Review ArticleR
Open Access

The Blood–Brain Barrier Challenge for the Treatment of Brain Cancer, Secondary Brain Metastases, and Neurological Diseases

ULRICH H. WEIDLE, JENS NIEWÖHNER and GEORG TIEFENTHALER
Cancer Genomics & Proteomics July 2015, 12 (4) 167-177;

Abstract

Formation of metastases from various tumor entities in the brain is a major problem for the treatment of advanced cancer. We describe target molecules and tools for the delivery of small molecules or proteins across the blood–brain barrier (BBB), and the treatment of brain tumors and metastases with antibody-related moieties. In addition, drugs preventing formation of metastases or interfering with the growth of established metastases are described, as well as pre-clinical metastasis models and corresponding clinical data. Furthermore, we discuss the delivery of effector proteins and antibody-based moieties fused with an antibody-based scaffold across the BBB in several model systems which might be applicable for the treatment of brain metastases.

Although some primary brain tumors such as glioblastoma are associated with a dismal prognosis (1), metastatic lesions originating from various primary tumors outside the brain are in fact responsible for 90% of cancer deaths from brain malignancies (2). Thus, primary brain tumors such as glioblastoma mainly act through local invasive growth and rarely metastasize to organs outside of the brain, whereas many peripheral tumors, such as pancreatic carcinoma or small cell lung carcinoma (SCLC), have usually metastasized to distant organs before diagnosis (1, 3). Moreover, while metastases derived from certain types of tumors such as SCLC colonize various distant organs, others exhibit a pronounced organ-specific tropism of metastasis (3-7). Prostate cancer preferentially metastasizes to the bones, colon cancer to the liver, and sarcoma to the lungs (4). Importantly, distant brain metastases most commonly arise from primary tumors of the lung (50-60%), breast (15-20%), melanoma (5-10%) and the gastrointestinal tract (4-6%) (8, 9). The incidence of such brain metastasis is estimated to be approximately 170,000/year in the USA, 10-times the number of primary brain tumors (10). Accordingly, successful treatment of primary brain tumors and brain metastases poses a major medical problem which almost certainly will be significantly affected once efficient and reliable delivery of drugs into the brain become available.

The Blood–Brain Barrier (BBB)

The BBB is a highly selective barrier regulating the uncontrolled diffusion of most molecules into the brain. Thus, tissue homeostasis is maintained by enabling the transport of selected substances necessary for the brain, while access to the brain is blocked for most other molecules, most notably for toxic metabolites and xenobiotics (11). Thus, for a small molecule, free diffusion across the BBB requires both lipophilicity and a molecular mass smaller than 400-500 Da (12, 13). Most large molecules such as immunoglobulins, however, are not allowed to cross the BBB unless transported actively into the brain. On the other hand, due to the presence of neonatal fragment crystallizable region (Fc) receptors (FcRn) and other clearance mechanisms, IgG antibodies are actively transported from the brain into the circulation (14). In patients with brain tumors, leakiness of the BBB has been observed (15). The complete surface area of the BBB comprises approximately 20 m2, with a total length of capillaries in the brain of approximately 600,000 m (11). The pivotal component of the BBB (Figure 1) is a monolayer of endothelial cells in brain capillaries which are connected by tight junctions (TJ). Absence of fenestration also contributes to the barrier properties of brain endothelial cells. In addition, pericytes, astrocytes and neurons are involved in controlling permeability and other functions of the BBB (11-13, 16-17). The TJ between endothelial cells are composed of proteins such as occludins, claudins and junctional adhesion molecules. The endothelial cells are also covered by a specialized extracellular matrix and the basement membrane which is composed of collagen (particularly type IV), fibronectin, laminin, tenascin and proteoglycans.

Three classes of transport systems have been identified in the BBB: receptor mediated transport (RMT), carrier-mediated transport (CMT), and active efflux transport (AET) (11). RMT is based on endocytosis at the luminal (blood) side, intracellular transport, and exocytosis at the abluminal (brain) side of the endothelium. RMT allows large molecules such as proteins to be transported, thus being potentially useful for the specific delivery of anti-tumor protein therapeutics into the brain. Examples for receptors involved in RMT are transferrin receptor (TfR), insulin receptor (IR), leptin receptor, and lipoprotein-related protein-1 and -2 receptors (18, 19). CMT is mediated by members of the solute carrier (SLC) receptor family (20). This system is involved in the transport of specific substrates such as amino acids, sugars, organic anions and cations, metabolites, nutrients and neurotransmitters. Finally, AET is an ATP-dependent mechanism responsible for the transport of compounds from the brain into the circulation and is mediated by multidrug resistance protein1 (ABCB1) (21), breast cancer resistance protein (ABCG2) (22) and the multidrug resistance-associated protein (ABCC1) (23) family of proteins. For example, ABCB1 is involved in the resistance of central nervous system (CNS) tumors to treatment with paclitaxel and anthracyclines (21). ABCG2 substrates are mitoxantrone, topotecan, methotrexate and sulfated conjugates (22). ABCC1 family members are efflux pumps and capable of transporting structurally diverse lipophilic drugs such as anthracyclins, vinca alkaloids, methotrexate and camptothecins (23).

General Remarks on Drug Delivery Across the BBB

In the following, we focus on the delivery of drugs across the BBB; we do not discuss direct delivery of drugs into the CNS such as intracerebral administration (intrathecal or intraventricular), or convection-enhanced distribution. We cover delivery of small-molecule and protein therapeutics both via targeted and non-targeted approaches. With regard to targeted approaches, we focus on receptor-mediated endocytosis of protein therapeutics. Delivery of other moieties such as liposomes, dendrimers, quantum dots, nanoparticles and micelles using internalizing antibodies (24) are not the focus of this review. Similarly, exosome-mediated delivery (25), localized exposure to high-density focused ultrasound, use of vasoactive compounds such as bradykinin, blockage of active efflux transporters, modulation of tight junctions by enterotoxins (26) and cationisation of drugs (27) are not discussed.

Animal Models of Brain Metastasis

In animal models of brain metastasis, tumor cells were shown to leave the blood vessels, migrate along those vessels, and interact with the inflamed microenvironment of the brain, thus establishing micrometastases. In addition, communication with activated microglia and astrocytes was observed. Once established tumors have formed, angiogenesis can be initiated by vessel cooption, but also dormant solitary tumors were observed to reside within the brain (28-30). Accordingly, numerous animal models for brain metastasis have been established based on syngeneic rodent models, human rodent xenograft models, both ectopic and orthotopic, and orthotopic genetically modified mouse models. In some cases, variants of tumor cell lines prone to form metastases were established by repeated in vivo passages and selection for brain tropism (31). In addition, intracardiac, intracarotid, or orthotopic inoculation are possible means of establishing experimental brain metastases (31-36). For example, triple-negative breast cancer cell lines such as MDA-MB-231, 4T1 and CN34 were selected for brain tropism of metastasis (37-39). Similarly, human epidermal growth factor receptor-2 (HER2)-transfected 231-BR cells, a metastatic cell line derived from MDA-MB-231, have a 2.5- to 3-fold greater potential to form brain metastases than the non-transfected parental cell line (40, 41).

