Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

Abstract

Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery.

Keywords: brain metastases; drug delivery; immunotherapy; nanomedicine.

Figure 1

Schematic illustrating pathophysiological aspects of metastasis to the brain. Brain metastasis is an inefficient process marked by high rates of cellular attrition, and impacted by a myriad of selection pressures that drive clonal evolution. This includes requirements intrinsic to the metastatic cascade (capabilities for “metastatic fitness” are indicated in horizontal tracks) as well as extrinsic factors that drive the selection of particular tumor cell clones able to successfully establish brain metastases (vertical tracks; e.g., chemotherapy, radiotherapy or surgery) (adapted from [46]).

Figure 2

Typical histological appearance of brain metastases from different primary tumor types. Hematoxylin and eosin (H&E)-stained tissue sections show that brain metastases usually exhibit morphology typical of the primary tumor of origin. Features often seen in brain metastasis surgical specimens are highlighted: intact and dilated blood vessels (arrows; high microvascular density in the renal cell carcinoma-brain metastasis shown), hemorrhagic regions typical of melanoma brain metastases (white asterisks), necrotic tissue (“n”) and reactive gliosis around tumor cell nests with pushing margins (yellow asterisks). Scale bars = 250 μm. ca., carcinoma; adenoca. adenocarcinoma.

Figure 3

Summary of the approaches discussed in Section 4, including therapeutic classes, their molecular targets and examples of experimental or clinically approved agents.

Figure 4

Emerging strategies for detection and treatment of brain metastases. (A) Bioengineering and molecular oncology research are beginning to identify approaches that specifically target vulnerabilities of brain metastases, including microenvironmental adaptations. Through flexibility of design, nanomedicine approaches offer exciting possibilities for overcoming drug delivery and therapeutic index challenges in the metastatic brain cancer patient population. Externally-augmented drug release and/or activation may be a useful therapeutic tool in some circumstances. (B) Typical structure of a polymer-based nanocarrier with various functional groups. bis-scFv, bispecific single-chain variable fragment; IgG, immunoglobulin; kDa, kilodalton; nm, nanometer.