Koselugo (selumetinib)

In addition, the high expression of model gene produced drug resistance to trametinib, selumetinib and RDEA119 (refametinib). The prognostic risk model based on six prognostic related DEGs is an independent prognostic factor of HCC, which can effectively predict the survival and prognosis of HCC patients.

P1, N=32, Terminated, Merck Sharp & Dohme LLC | Phase classification: P1b --> P1 | Completed --> Terminated; Business Reasons

P2, N=21, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

While the effectiveness of MEK inhibitors such as selumetinib is established in NF1-associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS-driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling.

P2, N=10, Completed, Children's Hospital Medical Center, Cincinnati | Suspended --> Completed | Trial completion date: Jun 2025 --> May 2024 | Trial primary completion date: Dec 2024 --> May 2024

P2, N=33, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

P2, N=647, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024

P2, N=19, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

This study demonstrates that combining MALDI-MSI with LC/MS-MS can highly contribute to the characterization of the fate of photosensitive compounds in the skin, an essential prerequisite to the development of compound-specific photoprotective measures. It will also pave the way for innovative topical delivery strategies for NF1 treatment.

These events are generally manageable and should be considered alongside treatment benefit. Information sharing is warranted as further experience is gained.

The approval and widespread availability of mitogen-activated protein kinase (MEK) inhibitors such as selumetinib for NF1-related plexiform neurofibromas have revolutionized the standard of care for patients with NF1, however their effective utilization hinges on early recognition of NF1...Increasing the availability and accessibility of genetic testing at an affordable cost and optimizing personalized NF1 care are essential for NF1 management. Developing regional guidelines for NF1 management and establishing NF1 centers of excellence may facilitate better care and outcomes for patients with NF1 in the GCC region.

P=N/A, N=150, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

A total of 1388 ADE reports related to selumetinib were extracted, and 53 positive signals were detected by ROR and MHRA methods, of which 20 signals were not mentioned in the package insert, including ingrowing nail, hyperphosphatemia, cardiac valve disease, hematuria, neutropenia, etc. Analysis of the toxicological mechanism of six SOCs involved in positive ADE signals revealed that the key targets included EGFR, STAT3, AKT1, IL6, BCL2, etc., and the key pathways included PI3K/Akt pathway, apoptosis, ErbB signaling pathway, and EGFR tyrosine kinase inhibitor resistance, etc. Molecular docking assays showed spontaneous binding of selumetinib to key targets in these pathways. The pharmacovigilance analysis identified some new potential ADEs of selumetinib, and the network toxicology analysis showed that the toxic effects of selumetinib may be related to PI3K/Akt pathway, apoptosis, ErbB signaling pathway, EGFR tyrosine kinase inhibitor resistance and other pathways.

P=N/A, N=400, Recruiting, AstraZeneca | N=100 --> 400

P2, N=83, Completed, University of Oxford | Unknown status --> Completed

P2, N=132, Recruiting, OHSU Knight Cancer Institute | Trial primary completion date: Dec 2024 --> Dec 2025

The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects...Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells...In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.

P2, N=25, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jun 2024 --> Jun 2025

In this study, we explored the suppression mechanism of the phosphorylation process in the presence of MEK allosteric inhibitors, such as selumetinib, trametinib, cobimetinib, and CH5126766, by employing molecular dynamics simulations accompanied by principal component analysis. The results conclude that a strong interaction of allosteric inhibitors with the activation loop restricts the movement of Ser222 toward Mg-ATP, which could be the dominant factor for the suppression of phosphorylation in MEK1. This research will provide novel insights to design effective anticancer therapeutics for targeting MEK1 in the future.

We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). Accordingly, we observed G1 phase arrest but not apoptosis or cell death (measured by cleaved caspase-3, AIFM1 regulation, sub-G0/G1 phase). We conclude that the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block the proliferation of ICC cell lines in vitro; however, potential clinical applications must be critically examined, as a proliferation block could also induce resistance to standard therapies.

P2, N=60, Completed, Academic and Community Cancer Research United | Active, not recruiting --> Completed

CPNE1 could be a predictive biomarker and a potential target for biological therapy in STAD.

P=N/A, N=150, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors.

P=N/A, N=100, Recruiting, AstraZeneca | Trial completion date: Jul 2027 --> Nov 2027 | Trial primary completion date: Jul 2027 --> Nov 2027

P2, N=10, Suspended, Children's Hospital Medical Center, Cincinnati | N=34 --> 10 | Trial primary completion date: Jun 2024 --> Dec 2024

Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Lung cancer is one of the most common and deadliest cancers. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

In summary, our findings demonstrated the critical role of ITGA2 in enhancing chemotherapy resistance in CRC cells and suggested that selumetinib can restore the sensitivity of chemotherapy-resistant CRC cells to 5-FU by inhibiting ITGA2 expression.

There is no standard pharmacologic treatment for GCMN. We present the case of an 8-year-old female with kaposiform lymphangiomatosis caused by an NRAS mutation whose nevus spilus-type GCMN improved on oral selumetinib.

P2, N=41, Not yet recruiting, University of Alabama at Birmingham | Trial completion date: Jun 2030 --> Dec 2030 | Trial primary completion date: Jun 2029 --> Dec 2029

Selumetinib was the first and, as of February 2024, is the only medicine that can be prescribed by doctors to help children with NF1-related PN. Clinical Trial Registration: NCT01362803 (SPRINT) (ClinicalTrials.gov).

P2, N=34, Suspended, Children's Hospital Medical Center, Cincinnati | Active, not recruiting --> Suspended

Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244. A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients.

HR cases were more sensitive to erlotinib, CI-1040, and AZD6244. These findings supplemented the understanding of gene mutations in AML, and constructed models had good application prospect to provide effective information for predicting prognosis and treatment response of AML.

Selumetinib exhibited weak inhibitory effects on other human UGTs and was unlikely to trigger off UGTs-mediated DDIs except for UGT2B7. Therefore, the combination of selumetinib with the substrate drug of UGT2B7 requires additional attention to avoid adverse events in clinical treatment.

Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication.

P3, N=510, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P1/2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=165, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2028

scRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials.