Primary brain cancer and secondary brain tumors that have metastasized from other sites in the body remain devastating diagnoses associated with disproportionately high mortality rates, in spite of intensive research efforts to identify more effective drugs.
While the reasons behind a lack of therapeutic success are multifaceted, a significant challenge is the presence of the cellular blood brain barrier
(BBB) surrounding the brain, which limits effective drug delivery. A lack of understanding and significant misconceptions about the nature of the BBB in cancer as well as exclusion of patients with brain metastases from clinical trials have compounded the failure of promising drugs.
But the stalemate may be on the verge of breaking as an increasing appreciation of the importance of the BBB and technological advancements are allowing researchers to rethink clinical trial and drug design in an effort to improve patient outcomes.
Drug developers are moving forward with scores of new agents that may cross the BBB in several classes of therapy including chemotherapies, molecularly targeted agents, and immunotherapies. More than 20 targeted agents that are believed to penetrate the BBB are in clinical development either for gliomas or for patients with primary cancers that have metastasized to the brain (Table)
.How BBB Blocks Therapy
Patients with brain tumors have an abysmally poor prognosis, with median survival after diagnosis between 4 months and 15 months. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, while secondary metastatic brain tumors are a devastating and increasingly common complication of other primary tumor types. Researchers have estimated that 20% to 40% of newly diagnosed patients with cancer in the United States develop brain metastases annually, which represented more than 650,000 people last year alone. Tumor types commonly associated with brain metastases include melanoma and cancers of the lung, breast, and colon. Brain metastases also can develop in patients with bladder, kidney, and gynecologic malignancies.
Currently available treatment options for both types of brain tumor are similar, involving a combination of surgery, chemotherapy, and radiation therapy. Extensive molecular profiling of tumors has revealed a number of novel targets for therapy but, despite significant promise in preclinical studies of brain cancer and substantial improvement in the treatment of systemic disease, these agents have uniformly failed to translate into the clinic for the treatment of brain tumors.
Brain cancer is notoriously hard to treat for a number of reasons, but one of the most significant challenges is that the brain resides behind a highly restrictive barrier that impedes effective drug delivery. First observed more than a century ago by Nobel laureate Paul Ehrlich and others, the BBB is now understood to be composed of specialized endothelial cells that, in concert with other neurological cell types, line the brain capillaries. The spaces between these cells are sealed with tight junctions forming a continuous monolayer that serves as a physical, metabolic, and immunologic barrier to the brain.
The BBB plays a vital role in tightly controlling the brain environment by protecting it from toxic substances, removing waste products, and providing a delicate balance of essential nutrients, ions, and hormones. An unfortunate consequence is that it also limits drug access to the brain, providing an inadvertent therapeutic sanctuary for neurological diseases, including cancer.
Whether or not a molecule can penetrate the BBB is dependent upon its size and physiochemical profile; nearly all large molecule drugs and up to 98% of small molecule drugs are thought to be prevented from crossing the BBB, and factors including the degree of plasma protein binding, lipophilicity, and charge distribution of the drug affect its ability to reach the brain. The BBB is also lined with transporters and receptors that act as sentries, actively regulating what gets in and what comes out. Even if a drug is able to pass through the BBB unimpeded, its accumulation in the brain may be limited by efflux transporters.New Insights Emerge
Our understanding of the BBB and particularly its impact on drug delivery has evolved considerably in recent years. What has become increasingly clear in the context of cancer is that the BBB itself is actually altered by the presence of tumors in the brain.
One of the hallmarks of cancer is increased angiogenesis (the formation of new blood vessels from existing vasculature), which tumors exploit to increase their blood supply. As a result, the blood vessels surrounding the tumor are highly abnormal, forming a tortuous and tangled mess. In addition, the endothelial cells that make up the BBB in patients with cancer are distinct from normal brain tissue, becoming more porous with increased expression of membrane transporters.