Attacking the Blood-Brain Barrier: New Strategies for Primary and Metastatic Brain Tumors Abound

OncologyLive, July 2015, Volume 16, Issue 7

Drug developers are moving forward with scores of new agents that may cross the blood brain barrier in several classes of therapy including chemotherapies, molecularly targeted agents, and immunotherapies.

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.

These factors are thought to be manipulated by the tumor to allow metastatic tumor cells to invade the BBB and, historically, have led to a misconception that this aberrant, “leaky” barrier should afford improved drug delivery. In reality, these alterations have been found to do quite the opposite: the BBB becomes heterogeneous— leaky in parts and intact in others— leading to inconsistent delivery of therapeutic agents and persistence of the tumor. Thus, efforts to improve drug delivery will have to focus on overcoming both the intact BBB and the pathologically altered blood-brain tumor barrier (BBTB).

Approaching the Blood-Brain Barrier

The blood-brain barrier consists of tightly packed endothelial cells in brain capillaries and astrocytes. Chemotherapy drugs, left, have difficulty penetrating the membrane. Drugs designed to inhibit integrins (protein receptors) and angiogenesis, right, are among the targeted approaches in development.

Illustration by Pam Curry



For many anticancer drugs, less than 10% of the concentration found in the blood reaches the brain. In general, cytotoxic chemotherapies are too large to cross the BBB and have limited efficacy in the treatment of brain tumors.

At the turn of the millennium, temozolomide, a novel alkylating agent, proved to be an exception to that rule by demonstrating the ability to cross the BBB because of its small size and lipophilic properties. In 2005, temozolomide became the first new chemotherapy to be approved for the treatment of high-grade gliomas in more than 20 years.

Nevertheless, the concentration of temozolomide in the central nervous system (CNS) is still only 30% of its plasma concentration. Yet, chemotherapy remains standard of care for patients with this malignancy, reflecting the paucity of new, effective treatment options in the intervening years.

The development of temozolomide highlights one of the main ways in which researchers have attempted to design drugs to breach the BBB. In order to pass through the tight spaces of the BBB unassisted, molecules need to be small and have a high affinity for lipids (lipophilic) to allow lipid-mediated free diffusion.


Molecules predominantly pass across the BBB through transcytosis in which they are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. This process is mediated by electrostatic interactions, transporters (eg, the glucose transporter GLUT1), or receptors (eg, transferrin and low-density lipoprotein receptors). These transport mechanisms can be exploited to create drug delivery systems and, in the case of chemotherapy, nanotechnology is being explored to improve drug delivery across the BBB using strategies such as liposome encapsulation.

The novel agent aldoxorubicin employs circulating albumin to deliver chemotherapy. Aldoxorubicin consists of the anthracycline doxorubicin attached to an acid-sensitive linker that then facilitates binding of the conjugated drug to circulating albumin, which is known to accumulate preferentially in tumors. Early efficacy results in GBM suggest that albumin transports the drug across the BBB, according to CytRx Corporation, which is developing aldoxorubicin. Data presented at 2015 ASCO demonstrate a favorable cardiac safety toxicity profile.


More recently, researchers have been trying to more actively target chemotherapy to the BBB by exploiting transport receptors on the surface of the endothelial cells. Angiochem, a pharmaceutical company based in Quebec, has created a family of peptides known as angiopeps that allow transport across the BBB via LDLR-related protein 1 (LRP1). Their most promising drug candidate is ANG-1005, in which angiopep-2 is conjugated to paclitaxel, allowing targeted delivery of chemotherapy across the BBB.

Despite reports in 2012 that the company had discontinued development of ANG-1005, it is currently being evaluated in phase II trials and results of one ongoing study were recently presented at the 2015 ASCO Annual Meeting. A response assessment performed by fluorothymidine-positron emission tomography (FLT-PET) in the first cycle of treatment showed a reduction of >20% in 15 of 32 metastatic lesions in 10 patients. Responses during additional cycles were subsequently evaluated by magnetic resonance imaging (MRI) only; partial remission (PR) was observed in two patients, which lasted 6 and 18 cycles, respectively, and was ongoing at the time of the conference report.

Crossing the BBB: Selected Targeted Agents in Development (CLICK TO ENLARGE)

aTrial is ongoing but not recruiting participants.

ALK indicates anaplastic lymphoma kinase; BBB, blood-brain barrier; CDK, cyclin-dependent kinase; CNS, central nervous system; EGFR, epidermal growth factor receptor; GBM, glioblastoma multiforme; HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; MEK, mitogen activated protein kinase kinase; mTORC1, mammalian target of rapamycin complex 1; NSCLC, non-small cell lung cancer; PI3K, phosphatidylinositol-3-kinase; RT, radiation therapy; T-DM1, trastuzumab emtansine; TNBC, triple-negative breast cancer; VEGFR, vascular endothelial growth factor receptor; WBRT, whole brain radiation therapy.

Targeted Therapies

Monoclonal Antibodies

HER2-Targeting Agents

With the advent of high-throughput molecular profiling, researchers have identified key pathways that drive the development of both primary and secondary brain tumors and targeted therapies have been developed to inhibit these pathways.

