R2 Jaemin Kim/Prof. Seungjoon Oh Journal conference 1

Radioiodine(iodine-131)-refractory metastatic thyroid cancers  Poor prognosis In mouse models  selective MAPK pathway antagonists increase the expression of the sodium–iodide symporter and uptake of iodine In humans  unknown BACKGROUND BACKGROUND 2

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Radioiodine (iodine-131) - mainstay therapy of metastatic thyroid cancer of follicular origin (i.e., papillary thyroid cancer or follicular thyroid cancer). Radioiodine resistance is a/w poor prognosis - 10ysr = 60% vs. 10% (not refractory vs. refractory to I-131) Several trials(retinoids and lithium) - only yielded a modest clinical benefit BACKGROUND BACKGROUND 4

5 Table Classification of Thyroid Neoplasms Benign Follicular epithelial cell adenomas Macrofollicular (colloid) Normofollicular (simple) Microfollicular (fetal) Trabecular (embryonal) Hürthle cell variant (oncocytic) Malignant Approximate Prevalence, % Follicular epithelial cell Well-differentiated carcinomas Papillary carcinomas80–90 Pure papillary Follicular variant Diffuse sclerosing variant Tall cell, columnar cell variants Follicular carcinomas5–10 Minimally invasive Widely invasive Hürthle cell carcinoma (oncocytic) Insular carcinoma Undifferentiated (anaplastic) carcinomas C cell (calcitonin-producing) Medullary thyroid cancer<10 Sporadic Familial MEN 2 Other malignancies Lymphomas1–2 Sarcomas Metastases Others

70% of papillary thyroid cancers have gene mutations - RET or NTRK1 - the three isoforms of RAS (N, H, K) - BRAF these proteins → stimulates MAPK signaling ↑ thyroid hormone biosynthesis ↓ Na-I symporter & thyroid perxoidase in mouse, when BRAF gene or downstream signal switched off → tumors regain the ability to trap radioiodine. BACKGROUND BACKGROUND 6

Patients - inclusion criteria metastatic lesion that was not radioiodine-avid I-avid, SD or PD, despite radioiodine treatment 6 mo~more Study design - Described later METHODS METHODS 7

Results ~ patients were referred Finally 20 patients are enrolled.

Results 9

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Results 11

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13 -89%-80%

CONCLUSIONS CONCLUSIONS - Selumetinib → increases iodine uptake and retention in thyroid cancer that is refractory to radioiodine - Effectiveness may be greater in RAS-mutant disease 14