Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to the inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the combination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, the growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.

Directly targeting RAS is a promising approach for the treatment of RAS-altered malignancies. Recently, several groups have developed mutation-specific agents such as sotorasib and adagrasib, which directly target KRAS by covalently modifying KRAS(G12C). KRAS is commonly altered in adult malignancies, such as lung, pancreatic, and colorectal adenocarcinomas, but is less commonly altered in pediatric cancers. However, rare pediatric solid tumors harboring KRAS(G12C), HRAS(G12C), or NRAS(G12C) have been observed, including rhabdomyosarcoma and neuroblastoma tumors, as well as leukemias. The efficacy of KRAS(G12C) inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify HRAS(G12C) and NRAS(G12C) has not been completely characterized. In this study, we show that sotorasib, adagrasib, and the RAS-ON inhibitor RMC-6291 are effective in a neuroblastoma cell line altered by KRAS(G12C). We further demonstrated that sotorasib and adagrasib inhibited SOS-mediated guanine nucleotide exchange on HRAS(G12C) and NRAS(G12C). Sotorasib and RMC-6291 decreased ERK phosphorylation in cells expressing HRAS(G12C), KRAS(G12C), or NRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model; however, this treatment did not prolong survival as a single agent. These results suggest that combinations of targeted agents that include sotorasib may be required for clinical benefit in pediatric patients with HRAS(G12C)- or NRAS(G12C)-altered malignancies, in addition to those with KRAS(G12C)-altered malignancies.

Enhanced Recovery After Surgery (ERAS) protocols for bariatric surgery improve clinical outcomes. However, the impact of ERAS protocols on patient satisfaction is unknown. Virtual reality has been implemented as an effective adjunct to standard analgesic regimens. This study seeks to find out if immersive virtual reality in the immediate postoperative period could improve the subjective quality of recovery and further reduce opioid requirements for bariatric surgery patients compared with ERAS care alone. This is a single-centre, randomised clinical trial of patients recovering from laparoscopic bariatric surgery. Once in the post-anaesthesia care unit (PACU), participants will receive either an immersive virtual reality plus ERAS protocol or ERAS protocol alone. The primary outcome will be the Quality of Recovery-15 (QoR-15) score at PACU discharge. Secondary outcomes include PACU opioid requirements, length of PACU stay, PACU pain scores, QoR-15 score on postoperative day 1, hospital length of stay, opioid requirements, and opioid-related adverse effects until hospital discharge. Positive findings from this study could introduce virtual reality as a non-pharmacological adjunct during PACU care that improves subjective recovery for patients undergoing bariatric surgery. NCT04754165.

Establishment of a xenograft model of NRAS(G12C)-mutant leukemia

Sotorasib sensitivity is dependent on KRAS(G12C) expression

Sotorasib and adagrasib IC50 values for RAS isoforms