We have developed new technologies to image iron with positron emission tomography (PET) in an oxidation state specific fashion and conducted radiomic studies in animals and humans to better understand how to exploit iron dyshomeostasis for the detection or treatment of human diseases. We are recognized for the discovery that mTORC1 and/or MYC are primary drivers of cellular uptake of ferric iron via transferrin in tumors and neoplastic disorders like LAM. Achieving this in mice was enable by new technology development (e.g. 89Zr-labeled transferrin) to measure ferric iron deposition in the most clinically relevant animal models (e.g. GEMMs, PDX’s). I have also led seven clinical trials in patients with cancer or LAM studying ferric iron uptake using 68Ga-citrate PET (68Ga is a ferric iron biomimetic in vivo). Radiomic studies have shown that MYC and/or mTORC1 hyperactivity are the primary drivers of ferric iron uptake, a finding that has since motivated us to test if disorders bearing mutations in these pathways are susceptible to therapies that deplete or further exacerbate iron dyshomeostasis to promote “ferroptosis”. To further enable these studies, we recently developed the first chemical sensor (18F-TRX) to detect the cytosolic pool of bioactive ferrous iron (the so called “labile iron pool”) with PET. This radiotracer has enabled unprecedented measurements of cellular LIP in living subjects, which is essential to our understanding of iron regulation as LIP cannot be measured with conventional analytical techniques that require disrupting the native cellular environment (e.g. ICP-MS). Monitoring LIP in vivo with PET will help us predict if LIP concentration is sufficiently augmented to target therapeutically, or if treatments designed to induce ferroptosis are efficacious. In summary, my lab is internationally recognized as a leader in the development of theranostic strategies to target iron dyshomeostasis.
Relevant Publications
- Holland JP, Evans MJ, Rice SL, Wongvipat J, Sawyers CL, Lewis JS. Annotating MYC status with 89Zr-transferrin imaging. Nat Med. 2012 Oct; 18(10):1586-91. PMID: 23001181.
- Evans MJ, Holland JP, Rice SL, Doran MG, Cheal SM, Campos C, Carlin SD, Mellinghoff IK, Sawyers CL, Lewis JS. Imaging tumor burden in the brain with 89Zr-transferrin. J Nucl Med. 2013 Jan; 54(1):90-5. PMID: 23236019.
- Doran MG, Carnazza KE, Steckler JM, Spratt DE, Truillet C, Wongvipat J, Sawyers CL, Lewis JS, Evans MJ. Applying 8? Zr-Transferrin To Study the Pharmacology of Inhibitors to BET Bromodomain Containing Proteins. Mol Pharm. 2016 Feb 01; 13(2):683-8. PMID: 26725682.
- Behr SC, Aggarwal R, Seo Y, Aparici CM, Chang E, Gao KT, Tao DH, Small EJ, Evans MJ. A Feasibility Study Showing [68Ga]Citrate PET Detects Prostate Cancer. Mol Imaging Biol. 2016 12; 18(6):946-951. PMID: 27184068.
- Truillet C, Cunningham JT, Parker MFL, Huynh LT, Conn CS, Ruggero D, Lewis JS, Evans MJ. Noninvasive Measurement of mTORC1 Signaling with 89Zr-Transferrin. Clin Cancer Res. 2017 Jun 15; 23(12):3045-3052. PMID: 28007777.
- Mari Aparici C, Behr SC, Seo Y, Kelley RK, Corvera C, Gao KT, Aggarwal R, Evans MJ. Imaging Hepatocellular Carcinoma With 68Ga-Citrate PET: First Clinical Experience. Mol Imaging. 2017 Jan-Dec; 16:1536012117723256. PMID: 28893116.
- Aggarwal R, Behr SC, Paris PL, Truillet C, Parker MFL, Huynh LT, Wei J, Hann B, Youngren J, Huang J, Premasekharan G, Ranatunga N, Chang E, Gao KT, Ryan CJ, Small EJ, Evans MJ. Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer. Mol Cancer Res. 2017 09; 15(9):1221-1229. PMID: 28592703.
- Behr SC, Villanueva-Meyer JE, Li Y, Wang YH, Wei J, Moroz A, Lee JK, Hsiao JC, Gao KT, Ma W, Cha S, Wilson DM, Seo Y, Nelson SJ, Chang SM, Evans MJ. Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR. JCI Insight. 2018 11 02; 3(21). PMID: 30385712.
- Muir RK, Zhao N, Wei J, Wang YH, Moroz A, Huang Y, Chen YC, Sriram R, Kurhanewicz J, Ruggero D, Renslo AR, Evans MJ. Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography. ACS Cent Sci. 2019 Apr 24; 5(4):727-736. PMID: 31041393.
- Elevated labile iron in castration-resistant prostate cancer is targetable with ferrous iron-activatable antiandrogen therapy. Eur J Med Chem. 2023 Mar 05; 249:115110.Gonciarz RL, Sakhamuri S, Hooshdaran N, Kumar G, Kim H, Evans MJ, Renslo AR. PMID: 36708680; PMCID: PMC10210592.
- Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors. J Exp Med. 2022 04 04; 219(4).Jiang H, Muir RK, Gonciarz RL, Olshen AB, Yeh I, Hann BC, Zhao N, Wang YH, Behr SC, Korkola JE, Evans MJ, Collisson EA, Renslo AR. PMID: 35262628; PMCID: PMC8916116.