Constantinos G. Hadjipanayis

Exciting New Advances in Neuro-Oncology The Avenue to a Cure for Malignant Glioma

Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensity‐modulated or image‐guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence‐guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large‐scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem‐like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike. CA Cancer J Clin 2010;60:166–193.

EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell-containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87DeltaEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED.

Metallic iron nanoparticles for MRI contrast enhancement and local hyperthermia.

Current magnetic-nanoparticle technology is challenging due to the limited magnetic properties of iron oxide nanoparticles (IONPs). Increasing the saturation magnetization of magnetic nanoparticles may permit more effective development of multifunctional agents for simultaneous targeted cell delivery, magnetic resonance imaging (MRI) contrast enhancement, and targeted cancer therapy in the form of local hyperthermia. We describe the synthesis and characterization of novel iron-based nanoparticles (FeNPs) coated with biocompatible bis-carboxyl-terminated poly(ethylene glycol) (cPEG). In comparison to conventional IONPs similar in size (10 nm), FeNPs particles have a much greater magnetization and coercivity based on hysteresis loops from sample magnetometry. Increased magnetization afforded by the FeNPs permits more effective generation of local hyperthermia than IONPs when subjected to an oscillating magnetic field in a safe frequency range. Furthermore, FeNPs have a much stronger shortening effect on T2 relaxation time than IONPs, suggesting that FeNPs may be more effective MRI contrast agents. Next-generation FeNPs with a biocompatible coating may in the future be functionalized with the attachment of peptides specific to cancer cells for imaging and therapy in the form of local hyperthermia.

Brain cancer propagating cells: biology, genetics and targeted therapies

Cancer propagating cells (CPCs) within primary central nervous system (CNS) tumors (glioblastoma multiforme (GBM), medulloblastoma (MB) and ependymoma) might be integral to tumor development and perpetuation. These cells, also known as brain cancer propagating cells (BCPCs), have the ability to self-renew and proliferate. BCPCs can initiate new tumors in mice with high efficiency and these exhibit many features that are characteristic of patients brain tumors. Accumulating evidence suggests that BCPCs might originate from the transformation of neural stem cells (NSCs) and their progenitors. Furthermore, recent studies have shown that NSC surface markers also define BCPCs. Ultimately, treatments that include specific targeting of BCPCs might potentially be more effective at treating the entire tumor mass, translating to improved patient survival and quality of life.

Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy

Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood–brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

Current Dosing Paradigm for Stereotactic Radiosurgery Alone After Surgical Resection of Brain Metastases Needs to Be Optimized for Improved Local Control

PURPOSE To describe the use of radiosurgery (RS) alone to the resection cavity after resection of brain metastases as an alternative to adjuvant whole-brain radiotherapy (WBRT). METHODS AND MATERIALS Sixty-two patients with 64 cavities were treated with linear accelerator-based RS alone to the resection cavity after surgical removal of brain metastases between March 2007 and August 2010. Fifty-two patients (81%) had a gross total resection. Median cavity volume was 8.5 cm(3). Forty-four patients (71%) had a single metastasis. Median marginal and maximum doses were 18 Gy and 20.4 Gy, respectively. Sixty-one cavities (95%) had gross tumor volume to planning target volume expansion of ≥1 mm. RESULTS Six-month and 1-year actuarial local recurrence rates were 14% and 22%, respectively, with a median follow-up period of 9.7 months. Six-month and 1-year actuarial distant brain recurrence, total intracranial recurrence, and freedom from WBRT rates were 31% and 51%, 41% and 63%, and 91% and 74%, respectively. The symptomatic cavity radiation necrosis rate was 8%, with 2 patients (3%) undergoing surgery. Of the 11 local failures, 8 were in-field, 1 was marginal, and 2 were both (defined as in-field if ≥90% of recurrence within the prescription isodose and marginal if ≥90% outside of the prescription isodose). CONCLUSIONS The high rate of in-field cavity failure suggests that geographic misses with highly conformal RS are not a major contributor to local recurrence. The current dosing regimen derived from Radiation Therapy Oncology Group protocol 90-05 should be optimized in this patient population before any direct comparison with WBRT.

Current and future clinical applications for optical imaging of cancer: from intraoperative surgical guidance to cancer screening.

