Milena Guidi

Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies. The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS. In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases.

A successful case of an anaplastic meningioma treated with chemotherapy for soft tissue sarcomas

Malignant meningioma has a bad prognosis. Surgery and radiotherapy are the most effective therapeutic options, without an established role for chemotherapy. We report a case of 2-year-old male child with diagnosis of postoperative relapse of a malignant meningioma. Considering the rapid progression, the young age and the lack of effective therapeutic alternatives, the patient underwent multidisciplinary anticancer treatment with a protocol made for soft tissue sarcomas (EpSSG NRSSTS 2005 protocol), with positive outcome. This case represents a successful management of an anaplastic meningioma with a multimodal treatment, including chemotherapy, in a pediatric patient.

Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too.