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Expanded Access to Ulixertinib (BVD-523) in Patients With Advanced MAPK Pathway-Altered Malignancies

ABSTRACT: The objective of this expanded access program is to provide ulixertinib (BVD-523) for compassionate use in advanced cancer patients with MAPK pathway-altered solid tumor(s), including but not limited to KRAS, NRAS, HRAS, BRAF, MEK, and ERK mutations who have incomplete response to or have exhausted available therapies. Ulixertinib is available for treatment as monotherapy or in combination with other clinically tolerable agent(s), conditionally approved by the drug manufacturer.

DISEASE(S): Erk Mutation,Melanoma,Glioblastoma,Colorectal Cancer,Non Small Cell Lung Cancer,Mapk Gene Mutation,Bladder Cancer,Mek Mutation,Pancreatic Cancer,Small Bowel Cancer,Kras Activating Mutation,Ovarian Cancer,Braf Gene Mutation,Thyroid Cancer,Hras Gene Mutation,Gastric Cancer,Nras Gene Mutation,Esophageal Cancer,Head And Neck Cancer,Cholangiocarcinoma,Hepatocellular Carcinoma

PROVIDER: 2352905 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Carcinogenesis is a multistep process in which cells accumulate multiple genetic alterations, as they progress to a more malignant phenotype. It has been proposed that sequential accumulation of gene abnormalities in specific genes drives the transition from non-tumorous epithelia through preneoplastic lesion/benign tumor to cancer. Histologically, progression to invasive oral squamous cell carcinoma (OSCC) follows multistep ordered series beginning with mucosal epithelial cell hyperplasia, followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore speculated that genetic alterations-mediated multistep carcinogenesis would be involved in OSCC development, but their detailed molecular mechanisms are unknown. Herein, we clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data obtained from an OSCC pathological specimen, which consists of non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion. Numerous numbers of gene expression and signal activation were altered in the OSCC development. Of them, the expression of p63 was increased and MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion as well as in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ lesions and ERK was sequentially activated in invasive carcinoma lesions in OSCC specimens. ADP-ribosylation factor (ARF)-like 4c (ARL4C), the expression of which is reportedly induced by p63 and/or MEK/ERK-MAPK pathway in OSCC cells, has been shown to promote tumorigenesis. Immunohistochemically, in OSCC specimens, ARL4C was more frequently detected in tumor lesions, especially in invasive carcinoma lesions than in carcinoma in situ lesions. Additionally, ARL4C and phosphorylated ERK were merged at high frequency in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and EGFR-MEK/ERK-MAPK cooperatively induce ARL4C expression in OSCC cells. These results suggest that the stepwise activation of p63 and EGFR-MEK/ERK-MAPK contributes to OSCC tumor cell growth though regulation of ARL4C expression.

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Expanded Access to Ulixertinib (BVD-523) in Patients With Advanced MAPK Pathway-Altered Malignancies

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