Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma

Moreno, Víctor; Sepúlveda, Juan Manuel; Vieito, María; Hernández, Tatiana; Doger, Bernard; Saavedra, Omar; Ferrero, Olga; Sarmiento, R.; Arias, Marina; Alvaro, Juan de; Martino, Jorge Di; Zuraek, Marlene B.; Sánchez-Pérez, Tania; Aronchik, Ida; Filvaroff, Ellen; Lamba, Manisha; Hanna, Bishoy; Nikolova, Zariana; Braña, Irene

doi:10.1016/j.annonc.2020.03.294

Cited by 43 publications

(40 citation statements)

References 36 publications

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“…Thus, iBET-151 was effective as monotreatment for GC in the mouse models, but showed a modest effect. Initial BET inhibitor clinical trial results indicated very modest activities and a narrow therapeutic index [48]. Therefore, to improve the therapeutic efficacy of BET inhibition, we conclude that the BET inhibitor should be combined with another agent.…”

Section: Ibet-151 Inhibits Tumor Growth In Gc Xenograft Mouse Modelsmentioning

confidence: 92%

Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer

et al. 2021

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Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. ResultsWe found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity.

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Section: Ibet-151 Inhibits Tumor Growth In Gc Xenograft Mouse Modelsmentioning

confidence: 92%

Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer

et al. 2021

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“…Based on published clinical data, these toxicities appear to be common for this class of drugs regardless of the type of cancer being treated or the chemical structure of the BETi being tested. 62,115 Again, these studies highlight the importance of identifying pharmacodynamic biomarkers for BETi, which could help guide dose-escalation studies. Once maximum drug activity is identified in the plasma or intratumorally, higher doses are likely to elicit strong off-target effects.…”

Section: Lessons From Clinical Trialsmentioning

confidence: 99%

Achieving clinical success with BET inhibitors as anti-cancer agents

2021

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The transcriptional upregulation of oncogenes is a driving force behind the progression of many tumours. However, until a decade ago, the concept of ‘switching off’ these oncogenic pathways represented a formidable challenge. Research has revealed that members of the bromo- and extra-terminal domain (BET) motif family are key activators of oncogenic networks in a spectrum of cancers; their function depends on their recruitment to chromatin through two bromodomains (BD1 and BD2). The advent of potent inhibitors of BET proteins (BETi), which target either one or both bromodomains, represents an important step towards the goal of suppressing oncogenic networks within tumours. Here, we discuss the biology of BET proteins, advances in BETi design and highlight potential biomarkers predicting their activity. We also outline the logic of incorporating BETi into combination therapies to enhance its efficacy. We suggest that understanding mechanisms of activity, defining predictive biomarkers and identifying potent synergies represents a roadmap for clinical success using BETi.

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“…The BET proteins are a group of “histone readers” that act downstream of histone acetylation by binding to histone acetyl marks and recruiting transcription factors to DNA. Birabresib was the first BET to be evaluated in a clinical trial, but with no responses seen in DLBCL patients ( n = 2) in the first-in-human study [ 73 ]. In another preliminary analysis of a dose escalation phase I study of the BET inhibitor CPI-0610 in B-NHL ( n = 44, 8 with FL), one PR was seen in FL patients [ 74 ].…”

Section: Relapsed/refractory Follicular Lymphoma-approved and Investigational Approachesmentioning

confidence: 99%

Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies

Hanel

Epperla

2021

J Hematol Oncol

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Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.

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Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma

Cited by 43 publications

References 36 publications

Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer

Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer

Achieving clinical success with BET inhibitors as anti-cancer agents

Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies

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