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CaSR modulator in neuroblastoma model

ABSTRACT: CaSR modulator in neuroblastoma model

PROVIDER: PRJNA297180 | ENA |

REPOSITORIES: ENA

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Project description:Neuroblastoma is the most common extracranial solid childhood tumor with clinical manifestations ranging from benign tumors that spontaneously regress to highly aggressive metastatic disease. Unfortunately, there is no therapy known to be curative for high-risk neuroblastoma. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that senses plasmatic fluctuation in the extracellular concentration of calcium and plays a key role in maintaining calcium homeostasis. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. The activation of CaSR with cinacalcet, a positive allosteric modulator of CaSR, reduces neuroblastoma tumor-growth by promoting differentiation, ER stress and apoptosis. However, these promising results came with an associated side effect, since cinacalcet exposure resulted in hypocalcemia. Based on the biased signaling shown by calcimimetics, we aimed to identify a new drug that might exert tumor-growth inhibition similar to cinacalcet without affecting plasma calcium levels. We identified a structurally different calcimimetic AC-265347 as a promising therapeutic agent for neuroblastoma, since it reduced tumor-growth by induction of differentiation, without affecting plasma calcium levels. Microarrays analysis suggested biased allosteric modulation of the CaSR signaling by both calcimimetics towards distinct intracellular pathways since no upregulation of genes involved in calcium signaling and ER stress were observed in PDX models exposed to AC-265347. Moreover, the most significant upregulated biological pathways promoted by AC-265347 were linked to RHO GTPases signaling. AC-265347 also up-regulated cancer testis antigens (CTAs), thus providing new opportunities for CTA-based immunotherapies. Taken together, this study helps to shed light about the importance of the biased allosteric modulation when targeting GPCRs in cancer. More importantly, the capacity of AC-265347 to promote differentiation of malignant neuroblastoma cells provides new opportunities, alone or in combination with other drugs, to control minimal residual disease and to prevent relapse in patients affected with neuroblastoma.

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CaSR modulator in neuroblastoma model

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