By Jennifer Souratha
Cancer treatments aim to attack rogue cells that cause chaos in the body. An anticancer agent’s main objective is to reach the target cells and, in a therapeutic window, defeat them without damaging the rest of the body. In this fight, the battlefield of solid tumors can be problematic. Solid tumors present drug delivery challenges due to their unique characteristics. The mass that makes up a solid tumor includes tumor cells, tumor stroma, and a hypoxic tumor microenvironment that can have high interstitial fluid pressure, abnormal blood vessels, and restricted blood flow. While higher doses of a therapeutic might increase drug concentrations at the intended target, many approved cancer therapies have narrow therapeutic indices, which limit their dosing ranges. Therefore, delivery of anticancer agents to target cells in solid tumors, without causing other negative effects, can often be challenging to achieve.
Accumulation of hyaluronan in many solid tumors is associated with tumor progression and poor prognosis. Hyaluronidases are enzymes that degrade hyaluronan, allowing for an increase in vascular permeation to the tissues and a decrease in the tumor’s hypoxic environment. At the 2016 AAPS National Biotechnology Conference, Halozyme will present a preclinical evaluation of their investigational new drug, PEGylated recombinant hyaluronidase PH20 (PEGPH20), in conjunction with cetuximab. Using cetuximab as an example anti-tumor therapeutic, our research team at Halozyme investigated the uptake of this therapeutic antibody in a mouse model of human pancreatic cancer. Testing the plasma, we evaluated the differences in the circulating antibody drug levels with and without PEGPH20. Lower circulating levels of cetuximab were measured when PEGPH20 was included, supporting the hypothesis that the enzyme increased the uptake of cetuximab in the tumor. Using the same tumor model, we examined PET scans to quantitatively assess the uptake of radiolabeled cetuximab in the presence of PEGPH20. We observed enhanced drug delivery to the tumor with the addition of PEGPH20.
Solid tumors can be difficult to reach because of their defenses. This work highlights how targeting hyaluronan, a known component of the complex tumor microenvironment, may enhance the delivery of anticancer agents into solid tumors and allow them to reach their targets in a preclinical model and warrants the continued research of this investigational drug.