Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR

Behr, Spencer C.; Villanueva-Meyer, Javier; Li, Yan; Wang, Sinan; Wei, Junnian; Moroz, Anna; Lee, Julia K.L.; Hsiao, Jeffrey C.; Gao, Kenneth T.; Ma, Wendy; Cha, Soonmee; Wilson, David M.; Seo, Youngho; Nelson, Sarah J.; Chang, Susan M.; Evans, Michael J.

doi:10.1172/jci.insight.93999

Cited by 26 publications

(50 citation statements)

References 28 publications

(36 reference statements)

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“…Since ferrous iron rapidly oxidizes once the native cellular environment is disrupted, it cannot be reliably quantified from tumor biopsies. Therefore, we developed a novel radiotracer termed 18 F-TRX to quantify LIP in situ with positron emission tomography (PET) (12). 18 F-TRX is based on the structure of artefenomel, an antimalarial with excellent pharmacokinetics that is currently in phase 2 clinical trials (13) (Figure 1C).…”

Section: Rsl3mentioning

confidence: 99%

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

et al. 2020

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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 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 herein whether tumor uptake of the novel LIP sensing radiotracer 18 F-TRX aligns with tumor sensitivity to LIP targeted therapies.Methods: 18 F-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 18 F-TRX uptake, respectively.Results: 18 F-TRX showed a wide range of tumor accumulation. An antitumor assessment study showed that the growth of U251 xenografts, the model with the highest 18 F-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 18 F-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 18 F-based imaging probes. Conclusions: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.

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Section: Rsl3mentioning

confidence: 99%

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

et al. 2020

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“…ECM contents might be destroyed along the way of glioma invasion and it has also been recently understood that iron avidity is enhanced in HGG because of inflammation. 56 , 57 R1 decreases as glioma invades brain tissue but may increase as a result of iron avidity in the proliferating/necrotic core. These 2 phenomena therefore act competitively on R1 value.…”

Section: Discussionmentioning

confidence: 99%

Multiparameter quantitative histological MRI values in high-grade gliomas: a potential biomarker of tumor progression

Reuter

Lommers

Balteau

et al. 2020

Neuro-Oncology Practice

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Background Conventional MRI poorly distinguishes brain parenchyma microscopically invaded by High-Grade Gliomas (HGG) from normal brain. By contrast, quantitative histological MRI (hMRI) measures brain microstructure in terms of physical MR parameters influenced by histochemical tissue composition. We aimed to determine the relationship between hMRI parameters in the area surrounding the surgical cavity and the presence of HGG recurrence. Methods Patients were scanned after surgery with a hMRI multiparameter protocol that allowed for estimations of R1=1/T1, R2*=1/T2*, Magnetization Transfer saturation (MTsat) and Proton Density. The initial perioperative zone (IPZ) was segmented on the postoperative MRI. Once recurrence appeared on conventional MRI, the area of relapsing disease was delineated (extension zone, EZ). Conventional MRI showing recurrence and hMRI were co-registered allowing for the extraction of parameters R1, R2*, MTsat and PD in 3 areas: the overlap area between the IPZ and EZ (OZ), the Peritumoral Brain Zone, PBZ (PBZ = IPZ-OZ), the area of recurrence (RZ = EZ-OZ). Results 31 patients with HGG who underwent gross-total resection were enrolled. MTsat and R1 were the most strongly associated with tumor progression. MTsat was significantly lower in OZ and RZ, compared to PBZ. R1 was significantly lower in RZ compared to PBZ. PD was significantly higher in OZ, compared to PBZ and R2* was higher in OZ, compared to PBZ or RZ. These changes were detected 4 to 120 weeks before recurrence recognition on conventional MRI. Conclusions HGG recurrence was associated with hMRI parameters variation after initial surgery, weeks to months before overt recurrence.

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“…62,63 When integrating with HP 13 C data, the 1 H spectral data and maps can be affinely registered to the 13 C data by applying the transformation matrix generated from the registration between the images acquired at two examinations, to enable voxel-byvoxel analysis. SIVIC can then be used to provide visual comparisons of 1 H and 13 C metabolic maps, as well as maps of standardized uptake values 64 from PET.…”

Section: Integration With Other Molecular Imaging Modalitiesmentioning

confidence: 99%

Hyperpolarized ¹³C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco

et al. 2020

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Based on the expanding set of applications for hyperpolarized carbon-13 (HP-13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP-13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP-13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information.

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Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR

Cited by 26 publications

References 28 publications

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

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

Multiparameter quantitative histological MRI values in high-grade gliomas: a potential biomarker of tumor progression

Hyperpolarized ¹³C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco

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Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR

Cited by 26 publications

References 28 publications

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

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

Multiparameter quantitative histological MRI values in high-grade gliomas: a potential biomarker of tumor progression

Hyperpolarized 13C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco

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Hyperpolarized ¹³C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco