A Phase II Clinical Trial of E7820 for Patients with Relapsed/Refractory Myeloid Malignancies with Mutations in Splicing Factor Genes

Bewersdorf, Jan Philipp; Stahl, Maximilian; Taylor, Justin; Chandhok, Namrata S; Watts, Justin M.; Derkach, Andriy; Wysocki, Mateusz; Kostantakis, Victoria; Lu, Sydney X.; Bourcier, Jessie; Hogg, Simon J.; Totiger, Tulasigeri M.; Abdel‐Wahab, Omar; Stein, Eytan M.

doi:10.1182/blood-2022-156830

Cited by 5 publications

(1 citation statement)

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“…Similarly, the PRMT5 inhibitors, JNJ-64619178, GSK3326595 and PF06939999, modify snRNP-associated Sm proteins [ 147 ] and are currently being used in solid tumors, non-Hodgkin lymphoma and MDS (NCT03573310, NCT03614728/NCT02783300/NCT04676516 and NCT03854227, respectively). In the same line, the anti-cancer sulfonamide compound E7820, which degrades the splicing factor RBM39 is being assessed in MDS, acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML) (NCT05024994), which have shown acceptable safety [ 148 ]. Moreover, the ATR inhibitor Ceralasertib is being tested in MDS and CMML (NCT03770429), although it does not directly affect splicing, those patients harboring splicing factor mutations are more sensitive to this treatment [ 149 ].…”

Section: Splicing Modulation For Therapeutic Benefitmentioning

confidence: 99%

Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

Alors-Pérez,

Pedraza-Arevalo,

Blázquez-Encinas

et al. 2023

J Exp Clin Cancer Res

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, mainly due to its late diagnosis and lack of effective therapies, translating into a low 5-year 12% survival rate, despite extensive clinical efforts to improve outcomes. International cooperative studies have provided informative multiomic landscapes of PDAC, but translation of these discoveries into clinical advances are lagging. Likewise, early diagnosis biomarkers and new therapeutic tools are sorely needed to tackle this cancer. The study of poorly explored molecular processes, such as splicing, can provide new tools in this regard. Alternative splicing of pre-RNA allows the generation of multiple RNA variants from a single gene and thereby contributes to fundamental biological processes by finely tuning gene expression. However, alterations in alternative splicing are linked to many diseases, and particularly to cancer, where it can contribute to tumor initiation, progression, metastasis and drug resistance. Splicing defects are increasingly being associated with PDAC, including both mutations or dysregulation of components of the splicing machinery and associated factors, and altered expression of specific relevant gene variants. Such disruptions can be a key element enhancing pancreatic tumor progression or metastasis, while they can also provide suitable tools to identify potential candidate biomarkers and discover new actionable targets. In this review, we aimed to summarize the current information about dysregulation of splicing-related elements and aberrant splicing isoforms in PDAC, and to describe their relationship with the development, progression and/or aggressiveness of this dismal cancer, as well as their potential as therapeutic tools and targets.

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Section: Splicing Modulation For Therapeutic Benefitmentioning

confidence: 99%