18F-fluoromisonidazole predicts evofosfamide uptake in pancreatic tumor model

Grkovski, Milan; Fanchon, Louise M.; Pillarsetty, Nagavarakishore; Russell, James; Humm, John L.

doi:10.1186/s13550-018-0409-1

Cited by 5 publications

(5 citation statements)

References 11 publications

(12 reference statements)

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“…Such a strategy involving FMISO-CLI would allow a rapid selection of subjects with positive hypoxic signal in order to successfully evaluate hypoxia-targeting drugs. This was recently highlighted by Grkovski et al who suggested that the poor outcome of the MAESTRO trial, evaluating the hypoxia-activated evofosfamide, was partly due to the inclusion of non-hypoxic tumours, which may have masked the benefit of the drug [5]. Such a result shows that not only CLI is relevant to assess tumour hypoxia, but also for preclinical drug development due to its high throughput capabilities also reported elsewhere [8].…”

Section: Discussionmentioning

confidence: 92%

“…Biomarkers of tumour hypoxia allow to improve the drug development process through the selection of individuals potentially eligible for therapies that target hypoxic environment in both preclinical and clinical settings [5]. FMISO is a well-known PET radiotracer of tumour hypoxia [3] able to produce a CR due to the emission of a positron with a maximal energy of 633 keV [2].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, PET/MRI imaging requires expensive systems and is usually characterised by measurement times ranging from 20 to 30 min for static imaging studies and up to 60–90 min when involving dynamic PET assessments or/and functional MRI imaging [4]. Thus, CLI could represent a fast, cost-effective and decisive tool to predict the efficacy of hypoxia-activated anticancer drugs since baseline hypoxia imaging is of crucial interest to successfully develop hypoxia-targeted drugs in both preclinical [5] and clinical settings [6]. In addition, the use of CLI in humans has also recently been demonstrated, providing CLI with an important translational aspect [7].…”

Section: Introductionmentioning

confidence: 99%

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Cherenkov luminescence imaging is a fast and relevant preclinical tool to assess tumour hypoxia in vivo

et al. 2018

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PurposeMolecular imaging techniques visualise biomarkers for both drug development and personalised medicine. In this field, Cherenkov luminescence imaging (CLI) seems to be very attractive by allowing imaging with clinical PET radiotracers with high-throughput capabilities. In this context, we developed a fast CLI method to detect tumour hypoxia with 18F-fluoromisonidazole (FMISO) for drug development purposes.MethodsColon cancer model was induced in mice by subcutaneous injection of 1 × 106 CT-26 cells. FMISO was injected, and simultaneous PET-blood oxygen level dependent (BOLD)-MRI followed by CLI were performed along with immunohistochemistry staining with pimonidazole.ResultsThere was a significant correlation between FMISO PET and CLI tumour uptakes, consistent with the BOLD-MRI mapping. Tumour-to-background ratio was significantly higher for CLI compared with PET and MRI. Immunohistochemistry confirmed tumour hypoxia. The imaging workflow with CLI was about eight times faster than the PET-MRI procedure.ConclusionCLI is a fast and relevant tool to assess tumour hypoxia. This approach could be particularly interesting for hypoxia-targeting drug development.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0464-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cherenkov luminescence imaging is a fast and relevant preclinical tool to assess tumour hypoxia in vivo

et al. 2018

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“…First, screening methods need to be developed based on tumor hypoxia to select the best candidates for this type of therapy. A growing number of studies have shown that PET/CT imaging can be an effective method to monitor HAPs uptake and therapeutic response ( 148 , 190 , 192 ). Second, biomarkers to predict drug sensitivity are needed.…”

Section: Conclusion and Suggestions For Future Investigationsmentioning

confidence: 99%

Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy

Zhao

2021

Front. Oncol.

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Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most important factors associated with resistance to conventional radiotherapy and chemotherapy. Therapies targeting tumor hypoxia have attracted considerable attention. Hypoxia-activated prodrugs (HAPs) are bioreductive drugs that are selectively activated under hypoxic conditions and that can accurately target the hypoxic regions of solid tumors. Both single-agent and combined use with other drugs have shown promising antitumor effects. In this review, we discuss the mechanism of action and the current preclinical and clinical progress of several of the most widely used HAPs, summarize their existing problems and shortcomings, and discuss future research prospects.

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“…In this context, we propose that imaging of hypoxia may help with patient stratification and therapy monitoring (19)(20)(21)(22). To this end, different magnetic resonance imaging (MRI)-and positron emission tomography (PET)-imaging based analyses have been explored to identify tumor hypoxia (23,24) and predict response to HAPs in pre-clinical models (19,25).…”

Section: Introductionmentioning

confidence: 99%

Targeting hypoxic habitats with hypoxia pro-drug evofosfamide in preclinical models of sarcoma

Jardim‐Perassi

Huang

et al. 2020

Preprint

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Hypoxic regions (habitats) within tumors are heterogeneously distributed and can be widely variant. Hypoxic habitats are generally pan-therapy resistant. For this reason, hypoxia-activated prodrugs (HAPs) have been developed to target these resistant volumes. The HAP evofosfamide (TH-302) has shown promise in preclinical and early clinical trials of sarcoma. However, in a phase III clinical trial, TH-302 did not improve survival in combination with doxorubicin (dox), most likely due to a lack of patient stratification based on hypoxic status. Herein, our goal was to develop deep-learning (DL) models to identify hypoxic habitats, using multiparametric (mp) MRI and co-registered histology, and to non-invasively monitor response to TH-302 in a patient-derived xenograft (PDX) of rhabdomyosarcoma and a syngeneic model of fibrosarcoma (RIF-1). A DL convolutional neural network showed strong correlations (>0.81) between the true hypoxic portion in histology and the predicted hypoxic portion in multiparametric MRI. TH-302 monotherapy or in combination with Dox delayed tumor growth and increased survival in the hypoxic PDX model (p<0.05), but not in the RIF-1 model, which had lower volume of hypoxic habitats. Control studies showed that RIF-1 resistance was due to hypoxia and not to other causes. Notably, PDX tumors developed resistance to TH-302 under prolonged treatment. In conclusion, response to TH-302 can be attributed to differences in hypoxia status prior therapy. Development of non-invasive MR imaging to assess hypoxia is crucial in determining the effectiveness of TH-302 therapy and to follow response. In further studies, our approach can be used to better plan therapeutic schedules to avoid resistance.One Sentence SummaryDevelopment of non-invasive MR imaging to assess hypoxia is crucial in determining the effectiveness of TH-302 therapy and to follow response.

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18F-fluoromisonidazole predicts evofosfamide uptake in pancreatic tumor model

Cited by 5 publications

References 11 publications

Cherenkov luminescence imaging is a fast and relevant preclinical tool to assess tumour hypoxia in vivo

Cherenkov luminescence imaging is a fast and relevant preclinical tool to assess tumour hypoxia in vivo

Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy

Targeting hypoxic habitats with hypoxia pro-drug evofosfamide in preclinical models of sarcoma

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