Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.
mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, β-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.
Activation of the mTOR pathway has been observed in osteosarcoma, however the inhibition of mammalian target of rapamycin (mTOR) complex 1 has had limited results in osteosarcoma treatment. Certain metabolic pathways can be altered by mTOR activation, which can affect survival. Our aim was to characterize the mTOR profile and certain metabolic alterations in pediatric osteosarcoma to determine the interactions between the mTOR pathway and metabolic pathways. We performed immunohistochemistry on 28 samples to analyze the expression of mTOR complexes such as phospho-mTOR (pmTOR), phosphorylated ribosomal S6 (pS6), and rapamycin-insensitive companion of mTOR (rictor). To characterize metabolic pathway markers, we investigated the expression of phosphofructokinase (PFK), lactate dehydrogenase-A (LDHA), β-F1-ATPase (ATPB), glucose-6-phosphate dehydrogenase (G6PDH), glutaminase (GLS), fatty acid synthetase (FASN), and carnitin-O-palmitoyltransferase-1 (CPT1A). In total, 61% of the cases showed low mTOR activity, but higher pmTOR expression was associated with poor histological response to chemotherapy and osteoblastic subtype. Rictor expression was higher in metastatic disease and older age at the time of diagnosis. Our findings suggest the importance of the Warburg-effect, pentose-phosphate pathway, glutamine demand, and fatty-acid beta oxidation in osteosarcoma cells. mTOR activation is linked to several metabolic pathways. We suggest performing a detailed investigation of the mTOR profile before considering mTORC1 inhibitor therapy. Our findings highlight that targeting certain metabolic pathways could be an alternative therapeutic approach.
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