The log in the title here refers to “logjammed,” a word that means a crowded mass of logs, which block a river or in the case of lead EpicentRx therapy, RRx-001 (nibrozetone), a crowded mass of cells that obstruct blood flow in tumor vessels. In a well cited 2021 manuscript from the highly impactful Journal of Medicinal Chemistry entitled “Discovery of RRx-001, a Myc and CD47 Downregulating Small Molecule with Tumor Targeted Cytotoxicity and Healthy Tissue Cytoprotective Properties in Clinical Development,” EpicentRx authors refer to RRx-001-induced “logjamming” of red blood cells in the tumor vasculature, as shown by the red arrow below.
The reason for the logjamming is that RRx-001 preferentially targets the endothelial cells, which line the surface of the most immature and dysfunctional tumor blood vessels. When those abnormal endothelial cells die, they slough off, and obstruct blood flow. Tumor endothelial cells are preferentially targeted by RRx-001 because of their much higher proliferation rate compared to the endothelial cells in normal tissues. This leads to regression or pruning of the obstructed vessels and improved rerouting of blood flow, which increases oxygenation and drug uptake, and accounts at least in part for the chemoradiosensitization properties of RRx-001.
Preclinical studies demonstrate that the more abnormal, immature and dysfunctional the tumor blood vessels, the better those tumors respond to RRx-001.
It is probably no coincidence that the vasculatures of small cell lung cancer (SCLC) and head and neck cancer tumors, which feature two ongoing late-stage clinical trials with RRx-001, REPLATINUM (Phase 3) and KEVLARx (Phase 2b), respectively, are highly abnormal and dysfunctional.