Preclinical evaluation of targeted therapies for central nervous system metastases

Abstract

The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood-brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.

Keywords: Blood–brain barrier; Central nervous system metastasis; Non-small cell lung cancer; Targeted therapy.

Fig. 1.

The blood–brain barrier. The blood–brain barrier (BBB) consists of a highly regulated neurovascular unit composed of endothelial cells connected by tight junctions, as well as pericytes and astrocytic foot processes. Together, these cellular components maintain central nervous system (CNS) homeostasis by tightly controlling intercellular and intracellular transport. Only therapies with chemical properties that enable them to permeate this barrier and be retained in the brain parenchyma can exert therapeutic efficacy. The drug properties most conducive to CNS-penetration include low molecular weight (MW) [<400 Dalton (Da)], high lipophilicity, less than eight to ten potential hydrogen-bonding sites, and low affinity for efflux transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The BBB may be damaged by infiltrating neoplastic lesions and/or local therapy (radiosurgery), although the significance of this damage to drug penetration is not fully understood.

Fig. 2.

Relationship between central nervous system compartments and vasculature. (A) Cerebrospinal fluid (CSF) is most commonly sampled through the cisterna magna in mice (outlined by the small square). (B) CSF flows in the subarachnoid space of the vertebral column and skull, providing a dynamic circulatory system that maintains central nervous system (CNS) homeostasis before draining into the venous system. The systemic vasculature interfaces with the CSF in the subarachnoid space (blood–CSF barrier), the brain parenchyma (blood–brain barrier) and (in the context of neoplastic lesions) the periphery of a tumor (blood–tumor interface). Each of these interphases represent a unique physiological barrier, with differing degrees of permeability and efflux transporter abundance. To evaluate intracranial drug concentration, the CSF is often sampled from the subarachnoid space through the cisterna magna in mice (pictured here) or from the lumbar spine in humans. The CSF and interstitial fluid (ISF) of brain parenchyma are separated by the brain–CSF interface, which is primarily made up of ependymal cells and discontinuous gap junctions. Bulk flow of the ISF and solutes favors movement from the ISF to the CSF, and hence drug concentration in the CSF is generally concordant with that in the ISF.

Fig. 3.

First-in-class versus next-generation tyrosine kinase inhibitors. (A) In comparison to chemotherapy, antibody-based therapeutics or radiation, small-molecule tyrosine kinase inhibitors (TKIs) demonstrate greater efficacy against brain metastases. However, most first-in-class TKIs have poor penetration into the central nervous system (CNS). Newer-generation TKIs have been specifically engineered to possess the pharmacokinetic properties necessary for treating intracranial disease. This has been achieved through optimizing parameters such as molecular weight, polar surface area and low affinity for efflux transporters, while retaining a high degree of kinase selectivity against their respective targets. Some examples of the chemical structures of both first- and next-generation TKIs are shown here. (B) Other systemic therapies can suffer from poor CNS penetration owing to multiple factors including size limitations (antibody-based therapeutics) or lipophobic properties (platinum-based chemotherapy). The properties of lorlatinib, as an example of a CNS-penetrant TKI, are shown. ALK, anaplastic lymphoma kinase; Da, Dalton; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma virus; P-gp, P-glycoprotein; RET, ‘rearranged during transfection’ protein.