Molecular Perspectives in Radioactive Iodine Theranostics: Current Redifferentiation Protocols for Mis-Differentiated Thyroid Cancer

Abstract

Thyroid cancer molecular oncogenesis involves functional dedifferentiation. The initiating genomic alterations primarily affect the MAPK pathway signal transduction and generate an enhanced ERK output, which in turn results in suppression of the expression of transcription of the molecules of iodine metabolomics. The clinical end result of these molecular alterations is an attenuation in theranostic power of radioactive iodine (RAI). The utilization of RAI in systemic therapy of metastatic disease requires restoration of the functional differentiation. This concept has been accomplished by modulation of MAPK signaling. Objective responses have been demonstrated in metastatic disease settings. RAI-refractoriness in "differentiated thyroid cancers" remains a clinical problem despite optimized RAI administration protocols. Functional mis-differentiation and associated RAI-indifference are the underlying primary obstacles. MAPK pathway modulation offers a potential for reversal of RAI-indifference and combat refractoriness. This review presents the latest clinical experience and protocols for the redifferentiation of radioiodine-refractory mis-differentiated thyroid cancer, providing a comprehensive overview of the current protocols and intervention strategies used by leading institutions. Timing and techniques of imaging, thyrotropin (TSH) stimulation methods, and redifferentiation agents are presented. The efficacy and limitations of various approaches are discussed, providing an overview of the advantages and disadvantages associated with each of the protocols.

Keywords: differentiated thyroid cancer; genomics; mis-differentiated thyroid cancer; molecular theranostics; radioactive iodine indifferent; radioactive iodine refractory; redifferentiation; theranostic potential; theranostic power; thyroid cancer.

Figure 2

Signal transduction pathways leading to generic phenotypic expressions of oncogenesis (A) and specific iodine transcriptomic expression (B). Panel (B) is a heat map depicting physiologic expression levels of iodine handling genes. From left to right: normal thyroid tissue, RAS-mutated cancers, non-RAS/non-BRAF cancers, and BRAF-mutated cancers. Darker colors indicate suppressed expression of genes. The lighter (brighter) colors of the iodine metabolic transcriptome under the “normal” column indicate regular expression of respective genes. The MAPK-ERK pathway is well established and studied for effective modulation towards redifferentiation. The PI3K-mTOR pathway’s role in functional dedifferentiation and redifferentiation interventions are under investigation. I–III: MAPK-ERK pathway interventions. BRAF inhibitors: dabrafenib, vemurafenib, and encorafenib; MEK inhibitors: trametinib, cobimetinib, binimetinib, and selumetinib. IV–V: PI3K-mTOR pathway interventions. mTOR inhibitor: everolimus; PI3K inhibitor: copanlisib. VI–VII: RTK fusion oncoprotein interventions. RET fusion inhibitors: selpercatinib and pralsetinib; NTRK fusion inhibitors: larotrectinib and entrectinib. VIII–XI: RTK interventions. Multikinase inhibitors: lenvatinib: FGFR, PDGFR, VEGFR, and C-KIT; sorafenib: PDGFR, VEGFR, and C-KIT. Cabozantinib: MET and VEGFR2. The RAS molecule is activated by multiple TKRs and serves as a common inducting molecule for downstream signaling. Further specifics, including FDA approval status, of the therapeutic agents listed in this figure are listed in Table 1. Created with Biorender.com (https://app.biorender.com, Accessed 1 May 2024).

Figure 1

MAPK-ERK pathway and its ERK-mediated feedback regulation. A constitutive activation of the MAPK pathway results in enhanced ERK output. The intranuclear interactions of the ERK-mediated transcriptional program is rather complicated. There are two major directions for ERK-mediated transcriptional modifications. First is the generic oncogenic program producing the hallmarks of cancer phenotype: Panel (A). The second, the subject of this review, is the disruption of follicular functional differentiation via interruption of expression of genes associated with thyroid functional differentiation: Panel (B), a heat map depicting physiologic expression levels of iodine handling genes. From left to right: normal thyroid tissue, RAS-mutated cancers, non-RAS/non-BRAF cancers, and BRAF-mutated cancers. Darker colors indicate suppressed expression of genes. The lighter (brighter) colors of the iodine metabolic transcriptome under the “normal” column indicate regular expression of respective genes. ERK has feedback control over the MAPK pathway via RAS and RAF. For RAS-mutated cancers, ERK feedback inhibition works via both RAS and RAF. MEK-only inhibition is considered adequate for clinical redifferentiation. ERK feedback inhibition does not work with mutated BRAF. To achieve a clinically effective redifferentiation, MEK and BRAF combined inhibition is often required. Created with Biorender.com (https://app.biorender.com, Accessed 1 May 2024).

Figure 3

A successful redifferentiation of a BRAF (+) RAI-indifferent metastatic thyroid cancer with combined BRAF and MEK inhibition treatment. The first column of images on the left is the representative views of I-124 PET/CT obtained prior to redifferentiation treatment. The column in the middle demonstrates the views of I-124 PET/CT obtained after the redifferentiation treatment. The last column on the right is the post-treatment whole-body scan with 150 mCi activity (MCRC series).

Figure 4

A flow chart for a comprehensive redifferentiation protocol. The pre-redifferentiation work-up includes (1) evaluation of the metastatic disease pattern and volume with functional/anatomic imaging, (2) Tg panel, (3) genomic and molecular profiling, and (4) determination of the clinically appropriate redifferentiation agent(s). Pre-redifferentiation work-up is completed 3–6 weeks prior to committing the redifferentiation drug therapy. The evaluation for RAI-refractory disease is performed by using I-124 PET/CT imaging. Preparation for imaging involves TSH stimulation. This can be performed with the rhTSH or withdrawal protocol. In the latter, the patients receive rhTSH injections on the first two days of the week block. I-124, 1–2 mCi, is administered on the third day. A complete image data set includes 3-day imaging for determination of cumulated activity (lesional and whole-body/bone marrow) and established MIRD voxel dosimetry. Each imaging time point also provides additional technical information (2–4 h imaging for calibration, 24 h imaging for conventional uptake determination, and 48 h is for SUV-based single-time-point predictive dosimetry). The patients then start the redifferentiation drug therapy. An evaluation of redifferentiation is performed in the fifth week block. This, essentially, is similar to I-124 imaging and the dosimetry protocol used prior to initiating the redifferentiation treatment. A decision to proceed with an anticipated RAI therapy is made at the end of this week. The TSH induction protocol is kept consistent for imaging and therapy interventions. With the rhTSH choice, the patients receive rhTSH injections on the first two days of the sixth week block. The RAI therapy is administered on the third day of the protocol week. The administered activity is determined by institutional preferences, typically in the range of 150–300 mCi I-131. The conventional post-treatment RAI scan, whole-body, and SPECT scan are performed on day 7 of the RAI administration. A 48 hour imaging is helpful for validation of pretreatment dosimetric evaluation. The restaging work-up is performed 3–6 m post-RAI-treatment and includes functional and anatomic imaging as well as the Tg panel.