Koselugo (selumetinib)

This study highlights the clinical and healthcare challenges of NF1 and PN in Saudi Arabia, emphasizing the need for a multidisciplinary approach that combines medical, psychological, and financial support. The limited access to Selumetinib represents a gap. Increasing treatment accessibility and financial support are key to improving the outcomes and QoL.

Drug sensitivity analysis revealed enhanced efficacy of agents like selumetinib in high-APOA1 tumors. This integrated, cross-layer evidence positions APOA1 as a tumor suppressor and actionable biomarker in LUAD, with implications for early detection, therapeutic stratification, and immunomodulatory strategies.

Selumetinib alters gene expression of hiPSC-derived RPE, with significant changes in genes involved in transport of ions and small molecules regulating cell volume and lysosomal acidification. Selumetinib may lead to subretinal fluid accumulation by both increasing secretions into this space and decreasing outflow.

P1/2, N=40, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed

In this study, we established chemoresistant uveal melanoma cell lines by exposing parental cells to dacarbazine, cisplatin, or gemcitabine and performed high-throughput drug screening incorporating normal human epidermal melanocytes (NHEMs) as a normal control to assess both efficacy and selectivity. Our screening identified temsirolimus and selumetinib as top candidates, with temsirolimus exhibiting strong tumor-selective cytotoxicity...Mechanistically, temsirolimus downregulated mammalian target of rapamycin (mTOR) signaling, as indicated by reduced p-mTOR, p-S6, and p-4EBP1 expression in tumor tissues. These findings demonstrate that temsirolimus selectively targets chemoresistant uveal melanoma cells, enhances chemotherapy efficacy, and suppresses tumor growth via mTOR inhibition, supporting its potential clinical application as a novel therapeutic strategy for chemoresistant uveal melanoma.

However, the disease recurred 6 months later, prompting the initiation of carboplatin therapy. Primary treatment with MAPK kinase inhibitors can lead to tumor regression in brainstem glioma in an adult patient with NF1. We recommend that patients with brainstem glioma undergo biopsy and mutation testing, especially those with an unusually aggressive clinical course.

Finally, we found that MEK inhibitors (selumetinib and trametinib) were more sensitive in the NET-high group and can inhibit the invasion and migration of LUAD cells. The NETs-related signature was able to predict the prognosis and immunotherapy outcome of LUAD patients.

The coordinated efforts of the MDT facilitated appropriate patient selection, individualized dose adjustments, effective management of adverse events, and long-term follow-up. These cases highlight the clinical utility of selumetinib and underscore the importance of MDT involvement in the management of pediatric NF1 patients with PNs in Japan.

P3, N=145, Active, not recruiting, AstraZeneca | Trial completion date: Mar 2025 --> Feb 2029

RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL-CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM.

All drugs tested showed single-agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

Patients with JXG, especially those under the age of 2, should undergo a thorough physical examination to evaluate for NF1.