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SAT-502 Clinical Hypothyroidism Associated with Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma: A Novel Adverse Effect of Peptide Receptor Radionuclide Therapy

ABSTRACT: Abstract Background: Peptide receptor radionuclide therapy (PRRT) is a relatively novel, emerging therapy for the treatment of metastatic pheochromocytoma and paraganglioma (PPGL). Lutetium 177 (177Lu)-DOTATATE (Lutathera ®) is a form of PRRT that is currently being evaluated for its treatment efficacy in metastatic PPGL. It acts by binding to somatostatin receptors 2 (SSTR2) which are present on PPGL and other tissues of neuroendocrine origin. Although subclinical thyroid dysfunction has been previously noted, development of clinical hypothyroidism post 177Lu-DOTATATE therapy has not been reported to date. Case: A 29-year-old male with Beckwith-Weidemann syndrome and metastatic, succinate dehydrogenase subunit B (SDHB) germline mutation-positive paraganglioma with normal metanephrines was enrolled at our center under the 177Lu-DOTATATE trial for the treatment of inoperable, metastatic PPGL (ClinicalTrials.gov NCT03206060). Prior to the first cycle of therapy, the patient underwent endocrine evaluation per protocol. He was noted to have suppressed thyroid stimulating hormone (TSH) of <0.01 mcIU/mL (normal: 0.27 - 4.2 mcIU/mL), and a normal free thyroxine (FT4) of 1.3 ng/dL (0.9 - 1.7 ng/dL), indicating subclinical hyperthyroidism. Thyroid auto-antibodies were not measured at that time point. The patient denied symptoms of hyper- or hypothyroidism. On physical examination, there was no thyromegaly or cervical lymphadenopathy. Serial monitoring of thyroid function tests (TFTs) was pursued. One month after the first cycle of 177Lu-DOTATATE therapy, the patient complained of new onset fatigue and weight gain. The TSH had markedly increased (73.04 mcIU/mL), along with a reduction in FT4 levels (0.3 mg/dL). Mass spectrometry measures revealed a low total T4 (1.3 ng/dL; 4.9 - 10.5 ng/dL), and a low total T3 (57 ng/dL; 87 - 169 ng/dL). Thyroid peroxidase antibodies were >1000 IU/mL (0.0 - 34.9 IU/mL), and anti-thyroglobulin antibodies were 668 IU/mL (0.0-40.0 IU/mL). Weight-based levothyroxine therapy was initiated and the follow-up TFTs normalized. The baseline diagnostic Gallium 68-DOTATATE scan performed prior to PRRT demonstrated an increased diffuse uptake in the entire thyroid gland (maximum standardized uptake value: 14.3) and post-treatment SPECT-CT scan revealed similar increased, diffuse 177Lu-DOTATATE uptake in the thyroid gland. The patient currently has stable metastatic disease and continues to be under 177Lu-DOTATATE therapy. Conclusion: We report the first known case of clinical hypothyroidism post 177Lu-DOTATATE therapy in a patient who likely had subclinical hyperthyroidism prior to treatment. The possible mechanism was development of thyroiditis. Further studies are necessary to evaluate the mechanisms of PRRT-induced endocrine abnormalities and their clinical implications.

SUBMITTER: Gubbi S

PROVIDER: S-EPMC7209344 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Project description:BackgroundLutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited.Case descriptionA 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.SummaryWe report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland.ConclusionsThyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.

Project description:PurposeA series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68-labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics.MethodsThe precursor LuFL (20) and [natLu]Lu-LuFL (21) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [177Lu]Lu-LuFL ([177Lu]21) and [177Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy.ResultsLuFL (20) and [natLu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC50: 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC50: 6.69 ± 0.88 nM). In vitro cellular studies showed that 18F-/177Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [18F]/[177Lu]21 revealed higher tumor uptake and longer tumor retention than those of [68 Ga]/[177Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [177Lu]21 group, than for the control group and the [177Lu]Lu-FAPI-04 group.ConclusionThe novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with 18F- and 177Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy.

Project description:Peptide receptor radionuclide therapy (PRRT) using 177Lutetium-DOTA-octreotate (LuTate) for neuroendocrine tumours (NET) is now an approved treatment available in many countries, though primary or secondary resistance continue to limit its effectiveness or durability. We hypothesised that a genome-wide CRISPR/Cas9 screen would identify key mediators of response to LuTate and gene targets that might offer opportunities for novel combination therapies for NET patients. Methods: We utilised a genome-wide CRISPR-Cas9 screen in LuTate-treated cells to identify genes that impact on the sensitivity or resistance of cells to LuTate. Hits were validated through single-gene knockout. LuTate-resistant cells were assessed to confirm LuTate uptake and retention, and persistence of somatostatin receptor 2 (SSTR2) expression. Gene knockouts conferring LuTate sensitivity were further characterised by pharmacological sensitisation using specific inhibitors and in vivo analysis of the efficacy of these inhibitors in combination with LuTate. Results: The CRISPR-Cas9 screen identified several potential targets for both resistance and sensitivity to PRRT. Two gene knockouts which conferred LuTate resistance in vitro, ARRB2 and MVP, have potential mechanisms related to LuTate binding and retention, and modulation of DNA-damage repair (DDR) pathways, respectively. The screen showed that sensitivity to LuTate treatment in vitro can be conferred by the loss of a variety of genes involved in DDR pathways, with loss of genes involved in Non-Homologous End-Joining (NHEJ) being the most lethal. Loss of the key NHEJ gene, PRKDC (DNA-PK), either by gene loss or inhibition by two different inhibitors, resulted in significantly reduced cell survival upon exposure of cells to LuTate. In SSTR2-positive xenograft-bearing mice, the combination of nedisertib (a DNA-PK specific inhibitor) and LuTate produced a more robust control of tumour growth and increased survival compared to LuTate alone. Conclusions: DDR pathways are critical for sensing and repairing radiation-induced DNA damage, and our study shows that regulation of DDR pathways may be involved in both resistance and sensitivity to PRRT. Additionally, the use of a DNA-PK inhibitor in combination with LuTate PRRT significantly improves the efficacy of the treatment in pre-clinical models, providing further evidence for the clinical efficacy of this combination.

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SAT-502 Clinical Hypothyroidism Associated with Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma: A Novel Adverse Effect of Peptide Receptor Radionuclide Therapy

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