Optical imaging is an inexpensive, fast, and sensitive imaging approach for the noninvasive detection of human cancers in locations that are accessible by an optical imaging device. Light is used to probe cellular and molecular function in the context of cancer in the living body. Recent advances in the development of optical instrumentation make it possible to detect optical signals produced at a tissue depth of several centimeters. The optical signals can be endogenous contrasts that capture the heterogeneity and biological status of different tissues, including tumors, or extrinsic optical contrasts that selectively accumulate in tumors to be imaged after local or systemic delivery. The use of optical imaging is now being applied in the clinic and operating room for the localization and resection of malignant tumors in addition to screening for cancer.

Beyond the World Health Organization grading of infiltrating gliomas: advances in the molecular genetics of glioma classification

BACKGROUND Traditional classification of diffuse infiltrating gliomas (DIGs) as World Health Organization (WHO) grades II-IV is based on histological features of a heterogeneous population of tumors with varying prognoses and treatments. Over the last decade, research efforts have resulted in a better understanding of the molecular basis of glioma formation as well as the genetic alterations commonly identified in diffuse gliomas. METHODS A systematic review of the current literature related to advances in molecular phenotypes, mutations, and genomic analysis of gliomas was carried out using a PubMed search for these key terms. Data was studied and synthesized to generate a comprehensive review of glioma subclassification. RESULTS This new data helps supplement the existing WHO grading scale by subtyping gliomas into specific molecular groups. The emerging molecular profile of diffuse gliomas includes the studies of gene expression and DNA methylation in different glioma subtypes. The discovery of novel mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) provides new biomarkers as points of stratification of gliomas based on prognosis and treatment response. Gliomas that harbor CpG island hypermethylator phenotypes constitute a subtype of glioma with improved survival. The difficulty of classifying oligodendroglial lineage of tumors can be aided with identification of 1p/19q codeletion. Glioblastomas (GBMs) previously described as primary or secondary can now be divided based on gene expression into proneural, mesenchymal, and classical subtypes and the identification of mutations in the promoter region of the telomerase reverse transcriptase (TERTp) have been correlated with poor prognosis in GBMs. CONCLUSIONS Incorporation of new molecular and genomic changes into the existing WHO grading of DIGs may provide better patient prognostication as well as advance the development of patient-specific treatments and clinical trials.

Human Brat Ortholog TRIM3 Is a Tumor Suppressor That Regulates Asymmetric Cell Division in Glioblastoma

Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cells and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures, and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin, and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi-Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division.

Stereotactic Radiosurgery for Well-Circumscribed Fibrillary Grade II Astrocytomas: An Initial Experience

Objective: To examine the role of stereotactic radiosurgery in the management of patients with progressive, well-circumscribed grade II fibrillary astrocytomas. Methods: During a 13-year interval, 12 patients (median age: 25 years) required multimodality management for recurrent or unresectable World Health Organization (WHO) grade II fibrillary astrocytomas. Tumors involved the brainstem (n = 4), thalamus (n = 1), cerebellum (n = 1), frontal lobe (n = 4), temporal lobe (n = 1), and parietal lobe (n = 1). Diagnosis was confirmed by stereotactic biopsy (n = 5), partial resection (n = 5), and near total resection (n = 2). Multimodality management of patients prior to radiosurgery included fractionated radiation therapy (n = 4), stereotactic cyst drainage (n = 1), and ventriculoperitoneal shunt placement (n = 2). Tumor volumes varied from 1.2 to 45.1 cm3. The median radiosurgical dose to the tumor margin was 16 Gy. Results: After radiosurgery, serial imaging showed complete tumor resolution in 1 patient, reduced tumor volume in 4, stable tumor volume in 3, and delayed tumor progression in 4 (3 patients with increase in cyst size only). Therapy after radiosurgery included additional cytoreductive surgery (n = 1) for recurrence of a higher grade tumor, stereotactic cyst aspiration (n = 1), and stereotactic intracavitary irradiation (n = 1). All patients were alive at a median follow-up of 52 months after radiosurgery and 103 months after diagnosis. In 8 patients, follow-up lasted more than 60 months. Conclusion: Stereotactic radiosurgery is a potential alternative or adjunctive strategy in the management of selected patients with WHO grade II fibrillary astrocytomas.