Unsanctifying the sanctuary: challenges and opportunities with brain metastases

Abstract

While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.

18F-FET PET Uptake Characteristics in Patients with Newly Diagnosed and Untreated Brain Metastasis

“…However, the diagnostic performance of this technique is limited regarding the differentiation between primary and secondary intracerebral malignancies, tumor delineation, differentiation of recurrent brain metastasis from posttherapeutic effects, and providing prognostic information in newly diagnosed brain tumors (8,9). Thus, there is an increasing demand for additional imaging options.…”

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

“…37,48,49,52 Magnetic resonance-guided focused ultrasound (MRgFUS) uses acoustic waves in the ultrasound spectrum to transiently raise the temperature or activate molecules at a specific location. This emerging technology is used primarily for thermal ablation of central brain locations, such as for the treatment of essential tremor and Parkinson's disease.…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…Invasive tumor cells that lie beyond the enhancing tumor border in areas protected by the intact BBB limit the efficacy of systemically administered drugs 19,306,307,318 , and locally administered therapeutics do not diffuse well beyond the resection cavity 165,278 . Standard polymeric nanoparticles can provide extended drug release; however, they are immobilized in the complex tumor parenchyma 319,320 and do not spread well within tumors.…”

“…Both primary and metastatic brain tumors carry dismal survival rates 10,19 , and the increasing age of the population in the developed world has created a dramatic increase 20 in the number of people living with age-related neurodegenerative diseases like dementia, Alzheimer's and Parkinson's. Additionally, nearly 20% of the adult population 21 experiences the debilitating effects of a mental illness like obsessivecompulsive disorder or clinical depression each year, generating over $44 billion in lost productivity in the US alone 22 .…”

“…Using this strategy, standard microbubble (MB) contrast agents [14] are first injected intravenously. In the region receiving FUS, the MBs are activated, producing a variety of mechanical, chemical and thermal effects [15][16][17][18] that lead to a transient disruption of tight junction complexes and induction of active transport of agents into the brain parenchyma [19,20]. Small animal studies have demonstrated that the BBB or blood-tumor barrier permeability is increased by MRgFUS [21], improving delivery of therapeutic agents, such as Herceptin and Doxil, as well as treatment outcomes in experimental models of diseases such as glioma and Alzheimer's [22][23][24][25].…”