Synthesis of the PET Tracer <sup>124</sup>I-Trametinib for MAPK/ERK Kinase Distribution and Resistance Monitoring

Pratt, Edwin C.; Isaac, Elizabeth; Stater, Evan P.; Yang, Guangbin; Ouerfelli, Ouathek; Pillarsetty, Nagavarakishore; Grimm, Jan

doi:10.2967/jnumed.120.241901

Cited by 8 publications

(11 citation statements)

References 19 publications

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“…Clinical imaging to quantify tumor vascularization and permeability is available (50), and clinical albumin imaging agents (58-61) may identify lesions with heterogeneous albumin extravasation (60,62) to guide treatment with highly protein-bound drugs (63). Such approaches, or even imaging with recently described KI radiotracers (64)(65)(66), may be integrated within a quantitative systems pharmacology framework to guide dosing, treatment selection, and possible combination therapy (67,68). In the case of BRAF-mutant cancers, such image-guided considerations may help a clinician weigh trade-offs between related KIs such as encorafenib and dabrafenib.…”

Section: Discussionmentioning

confidence: 99%

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Kronister

et al. 2022

Sci. Adv.

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BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non–small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

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Section: Discussionmentioning

confidence: 99%

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Kronister

et al. 2022

Sci. Adv.

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“…A concern regarding melanin-targeting molecules is that they may have increased toxicities because of their greater dissemination and retention throughout the body within different sites of metastases. However, studies of 131 I-ICF01012 and 131 I-ICF15002 have demonstrated promising anti-tumor results in vivo with limited toxicities [86,103].…”

Section: Melanin Targetingmentioning

confidence: 99%

Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma

et al. 2022

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Melanoma is a deadly disease that often exhibits relentless progression and can have both early and late metastases. Recent advances in immunotherapy and targeted therapy have dramatically increased patient survival for patients with melanoma. Similar advances in molecular targeted PET imaging can identify molecular pathways that promote disease progression and therefore offer physiological information. Thus, they can be used to assess prognosis, tumor heterogeneity, and identify instances of treatment failure. Numerous agents tested preclinically and clinically demonstrate promising results with high tumor-to-background ratios in both primary and metastatic melanoma tumors. Here, we detail the development and testing of multiple molecular targeted PET-imaging agents, including agents for general oncological imaging and those specifically for PET imaging of melanoma. Of the numerous radiopharmaceuticals evaluated for this purpose, several have made it to clinical trials and showed promising results. Ultimately, these agents may become the standard of care for melanoma imaging if they are able to demonstrate micrometastatic disease and thus provide more accurate information for staging. Furthermore, these agents provide a more accurate way to monitor response to therapy. Patients will be able to receive treatment based on tumor uptake characteristics and may be able to be treated earlier for lesions that with traditional imaging would be subclinical, overall leading to improved outcomes for patients.

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“…Due to anaplastic thyroid cancer’s aggressive nature and poor prognosis, there is a major lack of radiomic studies on it. However, utilizing radiomics can help predict resistance to an FDA approved therapy for ATC – trametinib ( 105 ). Trametinib is a highly potent, efficacious, yet toxic, treatment option for ATC, so modifying the dose is desirable ( 105 ).…”

Section: Thyroid Cancersmentioning

confidence: 99%

“…However, utilizing radiomics can help predict resistance to an FDA approved therapy for ATC – trametinib ( 105 ). Trametinib is a highly potent, efficacious, yet toxic, treatment option for ATC, so modifying the dose is desirable ( 105 ). In a study conducted by Pratt et.…”

Section: Thyroid Cancersmentioning

confidence: 99%

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Diagnostic Utility of Radiomics in Thyroid and Head and Neck Cancers

Gul¹,

Bonjoc²,

Gorlin³

et al. 2021

Front. Oncol.

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Radiomics is an emerging field in radiology that utilizes advanced statistical data characterizing algorithms to evaluate medical imaging and objectively quantify characteristics of a given disease. Due to morphologic heterogeneity and genetic variation intrinsic to neoplasms, radiomics have the potential to provide a unique insight into the underlying tumor and tumor microenvironment. Radiomics has been gaining popularity due to potential applications in disease quantification, predictive modeling, treatment planning, and response assessment – paving way for the advancement of personalized medicine. However, producing a reliable radiomic model requires careful evaluation and construction to be translated into clinical practices that have varying software and/or medical equipment. We aim to review the diagnostic utility of radiomics in otorhinolaryngology, including both cancers of the head and neck as well as the thyroid.

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Synthesis of the PET Tracer ¹²⁴I-Trametinib for MAPK/ERK Kinase Distribution and Resistance Monitoring

Cited by 8 publications

References 19 publications

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma

Diagnostic Utility of Radiomics in Thyroid and Head and Neck Cancers

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Synthesis of the PET Tracer 124I-Trametinib for MAPK/ERK Kinase Distribution and Resistance Monitoring

Cited by 8 publications

References 19 publications

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma

Diagnostic Utility of Radiomics in Thyroid and Head and Neck Cancers

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Product

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Synthesis of the PET Tracer ¹²⁴I-Trametinib for MAPK/ERK Kinase Distribution and Resistance Monitoring