Three types of microenvironment allowing the generation of brain metastases have been identified: the perivascular niche, the brain parenchyma, and the cerebrospinal fluid (CSF) or leptomeningeal niche, which is the microenvironment containing the CSF and the lining of the brain (42). Using transcriptional profiling of CN34 and MDA-MB-231 breast cancer cells, cyclo-oxygenase 2, epidermal growth factor receptor (EGFR) ligand, heparin-binding epidermal growth factor and α-2,6 sialyltransferase (STGALNAC5) were identified and validated as mediators for cancer cell passage through the BBB (43). The functional role of STGALNAC5 in brain metastasis was verified using BBB trans-migration assays and short-hairpin RNAs (37). Importantly, STGALNAC5 underscores the role of protein and, as a consequence, cell surface glycosylation in organ-specific metastatic interactions through cooption of an enzyme which is normally expressed in the brain. EGFR ligands and cyclo-oxygenase 2 were previously linked to breast cancer infiltration of the lungs, but not the bones or the liver (44, 45). RNA analysis of the metastasis-forming cell line 231-BR indicated down-regulation of several metastasis-suppressor genes and up-regulation of hexokinase 2, and correlation of hexokinase 2 up-regulation with poor prognosis and its possible value as a therapeutic target (45).

Other pre-clinical models were used to identify additional signaling pathways and components important for brain metastasis formation from primary breast cancer such as up-regulation of cysteine X cysteine (CXC) chemokine receptor 4/CXC chemokine ligand 12 (CXCL 12), vascular endothelial growth factor (VEGF), Notch, and phosphatidyl-inositol-3-kinase (46-48). Similarly, overexpression of transforming growth factor-β2 in B16 melanoma cells induced formation of metastases in brain parenchyma, while no impact on leptomingeal metastasis formation was observed (49). Transfection of A375 melanoma cells possessing a brain tropism due to a signal transducer and activator of transcription 3 expression vector also increased the incidence of brain metastases, which was linked to decreased expression of suppressor of cytokine signaling (50).

Figure 1.
Figure 1.

Schematic representation of the blood–brain barrier. The interaction of brain endothelial cells (BEC) with astrocytes and pericytes is shown.

Many therapeutic compounds have been evaluated in models of metastasis with brain tropism. End-points were usually either the prevention of the development of metastases, or shrinkage or stabilization of already established metastases (39). The 231-BR breast cancer model was used to identify critical factors regarding the treatment of brain metastases (38). For example, variable penetration of paclitaxel into 231-BR-derived brain metastases was observed. Unrestricted uptake of radiolabeled drug was seen in 10% of the lesions (≥50-fold higher than in normal brain), 14% of the lesions showed drug uptake as in normal brain tissue, and the remainder of the lesions fell in between these extremes. Not surprisingly, tumor cell death was observed only in 10% of metastases with the highest paclitaxel penetration (38). Similar observations were made for lapatinib. Here, 17% of the lesions were freely accessible while the others behaved like normal brain (38). Thus, mice bearing 231-BR tumors which were injected with lapatinib 5 days after tumor inoculation showed a 54% reduction of large metastases 24 days after the start of treatment which corresponded with reduced HER2 phosphorylation (41). Similarly, again using the 231-BR model, vorinostat (suberoylanilide hydroxamic acid), a BBB-permeating histone-deacetylase inhibitor, prevented formation of micrometastases (28%) and large metastases (62%) when the administration was started 3 days after tumor cell inoculation (51, 52). In some pre-clinical models, VEGF was shown to promote the formation of brain metastases, and treatment with anti-angiogenic agents led to reduction in metastatic outgrowth (28, 53). In additional pre-clinical models, inhibition of VEGF receptor 2 allowed for a critical period of blood flow normalization which optimally potentiated the therapeutic effect (54, 55). However, while treatment of Mel 57 melanoma-derived brain metastases with the VEGF receptor inhibitor ZD 6474 resulted in initial growth inhibition, this was followed by the formation multiple proangiogenic lesions which sustained tumor progression (56). Finally, using an orthotopic BT474 brain metastasis model, the combination of monoclonal antibodies against HER2 and VEGF resulted in reduced microvascular density and increased necrosis in brain lesions, and improved survival in comparison to treatment with the single agents (57).

Treatment of Brain Tumors and Brain Metastases with Small Molecules in the Clinic

The mainstay of treatment of primary brain tumors and brain metastases is surgery and radiation therapy, albeit with limited therapeutic benefit (58, 59). In addition, cytotoxic/ cytostatic agents with good CNS penetration are temozolomide, irinotecan, topotecan, procarbazine and carboplatin. Out of these, temozolomide is an approved agent for the treatment of astrocytoma and glioblastoma, whereas the clinical efficacy of other agents for treatment of brain tumors and metastases is still under investigation (59). In order to facilitate BBB passage, ANG 1005, a novel derivative of paclitaxel, was conjugated to a peptide vector (Angiopep-2) and is currently being evaluated in clinical trials (60). Interestingly, it was shown that non-SCLC-derived brain metastases express increased levels of EGF and phosphorylated EGFR compared to primary tumors from these patients (61). Thus, erlotinib, gefitinib and afatinib, which are EGFR inhibitors for the treatment of non-SCLC with activating EGFR mutations, are being evaluated in nine clinical trials for treatment of non-SCLC-derived brain metastases, with gefitinib and lapatinib as single agents, or in combination with temozolomide or whole-body irradiation. Here, there are promising hints of efficacy, which are yet to be confirmed in randomized clinical studies (61). The echinoderm microtubule-associated-protein-like 4/anaplastic lymphoma kinase (EML4–ALK) translocation which leads to constitutive activation of ALK has been identified in 3-5% of non-SCLC. There is evidence that the ALK-inhibitor crizotinib inhibits brain metastases. However, crizotinib is a substrate for drug efflux pumps and newer compounds might have a better efficacy profile (62-64).

Brain metastases are frequent in patients with malignant melanoma and are a common cause of death (65). Here, hyperactivation of rapidly accelerated fibrosarcoma (RAF) signaling is often observed (66). In clinical studies with a small number of patients, B-RAF inhibitors such as dabrafenib induced shrinkage of brain metastases or led to complete responses (67, 68). Unfortunately, however, these promising phase I results could not be reproduced in a prospective open-labeled phase II study in patients with untreated progressive melanoma-derived brain metastases. Overall, disease control in patients with B-RAF inhibitors was 72%, but complete responses were rare (69). It will be interesting to see whether ipilimumab can overcome immune tolerance of brain metastases after immune activation by cytotoxic T-lymphocyte antigen-4 blockade (70).

CNS metastases are quite common in patients with HER2-positive or triple-negative breast cancer. In fact, 30-55% of patients with HER2-positive breast cancer will develop brain metastases (71-74). Small-molecule HER2 inhibitors, such as papazanib, lapatinib, neratinib, afatinib and ARRY-380, are under investigation in patients with progressive CNS metastasis (67). Other agents under clinical evaluation in the control of breast cancer metastases are poly ADP-ribose polymerase inhibitors (such as olaparib, iniparib and veliparib), vorinostat, mammalian target of rapamycin inhibitor everolimus and phosphatidyl-inositol-3-kinase inhibitor BK 120 (67). Finally, brain metastases were visualized with 89Zr-labeled trastuzumab, indicating that at least to some extent this antibody can pass the BBB (75).

