Manipulating Aberrant Calcium Signaling to Target Relapsed High-Risk Neuroblastoma

Project Summary (30 lines) High-risk Neuroblastoma (HRNB) is an extracranial pediatric cancer in which up to 65% of patients are resistant to therapies. Recent biomedical advances have improved treatment options for cancer patients. Yet, there are no effective treatment for relapsed HRNB patients who have undergone treatment and experienced

tumor recurrence. Our long-term goal is to develop more effective treatments that target relapsed HRNB. A key feature of HRNB that drives disease progression is aberrant calcium (Ca2+) signaling. This offers targeted therapeutic potential for Ca2+ channel inhibitors. Other groups have made progress in creating and

identifying Ca2+ channel inhibitors that may be used for cancer treatment. Our group is taking an alternative approach by targeting Ca2+ signals that promote NB progression that are unique to relapsed HRNB. The proposed project will leverage the elevated levels of cytosolic Ca2+ in relapsed HRNB driven by enhanced

store-operated Ca2+ entry (SOCE) to promote mitochondrial Ca2+ overload and apoptosis. The hypothesis is that the activation of autophagy prevents mitochondrial Ca2+ overload and apoptosis in relapsed HRNB that otherwise might be prone to apoptosis due to the elevated SOCE. Therefore, combination treatment composed

of a novel drug 249 and an autophagy inhibitor will effectively kill relapsed HRNB. Targeting the mitochondrial Ca2+ transporters to regulate apoptosis may offer a new therapeutic approach for treating relapsed HRNB and a variety of cancers. A detailed understanding of mtCa2+ signaling will allow targeting of the diseased tissue without deleterious effects on healthy tissue.

In addition, this work includes undergraduate and graduate student researchers, including those from underrepresented minority groups. Therefore, this work will train the next generation of researchers and increase diversity in the biomedical workforce.