A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer

Vergote, Ignace; Heitz, Florian; Buderath, Paul; Powell, Matthew A.; Sehouli, Jalid; Lee, Christine M.; Hamilton, Anne; Fiorica, James V.; Moore, Kathleen N.; Teneriello, Michael; Golden, Lisa; Zhang, Wei; Pitou, Celine; Bell, Robert L.; Campbell, Robert M.; Farrington, Daphne L.; Bell‐McGuinn, Katherine M.

doi:10.1016/j.ygyno.2019.11.006

Cited by 42 publications

(38 citation statements)

References 26 publications

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“…One example is Ralimetinib (or LY2228820), which is a potent and selective inhibitor of p38α and p38β. Ralimetinib is now being tested, both alone and in combination with other agents, for the treatment of ovarian cancer, glioblastoma, and metastatic breast cancer [113]. Notably, some p38 inhibitors are also being tested for the treatment of other pathologies, such as rheumatoid arthritis and Parkinson's disease [114].…”

Section: Targeting P38 Mapk For Cancer Therapymentioning

confidence: 99%

“…In this regard, a number of clinical studies are currently testing the effects of these combination therapies in clinics. As mentioned above, promising results have been obtained in trials with the p38α inhibitor Ralimetinib in combination with radiotherapy and Temozolomide for the treatment of patients with glioblastoma, as well as with Gemcitabine to treat patients with ovarian cancer [113]. A second approach to improve the effectiveness of cancer treatments involves targeting other kinases downstream the p38 pathway, thus limiting the response to only a subset of p38-mediated responses.…”

Section: Targeting P38 Mapk For Cancer Therapymentioning

confidence: 99%

See 1 more Smart Citation

The p38 Pathway: From Biology to Cancer Therapy

Martínez-Limón

Joaquin

Caballero

et al. 2020

IJMS

224

180

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The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored.

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Section: Targeting P38 Mapk For Cancer Therapymentioning

confidence: 99%

Section: Targeting P38 Mapk For Cancer Therapymentioning

confidence: 99%

The p38 Pathway: From Biology to Cancer Therapy

Martínez-Limón

Joaquin

Caballero

et al. 2020

IJMS

224

180

View full text Add to dashboard Cite

show abstract

“…As mentioned above, p38α/β are central regulators of inflammation, which in many cases is involved in cancer initiation and progression [81]. Indeed, some of the specific p38α/β inhibitors that have been developed over the years, although having failed in inflammation-related clinical trials, were proven useful in treating cancers [82]. Interestingly, in some cancer cells, p38α/β may facilitate migration by several mechanisms, including an enhanced production of chemoattractants [83] or reduced expression of fibulin 3, which is a cell migration blocker [84].…”

Section: Role Of Nuclear P38α/β In Pathologiesmentioning

confidence: 99%

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

Maik-Rachline

Lifshits

Seger

2020

IJMS

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The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

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“…Neutropenia, thrombocytopenia, and anemia were the most frequent grade 3-4 AEs in both treatment arms; grade 3-4 elevations in alanine aminotransferase levels were observed more frequently in patients receiving the triple combination. 100 A further, novel kinase inhibitor that has shown activity against ovarian cancer in preclinical and early clinical studies is prexasertib (LY2606368), a selective, ATP-competitive inhibitor of the cell cycle checkpoint kinase 1 and 2 (CHK 1/2), which are expressed at higher levels in cancer cells compared with normal tissues. 101,102 Inhibition of CHK 1/2 activity leads to replication catastrophe, thereby inducing cell death and sensitizing cancer cells to the antitumor activity of PARP inhibitors.…”

Section: Protein Kinase-mediated Pathwaysmentioning

confidence: 99%

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease

Arend

Jackson-Fisher

Jacobs

et al. 2021

Cancer Biology & Therapy

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Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer.

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A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer

Cited by 42 publications

References 26 publications

The p38 Pathway: From Biology to Cancer Therapy

The p38 Pathway: From Biology to Cancer Therapy

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease

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