Treatment of Brain Tumors and Brain Metastases with Antibody-derived Moieties

Disruption of the BBB and change of composition of the extracellular matrix by CNS tumors is well-demonstrated (13). Accordingly, in patients with brain tumors, the BBB is leaky at the tumor center. The endothelium of blood vessels feeding the proliferating edge of the tumor and the surrounding brain tissue, however, is not compromised in its function and is as impermeable as an intact BBB (76). Thus, only 0.1-0.2% of administered therapeutic antibodies cross the BBB, enter the CSF, and are found in the brain at steady-state concentrations (77-79). Penetration of the BBB by antibodies can also be facilitated by cell-mediated immune responses leading e.g. to paraneoplastic neurological disorders in a fraction of patients with SCLC-derived brain metastases based on an immune response against autoantigen HuD protein shared by SCLC and neurons (80). In this respect, approval of bevacizumab for treatment of recurrent glioblastoma is a milestone for antibody-based treatment of brain tumors (13). In addition, bevacizumab therapy is currently being evaluated for the treatment of newly diagnosed glioblastoma, CNS lymphoma and secondary cerebral metastases derived from glioblastoma (13). However, regarding its mode of action, one should be aware of the fact that bevacizumab probably does not have to cross the BBB to function because of its ability to neutralize VEGF in the lumen of the capillaries of blood vessels in the brain (13). In general, however, the problem of limited CNS accessibility for antibody-derived therapeutics has to be solved in order to allow a more widespread use against brain tumors and metastases. These issues are presently being addressed in numerous pre-clinical and clinical investigations, targeting molecules such as EGFR, EGFR variant III (EGFRvIII), HER2 and tenascin C (81-86). In that respect, recent clinical studies have shown that brain metastases may be responsive to immunomodulatory treatment. Thus, ipilimumab, a cytotoxic T-lymphocyte antigen-4-based immune-checkpoint modulator, was evaluated in a clinical trial that enrolled both steroid-naïve and steroid-treated patients with melanoma and brain metastases (87). Partial responses were observed in patients of both cohorts. Occasional follow-up responses at distant sites were observed after treatment with ipilimumab and radiation. This phenomenon is referred to as the abscopal effect and a possible explanation is the unmasking of tumor antigens by radiation at local and distant sites, and the subsequent induction of an immune response (88, 89).

Receptor-mediated Drug Delivery Across the BBB

In order to improve the efficacy of delivery of potential protein-based therapeutic molecules across the BBB into brain tumors and metastases, several target molecules expressed on endothelial cells of the BBB and corresponding antibodies as delivery vehicles were examined. Such brain-delivery is based on receptor-mediated transcytosis, and the underlying principle is referred to as a molecular Trojan horse (MTH) strategy (90, 91). For example, the TfR is highly expressed in endothelial cells of the BBB (92), and is a recycling receptor which is internalized into clathrin-coated pits, independent of transferrin (92). TfR cycling is rapid and occurs within minutes and shuttles cargos from the lumen of the blood vessels into the brain parenchyma. Proof-of-concept experiments for brain delivery of TfR-specific antibodies were conducted with antibody OX26, a mouse mAb directed against rat TfR (93-95). The OX26 binding site on TfR is different from the Tf-binding site and therefore does not interfere with iron transport. Similarly, mouse TfR-specific antibodies 8D3 and R17-217 were isolated (96, 97). 8D3 conjugated to radiolabeled Aβ was used to visualize and quantify β-amyloid plaques in a mouse model of Alzheimer's disease (97). In an in vitro test using human brain capillaries, the most potent MTH was an antibody directed against the human IR (98). Similarly, in in vivo studies in mice, a genetically-engineered mouse–rat chimeric monoclonal antibody against the mouse TfR referred to as cTfRmAb was used successfully (99). In addition, ligands of low-density receptor related protein-1 and -2, receptor-related protein, apolipoprotein E and melanotransferrin/p97 were evaluated for delivery of paclitaxel or adriamycin in preclinical models (100-103). However, brain-specific drug delivery via lipoprotein-related proteins has not been shown yet and probably would require their higher expression on endothelial cells. Finally, the 15-kDa single domain antibodies FC5 and FC44 (104), derived from camelid phage libraries, enable receptor-mediated endocytosis of antibody–antigen complexes at the luminal side of brain endothelial cells (105, 106). The target of FC5 was identified as cell-division cycle 50A (106). However, the short plasma half-life of 10 minutes of these molecules is a critical issue.

Figure 2.
Figure 2.

Antibody-based moieties for delivery to the brain. A: Monoclonal antibodies (mAb) directed against the transferrin receptor (TfR) or human insulin receptor (hIR) fused to protein-based payloads. Possible payloads: Glial cell line-derived neurotrophic factor (GDNF), erythropoietin (EPO), brain-derived neurotrophic factor (BDNF), α-L iduronidase (IDUA) and single-chain Fv anti-Aβ mAb (scFv-Aβ). B: Bispecific antibody directed against TfR and β-site amyloid precursor protein cleaving enzyme (BACE1). C: Antibody directed against Aβ fused with a Fab fragment directed against the TfR. Protein payloads are shown in brown, antibody constant regions in grey, anti-TfR or anti-hIR variable regions or Fab fragments, anti-BACE1 variable regions and anti-Aβ variable regions are shown in pink, blue and green, respectively.

Figure 3.
Figure 3.

Cellular routing of antibody–antibody fusion proteins in brain endothelial cells. A: Antibody directed against amyloid Aβ fused to two Fab-fragments (dFabs) against the transferrin receptor (TfR). B: Antibody directed against amyloid Aβ fused to a single Fab (sFab) fragment against TfR. The white circles represent endosomes, TfR is shown by blue pentagons, V regions of the anti-Aβ monoclonal antibody are shown in green, constant antibody regions in grey and TfR-Fab moieties are shown in red.

Antibody–Effector Protein Fusions as Therapeutic Agents in Pre-clinical Models

Recombinant fusion proteins can be engineered for brain penetration by fusing an antibody directed against an endogenous BBB receptor such as IR or TfR to a therapeutic effector protein (97) (Figure 2A). Here, the targeting antibody acts as an MTH to ferry the effector moiety into the brain. An earlier version of this technology was based on affinity-mediated coupling of antibodies and effector proteins via the biotin-avidin technology (97). These approaches are also to be preferred, because general BBB disruption leads to chronic neuropathological changes and therefore cannot widely be used in humans (107, 108). In the newer versions of delivery molecules, the respective effector moiety can be fused either to the N- or to the C-terminus of the heavy chain of the BBB-targeting antibody and usually does not interfere with its target binding or other biological functions. For example, 2-3% of brain uptake at steady-state levels of fusion proteins between cTfRmAb and glial cell-derived neurotrophic factor, tumor necrosis factor receptor and erythropoietin was observed (109-112). Similarly, antibody fusion molecules with brain-derived neurotrophic factor (112) or potentially therapeutic enzymes such as β-glucuronidase (113) and iduronate-2-sulfatase (114) were evaluated.

Pharmacological effects on the CNS after i.v. administration of fusion proteins as outlined above were observed in mouse and rat for erythropoietin in stroke, for glial cell-derived neurotrophic factor in Parkinson's disease (115), and α-L-iduronidase in Hurler's syndrome. However, as a rule, fusion proteins based on TfR-or IR-specific antibodies are rapidly cleared from the circulation due to expression of these receptors on peripheral tissues such as kidney and liver (93).

Transfer of Antibody–Antibody Fusion Molecules Across the BBB in Pre-clinical Models

Therapeutic antibodies can be ferried across the BBB when fused to a binding moiety specific for an endocytosing BBB antigen. Such molecules were evaluated either as bispecific antibodies or as fusion proteins consisting of scFv or Fab effector moieties connected to a BBB-penetrating antibody (Figure 2B and C). The following examples are derived from studies on neurological disorders but probably can be extrapolated to treatment of brain cancer or secondary brain metastases. Proof-of-concept experiments were performed using a scFv Aβ-specific antibody fragment fused to a HIR-specific monoclonal antibody or to a cTfRmAb (116, 117). The anti-Aβ scFv was fused to both antibody CH3 domains, bound to Aβ amyloid, and caused disaggregation of the amyloid in the brain. Similarly, an antibody directed both against TfR and β-site amyloid precursor protein cleaving enzyme (BACE1) was evaluated in a bispecific format (118, 119). BACE1 is an aspartyl-protease involved in the production of Aβ in the brain and in the periphery, and inhibition of β-amyloid production in vivo was demonstrated using such fusion molecules. Using therapeutic doses (5-50 mg/kg), it was shown that low-affinity anti-TfR antibodies were transported more rapidly and efficiently into the brain, improving duration of exposure and brain uptake in comparison to high-affinity antibodies (117, 118). However, side-effects were observed: a single dose of 1 mg/kg caused severe acute clinical signs, as well as a profound reduction of reticulocyte counts in mice (118, 119). It was shown that the elimination of Ig-Fc-mediated effector functions prevented these acute clinical signs and mitigated the reduction of reticulocyte count (118, 119). These findings support efforts to identify target molecules more specific for the BBB.

