PT - JOURNAL ARTICLE AU - Ning Zhao AU - Yangjie Huang AU - Yung-hua Wang AU - Ryan K. Muir AU - Ying-Chu Chen AU - Junnian Wei AU - Nima Hooshdaran AU - Pavithra Viswanath AU - Youngho Seo AU - Davide Ruggero AU - Adam R. Renslo AU - Michael J. Evans TI - Ferronostics: Measuring Tumoral Ferrous Iron with PET to Predict Sensitivity to Iron-Targeted Cancer Therapies AID - 10.2967/jnumed.120.252460 DP - 2021 Jul 01 TA - Journal of Nuclear Medicine PG - 949--955 VI - 62 IP - 7 4099 - http://jnm.snmjournals.org/content/62/7/949.short 4100 - http://jnm.snmjournals.org/content/62/7/949.full SO - J Nucl Med2021 Jul 01; 62 AB - Although cancer has been known for decades to harbor an insatiable appetite for iron, only recently has the chemistry emerged to exploit this altered state therapeutically, by targeting the expanded cytosolic labile iron pool (LIP) of the cancer cell. The state of the art includes therapies that react with the LIP to produce cytotoxic radical species (in some cases also releasing drug payloads) and molecules that exacerbate LIP-induced oxidative stress to trigger ferroptosis. Effectively implementing LIP-targeted therapies in patients will require biomarkers to identify those tumors with the most elevated LIP and thus most likely to succumb to LIP-targeted interventions. Toward this goal, we tested whether tumor uptake of the novel LIP-sensing radiotracer 18F-TRX aligns with tumor sensitivity to LIP-targeted therapies. Methods: 18F-TRX uptake was assessed in vivo among 10 subcutaneous and orthotopic human xenograft models. Glioma and renal cell carcinoma were prioritized because these tumors have the highest relative expression levels of STEAP3, the oxidoreductase that reduces ferric iron to the ferrous oxidation state, in the Broad Institute Cancer Cell Line Encyclopedia. The antitumor effects of the LIP-activated prodrug TRX-CBI, which releases the DNA alkylator CBI, were compared in mice bearing U251 or PC3 xenografts, tumors with high and intermediate levels of 18F-TRX uptake, respectively. Results: 18F-TRX showed a wide range of tumor accumulation. An antitumor assessment study showed that the growth of U251 xenografts, the model with the highest 18F-TRX uptake, was potently inhibited by TRX-CBI. Moreover, the antitumor effects against U251 were significantly greater than those observed for PC3 tumors, consistent with the relative 18F-TRX–determined LIP levels in tumors before therapy. Lastly, a dosimetry study showed that the estimated effective human doses for adult male and female mice were comparable to those of other 18F-based imaging probes. Conclusion: We report the first evidence—to our knowledge—that tumor sensitivity to an LIP-targeted therapy can be predicted with a molecular imaging tool. More generally, these data bring a new dimension to the nuclear theranostic model by showing a requirement for imaging to quantify, in situ, the concentration of a metastable bioanalyte toward predicting tumor drug sensitivity.