Mentor Name: Dana-Lynn Koomoa-Lange

Up to 50% of neuroblastoma (NB) patients are diagnosed with high-risk NB (HRNB). Despite aggressive multi-modal therapies, 50-60% of HRNB patients relapse and develop resistance to chemotherapy. Metastatic relapse frequently results from the proliferation of disseminated tumor cells (DTCs). These DTCs are often present at diagnosis, can remain dormant for extended periods, evade therapies and immune detection, and may later resume proliferation. Understanding the signaling pathways that drive DTC proliferation is essential to developing more effective treatments for this devastating disease. Our research focuses on elucidating the role of aberrant calcium (Ca2+) signaling in NB, specifically the function of transient receptor potential melastatin 7 (TRPM7). TRPM7 is a channel permeable to Ca2+, Mg2+, and trace Zn+, and possesses an intrinsic serine/threonine kinase domain at its C-terminus. We have found that TRPM7 activity is markedly elevated in HRNB. TRPM7’s dual ion channel and kinase functions contribute to its complex role in cancer. Its kinase domain can be cleaved and act in the cytosol or translocate to the nucleus, where it phosphorylates proteins regulating gene expression, such as Histone H3 Ser10. Recent studies suggest TRPM7, predominantly located in the plasma membrane, regulates gene transcription, cell proliferation, and cell survival. TRPM7 also influences epithelial-mesenchymal transition (EMT) and can promote metastasis in certain cancers. Inhibition of TRPM7, using pharmacological inhibitors or siRNA, elicits a strong antiproliferative effect in NB cells, resulting in altered cell cycle progression, decreased proliferation, reduced viability, and disrupted autophagy. Our data, together with published studies, provide strong evidence supporting further investigation of TRPM7’s therapeutic potential in NB. These findings underpin our hypothesis that both TRPM7 channel and kinase activities are critical drivers of metastatic relapse in HRNB and represent promising therapeutic targets. The following specific aims are proposed: Aim 1: Determine the functional and mechanistic significance of TRPM7 in NB by assessing the effects of pharmacological inhibitors targeting the TRPM7 channel or kinase on cell proliferation, viability, and migration in HRNB cells derived from relapsed patients. Aim 2: Evaluate the therapeutic efficacy of the TRPM7 inhibitor FTY-720, both alone and in combination with clinically relevant NB therapies (FDA-approved Dinutuximab and Eflornithine used to treat HRNB & prevent relapse), on cell proliferation, viability, and migration in HRNB cells from relapsed patients.