An approach based on a TfRmAb–Fab fusion protein constructed in a modular manner was recently investigated (120, 121). One or two Fab fragments of an anti-TfR-specific antibody (122) were fused to an anti-Aβ monoclonal antibody. Both molecules were taken up by endothelial cells by transcytosis; however, whereas the monovalent construct mediated uptake, transcytosis and TfR recycling, the presence of two TfR-binding Fab fragments per anti-Aβ resulted in uptake and trafficking to lysosomes followed by reduction of TfR levels (Figure 3). In a transgenic mouse model of Alzheimer's disease, the antibody bearing one TfR-binding unit exhibited a 55-fold increase in amyloid plaque engagement compared to the parental antibody or the antibody with two TfR-binding moieties. Localization of the antibody with the monovalent TfR binder in the brain was shown by immunofluorescence-based signal amplification, however, information regarding quantitation in the brain and toxicity data are not yet available. Extension of these studies as outlined above to brain oncology might lead to therapeutically-promising approaches.

Concluding Remarks

Future progress in the treatment of brain tumors and brain metastases will depend on several issues. Importantly, from a technical point of view, optimization of delivery of small molecules and biological agents is a prerequisite for increasing treatment efficacy. In addition, inhibition of spread of established metastases might confer therapeutic benefit. Hopefully, stepwise increments of therapeutic benefit can be demonstrated in the years ahead.

  • Received May 20, 2015.
  • Revision received June 17, 2015.
  • Accepted June 18, 2015.

