenging or risky.
Precision Medicine and Targeted Therapies
Precision medicine in neurooncology involves tailoring treatments to the unique molecular characteristics of a patient’s tumor. This approach targets specific genetic alterations or pathways identified in the tumor, aiming for more effective treatment with fewer side effects than traditional chemotherapy. For example, inhibitors can target mutations in genes such as IDH (Isocitrate Dehydrogenase) and BRAF (v-RAF murine sarcoma viral oncogene homolog B1). IDH inhibitors are being investigated for their role in solid tumors, including gliomas, with promising results in some blood cancers.
BRAF inhibitors, such as vemurafenib and dabrafenib, are selective oral inhibitors that target the BRAF V600E mutation, found in some brain tumors, melanoma, and lung cancer. While many approaches have been developed to target EGFR alterations, including small molecule tyrosine kinase inhibitors like gefitinib and lapatinib, these have not consistently demonstrated improved outcomes in primary brain tumors.
Immunotherapy and Emerging Modalities
Immunotherapy represents a significant advancement, harnessing the body’s own immune system to combat brain tumors. Checkpoint inhibitors block proteins that tumors use to evade immune detection, thereby unleashing the immune system to attack cancer cells. Oncolytic viruses are another innovative approach, where genetically modified viruses selectively infect and destroy cancer cells while also stimulating an anti-tumor immune response. For example, the oncolytic adenovirus DNX-2401 has shown promise in clinical trials for recurrent glioblastoma, with some patients experiencing prolonged survival.
Chimeric antigen receptor (CAR) T-cell therapy involves engineering a patient’s own T-cells to recognize and target specific antigens on tumor cells. While showing success in blood cancers, CAR T-cell therapy faces challenges in solid tumors like brain tumors due to factors such as limited tumor infiltration and the immunosuppressive tumor microenvironment. However, combining oncolytic viruses with CAR T-cell therapy or checkpoint inhibitors is being explored to improve treatment efficacy by creating a more favorable environment for immune cells to attack the tumor.
Other modalities are under investigation. Convection-enhanced delivery (CED) is a drug delivery system that bypasses the blood-brain barrier by continuously infusing therapeutic agents directly into the tumor and surrounding brain tissue. This method allows for high local drug concentrations with minimal systemic side effects, beneficial for large molecules or drugs that do not readily cross the blood-brain barrier. Tumor-treating fields (TTFields) use alternating electrical fields to disrupt cancer cell division, offering a non-invasive treatment option that can be used with other therapies.
Enhancing Conventional Treatments
Conventional treatments like surgery and radiation therapy have seen continuous improvements. In surgical techniques, advancements like awake craniotomy allow surgeons to remove tumors in eloquent brain regions while the patient is awake, enabling real-time mapping of brain function to minimize neurological damage. Intraoperative imaging, including advanced MRI and CT, provides high-resolution images during surgery, helping neurosurgeons assess tumor removal and make necessary adjustments.
Fluorescence-guided surgery (FGS) uses special agents, such as 5-aminolevulinic acid (5-ALA), that accumulate in tumor cells and glow under blue light, allowing for better visualization of tumor margins and more complete resections, particularly in high-grade gliomas. Robotic-assisted surgery is also emerging, offering enhanced precision and control during complex procedures. Precision techniques have significantly improved radiation therapy targeting accuracy. Intensity-modulated radiation therapy (IMRT) and stereotactic radiosurgery (SRS) deliver highly focused radiation doses to the tumor while sparing surrounding healthy brain tissue. Proton therapy, an advanced form of radiation, offers a distinct advantage by delivering most of its radiation dose directly to the tumor with minimal exit dose, further reducing radiation exposure to normal tissues.