Koselugo (selumetinib)

The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted.

Patients with higher PPP1R14B expression responded more sensitively to drugs selumetinib and vorinostat, zebularine, azacitidine and VER155008. In summary, PPP1R14B was a potential diagnostic and prognostic biomarker of PCa and its high expression had closely association with tumor immune inhibition, proliferation and migration, providing a new target for drug therapy and immunotherapy in PCa.

P1, N=117, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Mar 2025

Gliomas are tumors arising in the central nervous system, frequently associated with Class I mutations and BRAF fusions. Further research into resistance mechanisms and long-term effects is necessary to optimize treatment strategies. Other therapies, such as everolimus and Selumetinib, also show potential and warrant further investigation.

The combination of targeted therapy drugs, such as selumetinib and perifosine that inhibit cell signaling pathways involved in cell survival and proliferation, with the expression of tumor suppressor transgenes, such as PTEN, may result in an efficient therapeutic approach against HCC. Moreover, the achieved data revealed that this innovative nanosystem presents a high antitumor effect, demonstrated not only by the enhancement on the programmed cell death, but also by the reduction in cell proliferation capacity. The generated formulation shows a high anticancer effect, demonstrating a high translational potential for future clinical application in HCC treatment.

Most patients achieved tumor stability and improved symptom control, and the majority of patients continue under treatment. Effective diagnosis and management were achieved through individualized utility of FDG-PET/CT and MRI imaging and targeted resource allocation.

This retrospective nationwide study revealed early onset, diverse tumor locations, and varying morbidities in children with NF1-PN, underscoring the need for early evaluation and optimal treatment. A prospective multicenter registry system is warranted to attain better management.

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.