References

  1. ↵
    1. Marchesi V
    : CNS cancer: metabolic changes in brain tumors. Nat Rev Clin Oncol 10: 607, 2013.
    OpenUrl
  2. ↵
    1. Fidler I,
    2. Ellis LM
    : The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185-188, 1994.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Poste G,
    2. Fidler IJ
    : The pathogenesis of cancer metastasis. Nature 283: 139-146, 1980.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Nguyen DX,
    2. Massagué J
    : Genetic determinants of cancer metastasis. Nat Rev Genet 8: 341-352, 2007.
    OpenUrlCrossRefPubMed
    1. Vogelstein B,
    2. Kinzler KW
    : Cancer genes and the pathways they control. Nat Med 10: 789-799, 2004.
    OpenUrlCrossRefPubMed
    1. Brabletz T
    : To differentiate or not-routes towards metastasis. Nat Rev Cancer 12: 425-436, 2012.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Weigelt B1,
    2. Peterse JL,
    3. van 't Veer LJ
    : Breast cancer metastasis: markers and models. Nat Rev Cancer 5: 591-602, 2005.
    OpenUrlCrossRefPubMed
  8. ↵
    1. MacDonald NJ,
    2. Steeg PS
    : Molecular basis of tumour metastasis. Cancer Surv 16: 175-199, 1993.
    OpenUrlPubMed
  9. ↵
    1. Chambers AF,
    2. MacDonald IC,
    3. Schmidt EE,
    4. Morris VL,
    5. Groom AC
    : Clinical targets for anti-metastasis therapy. Adv Cancer Res 79: 91-121, 2000.
    OpenUrlPubMed
  10. ↵
    1. Nathoo N,
    2. Chahlavi A,
    3. Barnett GH,
    4. Toms SA
    : Pathobiology of brain metastases. J Clin Pathol 58: 237-242, 2005.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Pardridge WM
    : Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 1: 131-139, 2002.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Laquintana V,
    2. Trapani A,
    3. Denora N,
    4. Wang F,
    5. Gallo JM,
    6. Trapani G
    : New strategies to deliver anticancer drugs to brain tumors. Expert Opin Drug Deliv 6: 1017-1032, 2009.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Chacko AM,
    2. Li C,
    3. Pryma DA,
    4. Brem S,
    5. Coukos G,
    6. Muzykantov V
    : Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: crossing the blood–brain barrier divide. Expert Opin Drug Deliv 10: 907-926, 2013.
    OpenUrlPubMed
  14. ↵
    1. Giragossian C,
    2. Clark T,
    3. Piché-Nicholas N,
    4. Bowman CJ
    : Neonatal Fc receptor and its role in the absorption, distribution, metabolism and excretion of immunoglobulin G-based biotherapeutics. Curr Drug Metab 14: 764-790, 2013.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Mathieu D,
    2. Fortin D
    : Chemotherapy and delivery in the treatment of primary brain tumors. Curr Clin Pharmacol 2: 197-211, 2007.
    OpenUrlPubMed
  16. ↵
    1. Jia W,
    2. Lu R,
    3. Martin TA,
    4. Jiang WG
    : The role of claudin-5 in blood–brain barrier (BBB) and brain metastases (review). Mol Med Rep 9: 779-785, 2014.
    OpenUrlPubMed
  17. ↵
    1. Correale J,
    2. Villa A
    : Cellular elements of the blood-brain barrier. Neurochem Res 34: 2067-2077, 2009.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Pardridge WM
    : Receptor-mediated peptide transport through the blood-brain barrier. Endocr Rev 7: 314-330, 1986.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Pardridge WM
    : Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 3: 90-105, 2003.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Hediger MA,
    2. Romero MF,
    3. Peng JB,
    4. Rolfs A,
    5. Takanaga H,
    6. Bruford EA
    : The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Introduction. Pflugers Arch 447: 465-468, 2004.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Demeule M,
    2. Régina A,
    3. Jodoin J,
    4. Laplante A,
    5. Dagenais C,
    6. Berthelet F,
    7. Moghrabi A,
    8. Béliveau R
    : Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier. Vascul Pharmacol 38: 339-348, 2002.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Huang Y,
    2. Sadée W
    : Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. Cancer Lett 239: 168-182, 2006.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Kruh GD,
    2. Belinsky MG
    : The MRP family of drug efflux pumps. Oncogene 22: 7537-7552, 2003.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Dufès C,
    2. A Robaian M,
    3. Somani S
    : Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Ther Deliv 4: 629-640, 2013.
    OpenUrlCrossRefPubMed
  25. ↵
    1. EL Andaloussi S,
    2. Mäger I,
    3. Breakefield XO,
    4. Wood MJ
    : Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12: 347-357, 2013.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Salama NN,
    2. Eddington ND,
    3. Fasano A
    : Tight junction modulation and its relationship to drug delivery. Adv Drug Deliv Rev 58: 15-28, 2006.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Smith MW,
    2. Gumbleton M
    : Endocytosis at the blood–brain barrier: from basic understanding to drug delivery strategies. J Drug Target 14: 191-214, 2006.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Kienast Y,
    2. von Baumgarten L,
    3. Fuhrmann M,
    4. Klinkert WE,
    5. Goldbrunner R,
    6. Herms J,
    7. Winkler F
    : Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16: 116-122, 2010.
    OpenUrlCrossRefPubMed
    1. Carbonell WS,
    2. Ansorge O,
    3. Sibson N,
    4. Muschel R
    : The vascular basement membrane as “soil” in brain metastasis. PLoS One 4: e5857, 2009.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Heyn C,
    2. Ronald JA,
    3. Mackenzie LT,
    4. MacDonald IC,
    5. Chambers AF,
    6. Rutt BK,
    7. Foster PJ
    : In vivo magnetic resonance imaging of single cells in mouse brain with optical validation. Magn Reson Med 55: 23-29, 2006.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Fidler IJ
    : Selection of successive tumour lines for metastasis. Nat New Biol 242: 148-149, 1973.
    OpenUrlCrossRefPubMed
    1. Brunson KW,
    2. Beattie G,
    3. Nicolsin GL
    : Selection and altered properties of brain-colonising metastatic melanoma. Nature 272: 543-545, 1978.
    OpenUrlCrossRefPubMed
    1. Schackert G,
    2. Fidler IJ
    : Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 48: 3478-3484, 1988.
    OpenUrlAbstract/FREE Full Text
    1. Fidler IJ
    : The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 21: 107-112, 2011.
    OpenUrlCrossRefPubMed
    1. Cruz-Munoz W,
    2. Man S,
    3. Xu P,
    4. Kerbel RS
    : Development of a preclinical model of spontaneous human melanoma central nervous system metastasis. Cancer Res 68: 4500-4505, 2008.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Daphu I,
    2. Sundstrøm T,
    3. Horn S,
    4. Huszthy PC,
    5. Niclou SP,
    6. Sakariassen PØ,
    7. Immervoll H,
    8. Miletic H,
    9. Bjerkvig R,
    10. Thorsen F
    : In vivo animal models for studying brain metastasis: value and limitations. Clin Exp Metastasis 30: 695-710, 2013.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Bos PD,
    2. Zhang XH,
    3. Nadal C,
    4. Shu W,
    5. Gomis RR,
    6. Nguyen DX,
    7. Minn AJ,
    8. van de Vijver MJ,
    9. Gerald WL,
    10. Foekens JA,
    11. Massagué J
    : Genes that mediate breast cancer metastasis to the brain. Nature 459: 1005-1009, 2009.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Lockman PR,
    2. Mittapalli RK,
    3. Taskar KS,
    4. Rudraraju V,
    5. Gril B,
    6. Bohn KA,
    7. Adkins CE,
    8. Roberts A,
    9. Thorsheim HR,
    10. Gaasch JA,
    11. Huang S,
    12. Palmieri D,
    13. Steeg PS,
    14. Smith QR
    : Heterogeneous blood–tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16: 5664-5678, 2010.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Fitzgerald DP,
    2. Palmieri D,
    3. Hua E,
    4. Hargrave E,
    5. Herring JM,
    6. Qian Y,
    7. Vega-Valle E,
    8. Weil RJ,
    9. Stark AM,
    10. Vortmeyer AO,
    11. Steeg PS
    : Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis 25: 799-810, 2008.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Palmieri D,
