Deadly DAaRTS destroy cancer cells via a tumor microenvironment–mediated trigger
James V. McCann, … , Jamie L. Null, Andrew C. Dudley
James V. McCann, … , Jamie L. Null, Andrew C. Dudley
Published July 2, 2018; First published June 4, 2018
Citation Information: J Clin Invest. 2018;128(7):2750-2753. https://doi.org/10.1172/JCI121527.
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Commentary

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

Abstract

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, TEM8-ADC 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.

Authors

James V. McCann, Jamie L. Null, Andrew C. Dudley

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Figure 1

TEM8-ADC kills cancer cells via a bystander mechanism dependent on TEM8-expressing tumor stroma.

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TEM8-ADC kills cancer cells via a bystander mechanism dependent on TEM8-...
The efficacy of the TEM8-ADC (i) as an antitumor agent is driven by DAaRTS. TEM8 expression in the tumor stroma, including fibroblasts, pericytes, and endothelial cells, localizes MMAE-linked TEM8-ADC to growing tumors (ii). Upon binding to stromal cells, the ADC is endocytosed and processed by lysosomal proteases such as cathepsin B (iii), thereby liberating cell-permeable MMAE that is exported by the drug transporter P-gp. Once MMAE is evicted from stromal cells, it is bioavailable to the rapidly proliferating cancer cells nearby (iv), where it induces apoptosis (provided these cancer cells do not express abundant P-gp themselves). For simplicity, processing of TEM8-ADC and eviction of free MMAE is only shown in CAFs; however, similar mechanisms may occur in cancer-associated pericytes and endothelial cells that also express TEM8.