Leveraging translational insights toward precision medicine approaches for brain metastases

Abstract

Due to increasing incidence and limited treatments, brain metastases (BM) are an emerging unmet need in modern oncology. Development of effective therapeutics has been hindered by unique challenges. Individual steps of the brain metastatic cascade are driven by distinctive biological processes, suggesting that BM possess intrinsic biological differences compared to primary tumors. Here, we discuss the unique physiology and metabolic constraints specific to BM as well as emerging treatment strategies that leverage potential vulnerabilities.

Fig 1.. The brain metastatic cascade.

Major steps include: invasion of the tumor cells from the primary site into the extending stroma; intravasation of tumor cells into the peripheral circulation; extravasation of tumor cells into an intracranial perivascular space; local invasion of tumor cells, perivascular growth, and angiogenesis. We note that peri-vascular growth and angiogenesis are two separate steps in the formation of a macrometastasis, and that VEGF is therapeutically relevant are targeting angiogenesis. The majority of tumor cells do not survive following extravasation, with less than 5% lying in a dormant state with the ability to proceed to a proliferative state. This schematic may not recapitulate many nuances of in vivo brain metastasis, as this work was mostly done on cell lines.

Figure 2:. Simplified schematic of BBB and BTB physiology and potential therapeutic strategies.

We illustrate biological changes exerted onto the BBB as a result of the brain metastatic cascade. Characteristics of therapeutic molecules that penetrate the BBB are listed. We also note therapeutic strategies augmenting drug efficacy (e.g. increasing immune cell efflux), as well as therapeutically relevant targets within the BTB.

Figure 3:. A translational workflow in analyzing patient-derived brain metastasis tissue and identifying new therapeutic targets.

Comparative genomic, transcriptomic, immunogenic, and proteomic analyses of BM to ECM/primary tumor may result in a privileged view of mechanisms of CNS dissemination and therapeutic resistance. BM tissue can be submitted for either genomic or transcriptomic analysis. Following DNA sequencing, comparative analyses between BM and primary tumor WES data may reveal somatic variants associated with increased frequency of BM. Functional validation of these candidate variants have revealed potential targets that are being investigated in trials. Similarly, single-cell expressing profiling has potential to understand TME cell populations or states that play a role in treatment response. While the majority of single-cell profiling efforts in brain tumors have been in gliomas, we anticipate some overlap between immunosuppressive signatures of gliomas to that of BM. These immunosuppressive and tumor-promoting facets of T, glial, and myeloid cell populations may provide new therapeutic opportunities.