    2. Bronder JL,
    3. Herring JM,
    4. Yoneda T,
    5. Weil RJ,
    6. Stark AM,
    7. Kurek R,
    8. Vega-Valle E,
    9. Feigenbaum L,
    10. Halverson D,
    11. Vortmeyer AO,
    12. Steinberg SM,
    13. Aldape K,
    14. Steeg PS
    : HER2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67: 4190-4198, 2007.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Gril B,
    2. Palmieri D,
    3. Bronder JL,
    4. Herring JM,
    5. Vega-Valle E,
    6. Feigenbaum L,
    7. Liewehr DJ,
    8. Steinberg SM,
    9. Merino MJ,
    10. Rubin SD,
    11. Steeg PS
    : Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100: 1092-1103, 2008.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Steeg PS,
    2. Camphausen KA,
    3. Smith QR
    : Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11: 352-363, 2011.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Minn AJ,
    2. Gupta GP,
    3. Siegel PM,
    4. Bos PD,
    5. Shu W,
    6. Giri DD,
    7. Viale A,
    8. Olshen AB,
    9. Gerald WL,
    10. Massagué J
    : Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Gupta GP,
    2. Nguyen DX,
    3. Chiang AC,
    4. Bos PD,
    5. Kim JY,
    6. Nadal C,
    7. Gomis RR,
    8. Manova-Todorova K,
    9. Massagué J
    : Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446: 765-770, 2007.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Palmieri D,
    2. Fitzgerald D,
    3. Shreeve SM,
    4. Hua E,
    5. Bronder JL,
    6. Weil RJ,
    7. Davis S,
    8. Stark AM,
    9. Merino MJ,
    10. Kurek R,
    11. Mehdorn HM,
    12. Davis G,
    13. Steinberg SM,
    14. Meltzer PS,
    15. Aldape K,
    16. Steeg PS
    : Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res 7: 1438-1445, 2009.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Hinton CV,
    2. Avraham S,
    3. Avraham HK
    : Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Clin Exp Metastasis 27: 97-105, 2010.
    OpenUrlCrossRefPubMed
    1. Nam DH,
    2. Jeon HM,
    3. Kim S,
    4. Kim MH,
    5. Lee YJ,
    6. Lee MS,
    7. Kim H,
    8. Joo KM,
    9. Lee DS,
    10. Price JE,
    11. Bang SI,
    12. Park WY
    : Activation of notch signaling in a xenograft model of brain metastasis. Clin Cancer Res 14: 4059-4066, 2008.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Adamo B,
    2. Deal AM,
    3. Burrows E,
    4. Geradts J,
    5. Hamilton E,
    6. Blackwell KL,
    7. Livasy C,
    8. Fritchie K,
    9. Prat A,
    10. Harrell JC,
    11. Ewend MG,
    12. Carey LA,
    13. Miller CR,
    14. Anders CK
    : Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res 13: R125, 2011.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Zhang C,
    2. Zhang F,
    3. Tsan R,
    4. Fidler IJ
    : Transforming growth factor-beta2 is a molecular determinant for site-specific melanoma metastasis in the brain. Cancer Res 69: 828-835, 2009.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Xie TX,
    2. Huang FJ,
    3. Aldape KD,
    4. Kang SH,
    5. Liu M,
    6. Gershenwald JE,
    7. Xie K,
    8. Sawaya R,
    9. Huang S
    : Activation of STAT3 in human melanoma promotes brain metastasis. Cancer Res 66: 3188-3196, 2006.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Palmieri D,
    2. Lockman PR,
    3. Thomas FC,
    4. Hua E,
    5. Herring J,
    6. Hargrave E,
    7. Johnson M,
    8. Flores N,
    9. Qian Y,
    10. Vega-Valle E,
    11. Taskar KS,
    12. Rudraraju V,
    13. Mittapalli RK,
    14. Gaasch JA,
    15. Bohn KA,
    16. Thorsheim HR,
    17. Liewehr DJ,
    18. Davis S,
    19. Reilly JF,
    20. Walker R,
    21. Bronder JL,
    22. Feigenbaum L,
    23. Steinberg SM,
    24. Camphausen K,
    25. Meltzer PS,
    26. Richon VM,
    27. Smith QR,
    28. Steeg PS
    : Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res 15: 6148-6157, 2009.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Baschnagel A,
    2. Russo A,
    3. Burgan WE,
    4. Carter D,
    5. Beam K,
    6. Palmieri D,
    7. Steeg PS,
    8. Tofilon P,
    9. Camphausen K
    : Vorinostat enhances the radiosensitivity of a breast cancer brain metastatic cell line grown in vitro and as intracranial xenografts. Mol Cancer Ther 8: 1589-1595, 2009.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. Kim LS,
    2. Huang S,
    3. Lu W,
    4. Lev DC,
    5. Price JE
    : Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis 21: 107-118, 2004.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Jain RK
    : Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7: 987-989, 2001.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Winkler F,
    2. Kozin SV,
    3. Tong RT,
    4. Chae SS,
    5. Booth MF,
    6. Garkavtsev I,
    7. Xu L,
    8. Hicklin DJ,
    9. Fukumura D,
    10. di Tomaso E,
    11. Munn LL,
    12. Jain RK
    : Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553-563, 2004.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Leenders WP,
    2. Küsters B,
    3. Verrijp K,
    4. Maass C,
    5. Wesseling P,
    6. Heerschap A,
    7. Ruiter D,
    8. Ryan A,
    9. de Waal R
    : Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res 10: 6222-6230, 2004.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Kodack DP,
    2. Chung E,
    3. Yamashita H,
    4. Incio J,
    5. Duyverman AM,
    6. Song Y,
    7. Farrar CT,
    8. Huang Y,
    9. Ager E,
    10. Kamoun W,
    11. Goel S,
    12. Snuderl M,
    13. Lussiez A,
    14. Hiddingh L,
    15. Mahmood S,
    16. Tannous BA,
    17. Eichler AF,
    18. Fukumura D,
    19. Engelman JA,
    20. Jain RK
    : Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci USA 109: E3119-3127, 2012.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. Nieder C,
    2. Spanne O,
    3. Mehta MP,
    4. Grosu AL,
    5. Geinitz H
    : Presentation, patterns of care, and survival in patients with brain metastases: what has changed in the last 20 years? Cancer 117: 2505-2512, 2011.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Owonikoko TK,
    2. Arbiser J,
    3. Zelnak A,
    4. Shu HK,
    5. Shim H,
    6. Robin AM,
    7. Kalkanis SN,
    8. Whitsett TG,
    9. Salhia B,
    10. Tran NL,
    11. Ryken T,
    12. Moore MK,
    13. Egan KM,
    14. Olson JJ
    : Current approaches to the treatment of metastatic brain tumours. Nat Rev Clin Oncol 11: 203-222, 2014.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Thomas FC,
    2. Taskar K,
    3. Rudraraju V,
    4. Goda S,
    5. Thorsheim HR,
    6. Gaasch JA,
    7. Mittapalli RK,
    8. Palmieri D,
    9. Steeg PS,
    10. Lockman PR,
    11. Smith QR
    : Uptake of ANG1005, a novel paclitaxel derivative, through the blood–brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res 26: 2486-2494, 2009.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Sun M,
    2. Behrens C,
    3. Feng L,
    4. Ozburn N,
    5. Tang X,
    6. Yin G,
    7. Komaki R,
    8. Varella-Garcia M,
    9. Hong WK,
    10. Aldape KD,
    11. Wistuba II
    : HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors. Clin Cancer Res 15: 4829-4837, 2009.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    1. Shaw AT,
    2. Kim DW,
    3. Nakagawa K,
    4. Seto T,
    5. Crinó L,
    6. Ahn MJ,
    7. De Pas T,
    8. Besse B,
    9. Solomon BJ,
    10. Blackhall F,
    11. Wu YL,
    12. Thomas M,
    13. O'Byrne KJ,
    14. Moro-Sibilot D,
    15. Camidge DR,
    16. Mok T,
    17. Hirsh V,
    18. Riely GJ,
    19. Iyer S,
    20. Tassell V,
    21. Polli A,
    22. Wilner KD,
    23. Jänne PA
    : Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368: 2385-2394, 2013.
    OpenUrlCrossRefPubMed
    1. Solomon B,
    2. Wilner KD2,
    3. Shaw AT3
    : Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther 95: 15-23, 2014.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Chuan Tang S,
    2. Nguyen LN,
    3. Sparidans RW,
    4. Wagenaar E,
    5. Beijnen JH,
    6. Schinkel AH
    : Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer 134: 1484-1494, 2014.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Byrne TN,
    2. Cascino TL,
    3. Posner JB
    : Brain metastasis from melanoma. J Neurooncol 1: 313-317, 1983.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Davies MA,
    2. Stemke-Hale K,
    3. Lin E,
    4. Tellez C,
    5. Deng W,
    6. Gopal YN,
    7. Woodman SE,
    8. Calderone TC,
    9. Ju Z,
    10. Lazar AJ,
    11. Prieto VG,
    12. Aldape K,
    13. Mills GB,
    14. Gershenwald JE
    : Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 15: 7538-7546, 2009.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Eichler AF,
    2. Chung E,
    3. Kodack DP,
    4. Loeffler JS,
    5. Fukumura D,
    6. Jain RK
    : The biology of brain metastases–translation to new therapies. Nat Rev Clin Oncol 8: 344-56, 2011.
    OpenUrlPubMed
  68. ↵
    1. Falchook GS,
    2. Long GV,
    3. Kurzrock R,
    4. Kim KB,
    5. Arkenau TH,
    6. Brown MP,
    7. Hamid O,
    8. Infante JR,
    9. Millward M,
    10. Pavlick AC,
    11. O'Day SJ,
    12. Blackman SC,
    13. Curtis CM,
    14. Lebowitz P,
    15. Ma B,
    16. Ouellet D,
    17. Kefford RF
    : Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase I dose-escalation trial. Lancet 379: 1893-1901, 2012.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Long GV,
    2. Trefzer U,
    3. Davies MA,
    4. Kefford RF,
    5. Ascierto PA,
    6. Chapman PB,
    7. Puzanov I,
    8. Hauschild A,
    9. Robert C,
    10. Algazi A,
    11. Mortier L,
    12. Tawbi H,
    13. Wilhelm T,
    14. Zimmer L,
    15. Switzky J,
    16. Swann S,
    17. Martin AM,
    18. Guckert M,
    19. Goodman V,
    20. Streit M,
    21. Kirkwood JM,
    22. Schadendorf D
    : Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13: 1087-1095, 2012.
    OpenUrlCrossRefPubMed
  70. ↵
    1. Della Vittoria Scarpati G,
    2. Fusciello C,
    3. Perri F,
    4. Sabbatino F,
    5. Ferrone S,
    6. Carlomagno C,
    7. Pepe S
    : Ipilimumab in the treatment of metastatic melanoma: management of adverse events. Onco Targets Ther 7: 203-209, 2014.
    OpenUrlPubMed
  71. ↵
    1. Lin NU,
    2. Amiri-Kordestani L,
    3. Palmieri D,
    4. Liewehr DJ,
    5. Steeg PS
    : CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res 19: 6404-6418, 2013.
    OpenUrlAbstract/FREE Full Text
    1. Olson EM,
    2. Abdel-Rasoul M,
    3. Maly J,
    4. Wu CS,
    5. Lin NU,
    6. Shapiro CL
    : Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol 24: 1526-1533, 2013.
    OpenUrlAbstract/FREE Full Text
    1. Pestalozzi BC,
    2. Holmes E,
    3. de Azambuja E,
    4. Metzger-Filho O,
    5. Hogge L,
    6. Scullion M,
    7. Láng I,
    8. Wardley A,
    9. Lichinitser M,
    10. Sanchez RI,
    11. Müller V,
    12. Dodwell D,
    13. Gelber RD,
    14. Piccart-Gebhart MJ,
    15. Cameron D
    : CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol 14: 244-248, 2013.
    OpenUrlCrossRefPubMed
  74. ↵
    1. Bendell JC,
    2. Domchek SM,
    3. Burstein HJ,
    4. Harris L,
    5. Younger J,
    6. Kuter I,
    7. Bunnell C,
    8. Rue M,
    9. Gelman R,
    10. Winer E
    : Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97: 2972-2977, 2003.
    OpenUrlCrossRefPubMed
  75. ↵
    1. Dijkers EC,
    2. Oude Munnink TH,
    3. Kosterink JG,
    4. Brouwers AH,
    5. Jager PL,
    6. de Jong JR,
    7. van Dongen GA,
    8. Schröder CP,
    9. Lub-de Hooge MN,
    10. de Vries EG
    : Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther 87: 586-592, 2010.
    OpenUrlCrossRefPubMed
  76. ↵
    1. Ningaraj NS
    : Drug delivery to brain tumours: challenges and progress. Expert Opin Drug Deliv 3: 499-509, 2006.
    OpenUrlPubMed
  77. ↵
    1. Poduslo JF,
    2. Curran GL,
    3. Berg CT
    : Macromolecular permeability across the blood–nerve and blood–brain barriers. Proc Natl Acad Sci USA 91: 5705-5709, 1994.
    OpenUrlAbstract/FREE Full Text
    1. Felgenhauer K
    : Protein size and cerebrospinal fluid composition. Klin Wochenschr 52: 1158-1164, 1974.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Lee J,
    2. Lund-Smith C,
    3. Borboa A,
    4. Gonzalez AM,
    5. Baird A,
    6. Eliceiri BP
    : Glioma-induced remodeling of the neurovascular unit. Brain Res 1288: 125-134, 2009.
    OpenUrlCrossRefPubMed
  80. ↵
    1. DeLuca I,
    2. Blachère NE,
    3. Santomasso B,
    4. Darnell RB
    : Tolerance to the neuron-specific paraneoplastic HuD antigen. PLoS One 4: e5739, 2009.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Heimberger AB,
    2. Suki D,
    3. Yang D,
    4. Shi W,
    5. Aldape K
    : The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med 3: 38, 2005.
    OpenUrlCrossRefPubMed
    1. Kuan CT,
    2. Wikstrand CJ,
    3. Bigner DD
    : EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 8: 83-96, 2001.
    OpenUrlCrossRefPubMed
    1. Sivasankaran B,
    2. Degen M,
    3. Ghaffari A,
    4. Hegi ME,
    5. Hamou MF,
    6. Ionescu MC,
    7. Zweifel C,
    8. Tolnay M,
    9. Wasner M,
    10. Mergenthaler S,
    11. Miserez AR,
    12. Kiss R,
    13. Lino MM,
    14. Merlo A,
    15. Chiquet-Ehrismann R,
    16. Boulay JL
    : Tenascin-C is a novel RBPJκ-induced target gene for Notch signaling in gliomas. Cancer Res 69: 458-465, 2009.
    OpenUrlAbstract/FREE Full Text
    1. Zalutsky MR,
    2. Reardon DA,
    3. Akabani G,
    4. Coleman RE,
    5. Friedman AH,
    6. Friedman HS,
    7. McLendon RE,
    8. Wong TZ,
    9. Bigner DD
    : Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med 49: 30-38, 2008.
    OpenUrlAbstract/FREE Full Text
    1. Reardon DA,
    2. Zalutsky MR,
    3. Akabani G,
    4. Coleman RE,
    5. Friedman AH,
    6. Herndon JE 2nd.,
    7. McLendon RE,
    8. Pegram CN,
    9. Quinn JA,
    10. Rich JN,
    11. Vredenburgh JJ,
    12. Desjardins A,
    13. Guruangan S,
    14. Boulton S,
    15. Raynor RH,
    16. Dowell JM,
    17. Wong TZ,
    18. Zhao XG,
    19. Friedman HS,
    20. Bigner DD
    : A pilot study: 131I-antitenascin monoclonal antibody 81C6 to deliver a 44-Gy resection cavity boost. Neuro Oncol 10: 182-189, 2008.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    1. Hernández-Pedro NY,
    2. Rangel-López E,
    3. Vargas Félix G,
    4. Pineda B,
    5. Sotelo J
    : An update in the use of antibodies to treat glioblastoma multiforme. Autoimmune Dis 2013: 716813, 2013.
    OpenUrlPubMed
  87. ↵
    1. Margolin K,
    2. Ernstoff MS,
    3. Hamid O,
    4. Lawrence D,
    5. McDermott D,
    6. Puzanov I,
    7. Wolchok JD,
    8. Clark JI,
    9. Sznol M,
    10. Logan TF,
    11. Richards J,
    12. Michener T,
    13. Balogh A,
    14. Heller KN,
    15. Hodi FS
    : Ipilimumab in patients with melanoma and brain metastases: an open-label, phase II trial. Lancet Oncol 13: 459-465, 2012.
    OpenUrlCrossRefPubMed
  88. ↵
    1. Kingsley DP
    : An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol 48: 863-866, 1975.
    OpenUrlAbstract/FREE Full Text
  89. ↵
    1. Stamell EF,
    2. Wolchok JD,
    3. Gnjatic S,
    4. Lee NY,
    5. Brownell I
    : The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 85: 293-295, 2013.
    OpenUrlCrossRefPubMed
  90. ↵
    1. Pardridge WM1,
    2. Boado RJ
    : Re-engineering biopharmaceuticals for targeted delivery across the blood–brain barrier. Methods Enzymol 503: 269-292, 2012.
    OpenUrlCrossRefPubMed
  91. ↵
    1. Pardridge WM
    : Drug transport across the blood–brain barrier. J Cereb Blood Flow Metab 32: 1959-1972, 2012.
    OpenUrlCrossRefPubMed
  92. ↵
    1. Pardridge WM,
    2. Eisenberg J,
    3. Yang J
    : Human blood–brain barrier transferrin receptor. Metabolism 36: 892-895, 1987.
    OpenUrlCrossRefPubMed
  93. ↵
    1. Friden PM,
    2. Walus LR,
    3. Musso GF,
    4. Taylor MA,
    5. Malfroy B,
    6. Starzyk RM
    : Anti-transferrin receptor antibody and antibody–drug conjugates cross the blood–brain barrier. Proc Natl Acad Sci USA 88: 4771-4775, 1991.
    OpenUrlAbstract/FREE Full Text
    1. Pardridge WM,