Monoclonal antibodies (mAbs) are believed to be too large to cross the BBB and indeed, the HER2-targeting mAb trastuzumab has shown limited efficacy in the treatment of HER2-positive breast cancer brain metastases. Other HER2-targeting mAbs and the antibody- drug conjugate trastuzumab emtansine (T-DM1) are also assumed not to cross the BBB, though confirmatory data are scarce and a subset analysis of the EMILIA trial of T-DM1 suggested this agent may improve outcomes in patients with a history of CNS metastases.

There are several surgical-based techniques that have been developed for direct drug delivery to the CNS, such as intrathecal administration, and these have been tested with mAbs like trastuzumab, but are limited by their invasive nature.

Small Molecules

Unlike mAbs, a plethora of preclinical studies have suggested that many small molecule inhibitors can cross the BBB, but thus far none have conferred improved survival for patients with primary brain tumors and few have been extensively evaluated in clinical trials including patients with brain metastases. Data have typically been collected from a few case reports and small numbers of studies with limited numbers of patients, since brain metastases have historically been considered exclusion criteria in the vast majority of studies. However, a growing appreciation of the importance of the BBB in impeding even small molecule drug delivery combined with improvements in cellular imaging, permitting clearer examination of BBB penetration, is driving researchers to re-evaluate small molecule inhibitors in randomized clinical trials involving larger numbers of patients with brain metastases.

The most significant research investment has been in patients with breast cancer. Although lung cancer is the most common tumor type to metastasize to the brain, patients with HER2-positive breast cancer also are severely impacted by brain metastases—with up to 15% of patients affected.


The HER2 inhibitor lapatinib showed promise in combination with the chemotherapeutic agent capecitabine in patients with brain metastases in phase II trials. However, recently reported results from the phase III CEREBEL trial, which compared the incidence of CNS metastases in patients treated with this combination to patients treated with trastuzumabcapecitabine, found no difference between the two regimens.


Neratinib was the first HER2-targeted agent to show a statistically significant reduction in the incidence of CNS metastases in the phase II NEfERTT trial. Patients with HER2-positive locally recurrent or metastatic breast cancer treated with a combination of neratinib and paclitaxel experienced a significant decrease in the incidence of CNS metastases compared with those treated with trastuzumab and paclitaxel.

Nevertheless, excitement about the potential for the drug has dimmed due to recent data from the phase III ExteNet study. Treatment with neratinib following trastuzumab/chemotherapy for patients with HER2-positive early breast cancer produced modest increases in the 2-year invasive disease-free survival rate compared with placebo (93.9% vs 91.6%; P = .009), but nearly all patients experienced lowgrade diarrhea.


Buparlisib is a pan-class I phosphatidylinositol- 3-kinase (PI3K) inhibitor that is highly lipophilic and has been shown to cross the BBB. In a phase II study reported at 2015 ASCO, the combination of buparlisib and bevacizumab in patients with relapsed/refractory GBM demonstrated an overall response rate of 32% among 68 patients, with two complete responses (CRs) and 20 PRs, and was well tolerated.


Results from two ongoing phase I trials of Oncothyreon’s novel HER2 inhibitor ONT-380, which crosses the BBB very well, were also reported at ASCO. ONT-380 was combined with either trastuzumab/capecitabine or with T-DM1 in patients with HER2-positive breast cancer with brain metastases. Among 14 evaluable patients across both studies, there was one CR and four PRs, while the remaining nine patients had stable disease. Oncothyreon is planning a phase II study of ONT-380 in combination with capecitabine and trastuzumab.

Additional Agents

In trying to understand why small molecule inhibitors that appear to be able to cross the BBB are ineffective in the treatment of brain tumors, researchers have discovered that these drugs are often substrates for efflux transporters, which rapidly remove them from the brain environment before they can have a significant effect.

As a result, attempts are under way to create targeted therapies with improved physiochemical properties that allow them to cross the BBB and avoid efflux transporters. For the most part, these strategies are in the preclinical stages of development. AZD3759 and GNE-317 are two such drugs and initial clinical trial data for the former were presented at ASCO. To date, four patients with brain metastases have been enrolled in a phase I study of AZD3759 and, of the two participants who were evaluable, one experienced PR and the other stable disease.


The pressing need for new therapies to treat patients with GBM has made the field a fertile ground for exploring immunotherapy as a means to cross the BBB through a variety of approaches, with cancer vaccines as the most advanced strategy in terms of clinical development, according to the Cancer Research Institute.

One notable example is rindopepimut (CDX- 110), a peptide vaccine that generates an immune response against the epidermal growth factor receptor variant (EGFRvIII), which is highly expressed in GBM and is known to promote tumor angiogenesis. In phase II ReACT trial data presented at 2015 ASCO, the combination of rindopepimut plus bevacizumab improved the 6-month PFS rate compared with bevacizumab plus placebo (28% vs 16%) among patients with recurrent EGFRvIII-positive GBM and registered a trend toward a long-term OS benefit. The drug, which is being developed under the FDA’s breakthrough therapy program, is being evaluated in patients with newly diagnosed GBM in the phase III ACT IV, which has completed its enrollment of 745 patients.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.

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