Effect of Lactate Export Inhibition on Anaplastic Thyroid Cancer Growth and Metabolism.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive malignancy without effective treatments. ATC cells demonstrate upregulated glycolysis (Warburg effect), generating lactate that is subsequently exported by monocarboxylate transporter 4 (MCT4). This study aims to determine whether MCT4 inhibition can suppress ATC growth. STUDY DESIGN: ATC cell lines 8505C, JL30, and TCO1 were grown in low (3 mmol/L; LG) or high (25 mmol/L; HG) glucose medium containing the lactate shuttle inhibitors acriflavine (10-25 µmol/L; ACF), syrosingopine (100 µmol/L; SYR), or AZD3965 (20 µmol/L; AZD). Lactate level and cell proliferation were measured with standard assays. Seahorse analysis was performed to determine glycolytic response. RESULTS: Compared with HG, addition of ACF to LG decreased lactate secretion for both 8505C (p < 10-5) and JL30 (p < 10-4) cells, whereas proliferation was also reduced (p < 10-4 and 10-5, respectively). During Seahorse analysis, addition of oligomycin increased acidification by 84 mpH/min in HG vs 10 mpH/min in LG containing ACF (p < 10-5). Treatment with LG and SYR drastically diminished 8505C and TCO1 growth vs HG (p < 0.01 for both). LG and AZD treatment also led to reduced proliferation in tested cell lines (p ≤ 0.01 for all) that was further decreased by addition of ACF (p < 10-4 vs HG, p ≤ 0.01 vs LG and AZD). CONCLUSION: Inhibition of lactate shuttles significantly reduced proliferation and glycolytic capacity of ATC cells in a low-glucose environment. Targeting suppression of glycolytic and lactate processing pathways may represent an effective treatment strategy for ATC.

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia.

As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.