Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma

Yoo, Changhoon; Kang, JiHoon; Lim, Ho Yeong; Kim, Jee Hyun; Lee, Myung Ah; Lee, Kyung Hun; Kim, Tae You; Ryoo, Baek Yeol

doi:10.4143/crt.2018.226

Cited by 43 publications

(34 citation statements)

References 26 publications

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“…In a Phase I study by Yoo et al, OPB-111077 was administered to sorafenib-refractory HCC patients to examine toxicity and safety profiles [95]. The drug was well tolerated overall, with limited patients experiencing dose-limiting toxicities and no treatment-related deaths reported.…”

Section: Targeting Stat3mentioning

confidence: 99%

JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

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Section: Targeting Stat3mentioning

confidence: 99%

JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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“…However, the clinical trials for both lead structure drugs were terminated due to minimal antitumor activity, toxicity issues and poor pharmacokinetics. Another STAT3 inhibitor, OPB-111077, has completed a phase I trial for solid cancers (NCT02250170), and phase I/II trials are recruiting for acute myeloid leukemia (AML) (NCT03197714) and other refractory tumors (NCT03158324) [82,83]. Efficacies of the above-mentioned STAT3 SH2 inhibitors in vitro and in vivo are summarized in Table 1.…”

Section: Stat3 Inhibitorsmentioning

confidence: 99%

Direct Targeting Options for STAT3 and STAT5 in Cancer

Orlova

Wagner

Araujo

et al. 2019

Cancers

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Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.

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“…To improve the activity of OPB-31121, OPB-111077 was developed, which is the primary metabolite of OPB-31121. This compound achieved better tissue retention and inhibited the growth of various cancers and has currently completed several phase I clinical trials in advanced cancers [184,185]. A particularly encouraging response was observed in one of the trials involving a subset of lymphomas (diffuse large B-cell lymphoma, DLBCL) and thus OPB-111077 is being assessed in further trials for clinical efficacy [184].…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

Morgan

Macdonald

2020

Viruses

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Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.

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Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma

Abstract: OPB-111077 was well tolerated in patients with advanced HCC after sorafenib failure, but only showed limited preliminary efficacy outcomes. Further investigation of the role of the STAT3 signaling pathway in HCC and the development of biomarkers for STAT3 inhibitors are warranted.

Cited by 43 publications

References 26 publications

JAK/STAT signaling in hepatocellular carcinoma

JAK/STAT signaling in hepatocellular carcinoma

Direct Targeting Options for STAT3 and STAT5 in Cancer

Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

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