    2. Buciak JL,
    3. Friden PM
    : Selective transport of an anti-transferrin receptor antibody through the blood–brain barrier in vivo. J Pharmacol Exp Ther 259: 66-70, 1991.
    OpenUrlAbstract/FREE Full Text
  95. ↵
    1. Lee HJ,
    2. Engelhardt B,
    3. Lesley J,
    4. Bickel U,
    5. Pardridge WM
    : Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood–brain barrier in mouse. J Pharmacol Exp Ther 292: 1048-1052, 2000.
    OpenUrlAbstract/FREE Full Text
  96. ↵
    1. Kissel K,
    2. Hamm S,
    3. Schulz M,
    4. Vecchi A,
    5. Garlanda C,
    6. Engelhardt B
    : Immunohistochemical localization of the murine transferrin receptor (TfR) on blood-tissue barriers using a novel anti-TfR monoclonal antibody. Histochem Cell Biol 110: 63-72, 1998.
    OpenUrlCrossRefPubMed
  97. ↵
    1. Lee HJ,
    2. Zhang Y,
    3. Zhu C,
    4. Duff K,
    5. Pardridge WM
    : Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Aβ peptide radiopharmaceutical. J Cereb Blood Flow Metab 22: 223-231, 2002.
    OpenUrlPubMed
  98. ↵
    1. Pardridge WM,
    2. Kang YS,
    3. Buciak JL,
    4. Yang J
    : Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood–brain barrier in vivo in the primate. Pharm Res 12: 807-816, 1995.
    OpenUrlCrossRefPubMed
  99. ↵
    1. Boado RJ,
    2. Zhang Y,
    3. Wang Y,
    4. Pardridge WM
    : Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood–brain barrier delivery in the mouse. Biotechnol Bioeng 102: 1251-1258, 2009.
    OpenUrlCrossRefPubMed
  100. ↵
    1. Liu Q,
    2. Zerbinatti CV,
    3. Zhang J,
    4. Hoe HS,
    5. Wang B,
    6. Cole SL,
    7. Herz J,
    8. Muglia L,
    9. Bu G
    : Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56: 66-78, 2007.
    OpenUrlCrossRefPubMed
    1. Gaillard PJ,
    2. Visser CC,
    3. de Boer AG
    : Targeted delivery across the blood–brain barrier. Expert Opin Drug Deliv 2: 299-309, 2005.
    OpenUrlCrossRefPubMed
    1. Karkan D,
    2. Pfeifer C,
    3. Vitalis TZ,
    4. Arthur G,
    5. Ujiie M,
    6. Chen Q,
    7. Tsai S,
    8. Koliatis G,
    9. Gabathuler R,
    10. Jefferies WA
    : A unique carrier for delivery of therapeutic compounds beyond the blood–brain barrier. PLoS One 3: e2469, 2008.
    OpenUrlCrossRefPubMed
  103. ↵
    1. Bertrand Y,
    2. Currie JC,
    3. Poirier J,
    4. Demeule M,
    5. Abulrob A,
    6. Fatehi D,
    7. Stanimirovic D,
    8. Sartelet H,
    9. Castaigne JP,
    10. Béliveau R
    : Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1. Br J Cancer 105: 1697-1707, 2011.
    OpenUrlCrossRefPubMed
  104. ↵
    1. Muruganandam A,
    2. Tanha J,
    3. Narang S,
    4. Stanimirovic D
    : Selection of phage-displayed llama single-domain antibodies that transmigrate across human blood–brain barrier endothelium. FASEB J 16: 240-242, 2002.
    OpenUrlFREE Full Text
  105. ↵
    1. Tanha J,
    2. Muruganandam A,
    3. Stanimirovic D
    : Phage display technology for identifying specific antigens on brain endothelial cells. Methods Mol Med 89: 435-449, 2003.
    OpenUrlPubMed
  106. ↵
    1. Abulrob A,
    2. Sprong H,
    3. Van Bergen en Henegouwen P,
    4. Stanimirovic D
    : The blood–brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J Neurochem 95: 1201-1214, 2005
    OpenUrlCrossRefPubMed
  107. ↵
    1. Pardridge WM
    : Biopharmaceutical drug targeting to the brain. J Drug Target 18: 157-167, 2010.
    OpenUrlCrossRefPubMed
  108. ↵
    1. Salahuddin TS,
    2. Johansson BB,
    3. Kalimo H,
    4. Olsson Y
    : Structural changes in the rat brain after carotid infusions of hyperosmolar solutions. An electron microscopic study. Acta Neuropathol 77: 5-13, 1988.
    OpenUrlCrossRefPubMed
  109. ↵
    1. Zhou QH,
    2. Boado RJ,
    3. Lu JZ,
    4. Hui EK,
    5. Pardridge WM
    : Monoclonal antibody–glial-derived neurotrophic factor fusion protein penetrates the blood–brain barrier in the mouse. Drug Metab Dispos 38: 566-572, 2010.
    OpenUrlAbstract/FREE Full Text
    1. Zhou QH,
    2. Hui EK,
    3. Lu JZ,
    4. Boado RJ,
    5. Pardridge WM
    : Brain-penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse. Brain Res 1382: 315-320, 2011.
    OpenUrlPubMed
    1. Zhou QH,
    2. Boado RJ,
    3. Hui EK,
    4. Lu JZ,
    5. Pardridge WM
    : Brain-penetrating tumor necrosis factor decoy receptor in the mouse. Drug Metab Dispos 39: 71-76, 2011.
    OpenUrlAbstract/FREE Full Text
  112. ↵
    1. Boado RJ,
    2. Zhang Y,
    3. Zhang Y,
    4. Pardridge WM
    : Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood–brain barrier. Biotechnol Bioeng 97: 1376-1386, 2007.
    OpenUrlCrossRefPubMed
  113. ↵
    1. Boado RJ,
    2. Zhou QH,
    3. Lu JZ,
    4. Hui EK,
    5. Pardridge WM
    : Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse transferrin receptor. Mol Pharm 7: 237-244, 2010.
    OpenUrlCrossRefPubMed
  114. ↵
    1. Lu JZ,
    2. Hui EK,
    3. Boado RJ,
    4. Pardridge WM
    : Genetic engineering of a bifunctional IgG fusion protein with iduronate-2-sulfatase. Bioconjug Chem 21: 151-156, 2010.
    OpenUrlCrossRefPubMed
  115. ↵
    1. Ohshima-Hosoyama S,
    2. Simmons HA,
    3. Goecks N,
    4. Joers V,
    5. Swanson CR,
    6. Bondarenko V,
    7. Velotta R,
    8. Brunner K,
    9. Wood LD,
    10. Hruban RH,
    11. Emborg ME
    : A monoclonal antibody-GDNF fusion protein is not neuroprotective and is associated with proliferative pancreatic lesions in Parkinsonian monkeys. PLoS One 7: e39036, 2012.
    OpenUrlCrossRefPubMed
  116. ↵
    1. Boado RJ,
    2. Zhang Y,
    3. Zhang Y,
    4. Xia CF,
    5. Pardridge WM
    : Fusion antibody for Alzheimer's disease with bidirectional transport across the blood–brain barrier and Aβ fibril disaggregation. Bioconjug Chem 18: 447-455, 2007.
    OpenUrlCrossRefPubMed
  117. ↵
    1. Yu YJ,
    2. Zhang Y,
    3. Kenrick M,
    4. Hoyte K,
    5. Luk W,
    6. Lu Y,
    7. Atwal J,
    8. Elliott JM,
    9. Prabhu S,
    10. Watts RJ,
    11. Dennis MS
    : Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 3: 84ra44, 2011.
    OpenUrlAbstract/FREE Full Text
  118. ↵
    1. Couch JA,
    2. Yu YJ,
    3. Zhang Y,
    4. Tarrant JM,
    5. Fuji RN,
    6. Meilandt WJ,
    7. Solanoy H,
    8. Tong RK,
    9. Hoyte K,
    10. Luk W,
    11. Lu Y,
    12. Gadkar K,
    13. Prabhu S,
    14. Ordonia BA,
    15. Nguyen Q,
    16. Lin Y,
    17. Lin Z,
    18. Balazs M,
    19. Scearce-Levie K,
    20. Ernst JA,
    21. Dennis MS,
    22. Watts RJ
    : Addressing safety liabilities of TfR bispecific antibodies that cross the blood–brain barrier. Sci Transl Med 5: 183ra57, 1-12, 2013.
    OpenUrlAbstract/FREE Full Text
  119. ↵
    1. Watts RJ,
    2. Dennis MS
    : Bispecific antibodies for delivery into the brain. Curr Opin Chem Biol 17: 393-399, 2013.
    OpenUrlCrossRefPubMed
  120. ↵
    1. Niewoehner J,
    2. Bohrmann B,
    3. Collin L,
    4. Urich E,
    5. Sade H,
    6. Maier P,
    7. Rueger P,
    8. Stracke JO,
    9. Lau W,
    10. Tissot AC,
    11. Loetscher H,
    12. Ghosh A,
    13. Freskgård PO
    : Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 81: 49-60, 2014.
    OpenUrlCrossRefPubMed
  121. ↵
    1. Bell RD,
    2. Ehlers MD
    : Breaching the blood–brain barrier for drug delivery. Neuron 81: 1-3, 2014.
    OpenUrlCrossRefPubMed
  122. ↵
    1. Bohrmann B,
    2. Baumann K,
    3. Benz J,
    4. Gerber F,
    5. Huber W,
    6. Knoflach F,
    7. Messer J,
    8. Oroszlan K,
    9. Rauchenberger R,
    10. Richter WF,
    11. Rothe C,
    12. Urban M,
    13. Bardroff M,
    14. Winter M,
    15. Nordstedt C,
    16. Loetscher H
    : Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis 28: 49-69, 2012.
    OpenUrlCrossRefPubMed
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The Blood–Brain Barrier Challenge for the Treatment of Brain Cancer, Secondary Brain Metastases, and Neurological Diseases
ULRICH H. WEIDLE, JENS NIEWÖHNER, GEORG TIEFENTHALER
Cancer Genomics & Proteomics Jul 2015, 12 (4) 167-177;
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