Challenges in the delivery of therapies to melanoma brain metastases

Abstract

Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. Recent approval of several molecularly-targeted agents and biologics has brought hope to patients with this previously untreatable disease. However, patients with symptomatic melanoma brain metastases have often been excluded from pivotal clinical trials. This may be in part attributed to the fact that several of the approved small molecule molecularly-targeted agents are substrates for active efflux at the blood-brain barrier, limiting their effective delivery to brain metastases. We believe that successful treatment of melanoma brain metastases will depend on the ability of these agents to traverse the blood-brain barrier and reach micrometastases that are often not clinically detectable. Moreover, overcoming the emergence of a unique pattern of resistance, possibly through adequate delivery of combination targeted therapies in brain metastases will be important in achieving a durable response. These concepts, and the current challenges in the delivery of new treatments to melanoma brain metastases, are discussed in this review.

Keywords: active efflux; blood-brain barrier; drug delivery; drug resistance; melanoma brain metastases; molecularly-targeted agents.

Fig.1

Signaling pathways and small molecule therapeutic targets relevant to current melanoma therapy. RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) pathways are the main signaling cascades linked to melanoma. The illustration represents the various mediators and regulators that are involved with melanoma pathogenesis. The key targets for various classes of small molecule inhibitors are also shown.

Fig.2

Anti-tumor immune response through CTLA-4 and PD-1 pathway blockade, and T-cell signaling in the treatment of melanoma. Blocking CTLA-4 signaling and PD-1 signaling strengthens the activation of anti-tumor T-cell response leading to tumor elimination. The activated T-cells are able to gain entry into the brain (not shown in the figure) and act at the site of brain metastases.

Fig.3

Challenges with respect to drug delivery in treating melanoma brain metastases. The contrast-enhancing larger tumors in the brain have a relatively leaky BBB that allows distribution of drug molecules. However, the presence of subclinical “protected” micrometastases behind an intact BBB, combined with the active efflux of drug molecules by efflux transporters at the BBB, may severely limit the delivery of anti-cancer agents to such “subclinical” tumors and will result in a lack of therapeutic efficacy.

Fig.4

Melanoma metastatic spread and a comprehensive outlook of small molecule drug delivery to tumor sites. The panel (a) depicts a subject bearing a primary melanoma tumor. The panel (b) illustrates the spread of melanoma from the primary tumor site to the major organs of melanoma metastases. The panel (c) emphasizes the idea that the current chemotherapeutics, though potent and initially effective, are limited by their ability to distribute to the brain. Many small molecule chemotherapeutics achieve therapeutic levels in the peripheral tumor locations, both primary tumors and metastases, outside the brain and can therefore initially elicit a positive response, before resistance is seen. However, limited drug distribution to regions of tumor in the brain can result in the establishment of a pharmacological sanctuary site, causing ineffective therapy.

Fig.5

This figure highlights that we do not fully understand the mechanism of extravasation of tumor cells to the brain from the peripheral primary tumors. A deeper understanding of the steps involved in the initial seeding of the metastatic tumor cells would provide insights into devising appropriate strategies to prevent the establishment of brain disease. The figure describes the conundrum of how the circulating tumor cells enter the brain at sites that have an intact BBB and is side-by-side with the lack of drug penetration across that same intact BBB, one that includes both tight junctions and efflux transport. Such a problem would be seen in regions of larger metastases that have an intact BBB, and undoubtedly in the micrometastatic sites early in the course of brain disease.

Fig.6

The figure emphasizes that the way the tumor cells express targets or develop resistance could be different based on their microenvironment. It is possible that in the brain microenvironment, selection pressure is different than that in the periphery. This may cause distinct gene expression profiles by tumor cells in the brain vs the periphery, which could result in development of unique patterns of resistance in the brain.