Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with Braf^V600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.

Purpose: Glucose transporters 1 (GLUT1) facilitates glucose uptake in cancer. An inverse relationship between I-131 and F-18 fluorodeoxyglucose (FDG) uptake in PET/CT (“flip-flop phenomenon”) was described for thyroid cancers (TCs) during dedifferentiation. We investigated the relationship among GLUT1 expression, proliferation, iodine concentration, and glucose uptake in different TC types, with emphasis on “poorly differentiated thyroid carcinoma” (PDTC). Methods: For immunohistochemistry, 95 thyroid tumors (follicular adenoma, papillary TC, follicular TC, PDTC, and anaplastic TC [ATC]) were investigated for GLUT1 expression and proliferation (Ki-67 index). For PET/CT study, 47 F-18 FDG PET/CT of patients with TC (22 PDTC), 39 corresponding I-124 PET/CT, and glucose and iodine uptake were evaluated. PTC and FTC were summarized under differentiated TC (DTC). Results: Immunohistochemistry: 65% of TC expressed GLUT1. The number of GLUT1-positive TC and GLUT1 expression increased with escalating dedifferentiation/aggressiveness of TC types (P < 0.001). A correlation between proliferation and GLUT1 expression was noted (P < 0.001). PET/CT study: F-18 FDG uptake was measured in 81% of cases. Occurrence of F-18 FDG-avid cases as well as median F-18 FDG maximum standardized uptake values were lowest in DTC, intermediate in PDTC, and highest in ATC. Accordingly, numbers of iodine-avid cases and median I-124 maximum standardized uptake value featured an inverse pattern. Conclusions: Dedifferentiation in TC is accompanied by GLUT1 upregulation and increased proliferation. PDTC was found to be intermediate between DTC and ATC in terms of GLUT1 expression and F-18 FDG or I-124 uptake, suggesting that the flip-flop phenomenon occurs at a dedifferentiation stage in between. Furthermore, the results suggest that F-18 FDG PET/CT is an important imaging modality for ATC and PDTC.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [¹⁷⁷Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [¹⁷⁷Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

This study aimed to assess the diagnostic performance of integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) of the breast for lesion detection and local tumor staging of patients with primary breast cancer in comparison to PET/computed tomography (CT) and MRI. The study was approved by the local institutional review board. Forty-nine patients with biopsy-proven invasive breast cancer were prospectively enrolled in our study. All patients underwent a PET/CT, and subsequently, a contrast-enhanced PET/MRI of the breast after written informed consent was obtained before each examination. Two radiologists independently evaluated the corresponding data sets (PET/CT, PET/MRI, and MRI) and were instructed to identify primary tumors lesions as well as multifocal/multicentric and bilateral disease. Furthermore, the occurrence of lymph node metastases was assessed, and the T-stage for each patient was determined. Histopathological verification of the local tumor extent and the axillary lymph node status was available for 30 of 49 and 48 of 49 patients, respectively. For the remaining patients, a consensus characterization was performed for the determination of the T-stage and nodal status, taking into account the results of clinical staging, PET/CT, and PET/MRI examinations. Statistical analysis was performed to test for differences in diagnostic performance between the different imaging procedures. P values less than 0.05 were considered to be statistically significant. Positron emission tomography/MRI and MRI correctly identified 47 (96%) of the 49 patients with primary breast cancer, whereas PET/CT enabled detection of 46 (94%) of 49 breast cancer patients and missed a synchronous carcinoma in the contralateral breast in 1 patient. In a lesion-by-lesion analysis, no significant differences could be obtained between the 3 imaging procedures for the identification of primary breast cancer lesions (P > 0.05). Positron emission tomography/MRI and MRI allowed for a correct identification of multifocal/multicentric disease in 3 additional patients if compared with PET/CT. For the definition of the correct T-stage, PET/MRI and MRI showed identical results and were correct in significantly more cases than PET/CT (PET/MRI and MRI, 82%; PET/CT, 68%; P < 0.05). Furthermore, the calculated sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for the detection of nodal positive patients (n = 18) were 78%, 94%, 88%, 88%, and 88% for PET/CT; 67%, 87%, 75%, 82%, and 80% for MRI; and 78%, 90%, 82%, 88%, and 86% for PET/MRI, respectively. Differences between the imaging modalities were not statistically significant (P > 0.05). Integrated PET/MRI does not provide diagnostic advantages for local tumor staging of breast cancer patients in comparison to MRI alone. Positron emission tomography/MRI and MRI enable an improved determination of the local tumor extent in comparison to PET/CT, whereas all 3 imaging modalities offer a comparable diagnostic performance for the identification of axillary disease.

Translation initiation is orchestrated by the cap binding and 43S preinitiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors. Significance: Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. EIF1AX-A113splice drives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4 also cooperates with c-MYC to sensitize mTOR to amino acid supply, thus generating vulnerability to mTOR kinase inhibitors. This article is highlighted in the In This Issue feature, p. 151