Deadly DAaRTS destroy cancer cells via a tumor microenvironment-mediated trigger

Targeting tumor stroma for anticancer therapy The concept that solid tumors are heterogeneous communities of interdependent cell types, rather than homogeneous spheres of malignant cancer cells, has fundamentally changed the [...]
Stromal cells within the tumor microenvironment play a supportive role in tumor growth, progression, and treatment resistance; therefore, these nonmalignant cells are potential therapeutic targets. In this issue of the JCI, Szot et al. devised a strategy to exploit the cell-surface marker TEM8 (also known as ANTXR1), which is expressed by cancer-associated stromal cells, as a zip code to deliver an antibody-drug conjugate (ADC) linked to the potent cancer-killing drug monomethyl auristatin E (MMAE). In preclinical tumor and experimental metastasis models of multiple cancer types, TEM8ADC targeted TEM8-expressing cancer-associated stromal cells, which processed and liberated membrane-permeable MMAE and released this drug via the P-glycoprotein (P-gp) drug transporter. Released MMAE killed cancer cells through a bystander mechanism that did minimal damage to the stromal cells themselves. P-gp-expressing tumor cells displayed MMAE resistance, suggesting that P-gp expression status may identify patients who might benefit the most from TEM8-ADC. This strategy, termed DAaRTS (drug activation and release through stroma), represents an elegant example of how selective expression of a cell-surface molecule on cancer-associated stroma can be exploited to facilitate drug delivery and shrink solid tumors.