Ferronostics: Measuring Tumoral Ferrous Iron with PET to Predict Sensitivity to Iron-Targeted Cancer Therapies

Abstract

Background: 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 include 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 herein 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 ten subcutaneous and orthotopic human xenograft models. Glioma and renal cell carcinoma were prioritized as these tumors have the highest relative expression levels of STEAP3, the oxidoreductase that reduces ferric iron to the ferrous oxidation state, in the Cancer Cell Line Encyclopedia. The antitumor effects of the LIP activated prodrug TRX-CBI, which releases the DNA alkylator cyclopropylbenzindoline (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 prior to therapy. Lastly, a dosimetry study showed that the estimated effective human doses for adult males and females were comparable to those of other ¹⁸F-based imaging probes. Conclusion: We report the first evidence that tumor sensitivity to a 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.