Although advances in pediatric oncology have resulted in cure rates exceeding 80% among children with cancer, progress in survival outcomes has begun to plateau in recent years. Mortality in this population remains largely associated with aggressive disease features, particularly tumor resistance to chemotherapy and metastatic spread. At the same time, the growing population of childhood cancer survivors has drawn increasing attention to the persistent and potentially serious late effects associated with conventional chemotherapy. Thus, it is crucial to discover drugs with specific antitumor action, effective and safe drugs that, combined with chemotherapy or radiotherapy, could chemosensitize or radiosensitize the tumor and reduce the severe side effects of both. Substance P (SP) peptide and its Neurokinin-1 receptor (NK-1R) are known to be involved in pediatric cancer, promotion and progression. Pediatric cancer overexpresses SP/NK-1R and NK-1R is essential for viability of cancer cells and is not essential for normal non-tumor cells. SP induces mitogenesis, exerts anti-apoptotic effects, and promotes angiogenesis, invasion and migration for metastasis in cancer cells and produces inflammation. Conversely, NK-1R antagonists, such as aprepitant and similar drugs, inhibit mitogenesis and induce apoptosis in pediatric cancer cells in a concentration-dependent manner. They also inhibit angiogenesis, invasion, and migration in pediatric cancer cells and have an anti-inflammatory effect. Moreover, aprepitant in combination with chemotherapy or radiotherapy can produce chemosensitization or radiosensitisation and decreases the severe side effects of both. This review updates the role of the SP/NK-1R axis in pediatric cancers and analyzes its potential as a therapeutic target. It highlights NK-1R antagonists, particularly aprepitant, and their potential as drugs for the treatment of pediatric cancer.

At present, there are no US Food and Drug Administration (FDA)-approved tocolytics for the management of preterm labor. To identify drugs for repurposing as tocolytics, a phenotypic high-throughput screen against a library of 1191 FDA-approved drugs was performed for inhibitors of in vitro uterine myometrial contractions. A total of 51 drugs inhibited calcium (Ca[2+]) mobilization in primary human myometrial cells. To minimize potential off-target effects, hit drugs were counterscreened against primary human aortic vascular smooth muscle cells, identifying 10 uterine-selective drugs. Of these, two drugs, the antiemetic fosaprepitant dimeglumine and the glucocorticoid ciclesonide, displayed favorable in vitro therapeutic indices (TIs > 5), inhibited contractions in human myometrial tissue ex vivo, and did not alter tone in the fetal murine ductus arteriosus ex vivo. Next, the potential synergy among hit drugs and clinically used tocolytics was evaluated using a high-throughput combination screen based on Ca[2+] mobilization in primary human myometrial cells. Four synergistic drug combinations incorporating ciclesonide, indomethacin, ivermectin, atosiban, or nelfinavir mesylate displayed favorable TIs of >5 and improved ex vivo tocolytic potency, efficacy, or both. Last, aprepitant, ciclesonide, and four synergistic drug combinations delayed delivery until term and improved neonatal viability and skin and lung maturation in a mouse model of induced preterm labor, with several combinations outperforming their component drugs. This approach established a systematic strategy for identifying uterus-selective tocolytics, and these findings support further preclinical development of repurposed drugs and drug combinations for the treatment of preterm labor to improve pregnancy and neonatal outcomes.

Chemotherapy-induced nausea and vomiting substantially impair patients' quality of life despite considerable advances in supportive care. Neurokinin-1 receptor antagonists, including oral aprepitant and intravenous fosaprepitant, constitute essential components of antiemetic regimens for highly emetogenic chemotherapy. In this prospective, non-randomized observational study, we compared the efficacy of oral aprepitant and intravenous fosaprepitant administered in combination with 5-hydroxytryptamine-3 receptor antagonists and dexamethasone in 136 chemotherapy-naive patients receiving cisplatin- or doxorubicin-cyclophosphamide-based regimens. Complete response rates during the acute (0-24 h), delayed (24-120 h), and overall (0-120 h) phases were comparable between the two groups, with no statistically significant differences in emesis severity. Multivariable analyses further demonstrated similar effectiveness irrespective of age, sex, or chemotherapy regimen. These findings indicate that no statistically significant differences in antiemetic efficacy were observed between aprepitant and fosaprepitant in routine clinical practice. Fosaprepitant may therefore represent a practical alternative when oral administration is not feasible.

The Substance P/neurokinin-1 receptor (SP/NK1R) pathway plays a significant role in several cancers, including pancreatic, breast, glioblastoma, and lung malignancies. This review highlights its involvement in metastasis, angiogenesis, proliferation, resistance, and apoptosis. Aprepitant, an NK1R antagonist and approved antiemetic, shows promising anticancer and protective effects, supporting its use in combination therapies. NK1R-targeted strategies may enhance treatment efficacy while reducing chemotherapy- and radiotherapy-induced toxicities.