Neuro-oncology

Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Interstitial therapy with targeted protein toxins for malignant brain tumors: We are investigating a new approach for the treatment of brain tumors which utilizes a new delivery approach for distribution of a class of potent, targeted anti-cancer compounds, called targeted protein toxins. Preclinical in vitro and in vivo experiments of toxins targeted to the transferrin receptor and epidermal growth factor (EGF) demonstrated significant antitumor activity against a variety of tumor types, including malignant gliomas. New methods of drug delivery have been developed to deliver these agents to brain tumors, and in vivo imaging methods are being developed to demonstrate drug distribution in patients. We completed a phase I trial of regional therapy with a conjugate of human transferrin (Tf) and malignant brain tumors. The results indicated that therapy with Tf-CRM107 produces tumor responses without severe neurologic or systemic toxicity. A multicenter Phase II study has now been finished. The results suggest similar efficacy and toxicity as was observed in the Phase I trial. A multi-institutional Phase III study recently began. The blood-brain barrier (BBB) breakdown that occurs with malignant brain tumors causes brain tumor-associated edema, a major source of morbidity and mortality. Acting through the glucocorticoid receptor (GR), dexamethasone partially restores BBB function, reducing brain tumor-associated edema (BTAE). Although steroids are effective, high doses are required, and their use is associated with debilitating receptor-mediated side effects. We initiated research designed to understand the mechanisms by which dexamethasone interacts with the BBB. Clinically, the goal is to achieve the positive effects of dexamethasone in reducing BTAE while avoiding GR-mediated side-effects. Three lines of investigation are underway. (1) Understanding the potential interaction of dexamethasone with the P-glycoprotein (Pgp) pump. The Pgp pump is the product of the multidrug resistance (MDR1) gene and is a normal BBB component, acting to restrict entry of many drugs into the CNS. Dexamethasone is a substrate for, and potential regulator of, the membrane-bound Pgp pump. The brains of tumor-bearing rats were examined for Pgp expression in control and dexamethasone-treated rats. In control tumors, vessels staining positively for Pgp were diminished in intensity and in number compared to normal brain, whereas in dexamethasone-treated animals Pgp remained detectable in tumor vessels, suggesting induced expression of Pgp in the tumor vessels by dexamethasone. In the brain tumor setting, this could reduce the efficacy of dexamethasone and other therapeutic drugs that are Pgp substrates. Thus, interaction of dexamethasone and Pgp in the brain tumor setting may complicate treatment of this disease. (2) Regulation and function of aquaporin-1 (AQP-1) in gliomas. Aquaporins are a family transmembrane water channels. AQP-1 is absent from normal brain but readily detectable in glioma (but not endothelial) cells both in vivo and in vitro. In human glioblastoma surgical specimens, a striking and selective upregulation of AQP-1 in the tumor cells around blood vessels is observed. This pattern of perivascular expression was suggestive of a role for AQP-1 in BTAE. However, additional investigation of the regulatory patterns of AQP-1 expression in glioma cells in vitro, and of patterns of expression of other related proteins in vivo, have led us to conclude that AQP-1 is upregulated specifically in glioma cells in the perivascular space in response to glycolysis, a preferred metabolic pathway in gliomas. This upregulation of AQP-1 assists the cell in maintaining a healthy intracellular alkaline pH and acidifying the extracellular pH. This provides a favorable environment for tumor invasion and spread along the cerebral vessels. We are currently assessing the feasibility of using AQP-1 as a therapeutic target. (3) A third line of investigation used proteomics to decipher the molecular mechanisms by which dexamethasone regulates blood-brain barrier function in tumor vessels. However, no candidate genes have yet been identified. Understanding the mechanisms by which steroids regulate the BBB in the tumor setting may lead to new drugs that are effective in treating BTAE, but lack the side effects/complications associated with steroid administration. To define the natural history of CNS hemangioblastomas associated with von Hippel-Lindau disease (vHL), and to correlate features of hemangioblastomas associated with development of symptoms and need for treatment, we reviewed serial magnetic resonance (MR)-imaging and clinical histories of 160 consecutive vHL patients with CNS hemangioblastomas. 655 hemangioblastomas were identified in the cerebellum (250), brainstem (64, all in posterior medulla), spinal cord (331, 96% in posterior half of spinal cord), and the supratentorial brain (10). Twenty-one of 29 (72%) symptom-producing cerebellar tumors had an associated cyst. By the time symptoms occurred and surgery was required the cyst was larger than the tumor causing it; cerebellar and brainstem cysts averaged 34-fold and 19-fold the size of their associated tumors at surgery. 95% of symptom-producing spinal hemangioblastomas had associated syringomyelia. Hemangioblastomas frequently demonstrated a growth pattern in which they would enlarge for a period of time followed by a period of arrested growth. By the time symptoms appeared the majority of the mass effect producing symptoms derived from the cyst, rather than the tumor causing the cyst. These tumors often have multiple periods of tumor growth separated by periods of arrested growth and many untreated tumors may remain the same size for several years. These findings should lead to identification of hemangioblastoma properties that predict symptom formation, permitting treatment of smaller tumors, which should reduce the morbidity associated with larger, symptomatic hemangioblastomas. Endolymphatic sac tumors (ELSTs) are rare, locally invasive, neoplasms that are associated with hearing loss, tinnitus, vertigo, aural fullness, and/or facial nerve dysfunction. In vHL, ELSTs frequently occur bilaterally and result in significant neurologic disability, including deafness. To determine the natural history, the mechanisms of early symptom formation, the precise histologic origin, and the optimal timing of treatment of ELSTs, we analyzed the imaging, clinical and surgical findings in vHL patients with ELSTs. We discovered that: morbid hearing loss in vHL patients without imaging evidence of ELSTs may result from a microscopic tumor in the endolymphatic sac or duct; hemorrhage and endolymphatic hydrops underlie the initial symptoms associated with ELSTs; the site of origin of ELSTs is the endolymphatic duct or sac; and the molecular biology of ELSTs, loss of heterozygosity of the vHL gene, supports their clinical association with vHL; early detection permits resection of small ELSTs with functional hearing, which can reduce the incidence and severity of neurologic dysfunction associated with these tumors. Finally, serial MRI of a series of patients with VHL revealed that tisse edema is a precursor to peritumoral cyst formation in the CNS, indicating that the cyst fluid is derived from coalescence of excess extracellular fluid in the region of CNS surrounding the tumor.