ALK ligand ALKAL2 potentiates MYCN‐driven neuroblastoma in the absence of ALK mutation

Abstract

High-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of highrisk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8-10% of primary NB patients are ALK-positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the "2p-gain" region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v-sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI-sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p-gain, may benefit from ALK TKI-based therapeutic intervention.

Neuroblastoma xenograft models demonstrate the therapeutic potential of 177Lu-octreotate

“…Furthermore, previous data on the transcriptional expression of the various SSTR subtypes in CLB-BAR, CLB-GE and IMR-32 support the high SSTR2 expression in our IHC data (Fig. 7 ) [ 50 , 51 ]. Our IHC findings may also indicate, in contrast to the mRNA expression, that SSTR3 could be a useful target for treatment.…”

“…7 mRNA expression of SSTR1–5 in NB cell lines CLB-BAR, CLB-GE, IMR-32 and SK-N-AS. Data were extracted from Van den Eynden et al [ 50 ] and Borenäs et al [ 51 ]. SK-N-AS was present in both studies and were used to normalize data from the two studies, for comparison …”

“…Therefore, 177 Luoctreotate should be considered a potential systemic treatment option, especially in high risk NB patients with high expression of SSTRs and with low response to present treatment options. [50] and Borenäs et al [51]. SK-N-AS was present in both studies and were used to normalize data from the two studies, for comparison…”

A GD2-aptamer-mediated, self-assembling nanomedicine for targeted multiple treatments in neuroblastoma theranostics

“… 3 Although high-risk NB (HRNB) is the most prevalent, when compared with the low-risk and intermediate-risk groups, outcomes in the high-risk group are considerably poorer. 3 , 4 , 5 Clinical HRNB primarily comprises children older than 18 months with distant metastatic spread and/or amplification of the MYCN oncogene. 6 At present, despite multiple combination treatments, including conventional or high-dose chemotherapy, surgical resection, radiotherapy, differentiation therapy, and immunotherapy, 1 , 7 the 5-year overall survival (OS) from HRNB has not yet changed substantially (<50%).…”

“…Because amplification of the MYCN oncogene is observed in approximately 20% of all NB cases and in approximately 50% of high-risk cases, MYCN amplification is defined as one of the strongest unfavorable prognostic markers. 5 A reduction in MYCN mRNA expression may inhibit proliferation, prevent multidrug resistance (MDR), and induce apoptosis of NB tumor cells. 36 In addition, doxorubicin (Dox) is a standard chemotherapeutic for NB, and Dox can intercalate into cytosine/guanine (CG) base pairs.…”