Innovative Approaches

An LRP-Directed Peptide-Drug Conjugate Against Cancers in the Brain

Diseases of the brain, such as brain cancers, are very difficult to treat because most drugs, including oncology drugs, cannot reach the brain at levels that are clinically therapeutic. Most drugs, including anti-cancer drugs, are unable to reach the brain because of the blood-brain barrier (BBB). Transport across the BBB and into tumors is critical for developing effective treatments for cancer in the brain.

The Blood-Brain Barrier (BBB)

The BBB has two major functions: to protect the brain and regulate brain homeostasis. The brain is protected by tight junctions between the endothelial cells of the capillaries in the brain and the presence of active efflux pumps (transport proteins that are involved in the extrusion of toxic substances). As a consequence, the overwhelming majority of small molecules, proteins and peptides do not cross the BBB. However, the brain needs many molecules for survival, including insulin, transferrin and low-density lipoprotein. Receptors present on the BBB actively transport these molecules from the blood into the brain. For example, insulin binds to the insulin-receptor which allows it to enter the brain. This mechanism is known as receptor-mediated transcytosis.

Using A Natural Mechanism to Allow Anti-Cancer Drugs to Enter the Brain

The lipoprotein receptor-related protein-1 (LRP-1) receptor is one of the most highly expressed receptors at the BBB and naturally transports numerous proteins to the brain. By linking the LRP-1 peptide binding sequence to therapeutic agents, the receptor can be targeted to exploit this native mechanism for crossing the BBB to deliver therapeutic agents into the brain.

GRN1005 is a peptide-drug conjugate (PDC) that consists of three molecules of paclitaxel, an approved and effective anti-cancer drug that in its naked form cannot penetrate the brain, covalently linked to a proprietary 19 amino acid peptide (AngioPep-2) to target LRP-1. GRN1005 is designed to cross the BBB via LRP-1 receptor mediated transcytosis. Since LRP-1 is also up-regulated in many tumors, entry into tumor cells may occur via LRP-1 mediated endocytosis once across the BBB and in the brain. LRP-1 is up-regulated in cancers in the brain as well other organs, enabling entry into tumors in the brain and in the periphery using the same receptor-mediated pathway.

GRN1005 was in-licensed from Angiochem, Inc., and Geron is clinically developing GRN1005 for the treatment of systemic cancer and metastases in the brain.

Inhibiting Telomerase in the Brain

Geron is collaborating with Angiochem, Inc. to research the use of receptor-targeting peptides to transport telomerase inhibitors into the central nervous system (CNS) for the potential treatment of cancers.