Napabucasin (BBI 608), a potent chemoradiosensitizer in rectal cancer

Nagaraju, Ganji Purnachandra; Farran, Batoul; Farren, Matthew R.; Chalikonda, Gayathri; Wu, Christina; Lesinski, Gregory B.; El‐Rayes, Bassel F.

doi:10.1002/cncr.32954

Cited by 22 publications

(14 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results confirm and extend the recent observation from Nagaraju and colleagues, who demonstrated a sensitization to CRT of HCT116 colon cancer cells following treatment with napabucasin in vivo [ 42 ]. However, their experiments were performed in a microsatellite-instable (MSI) cell line, and tumor growth was only monitored during treatment.…”

Section: Discussionsupporting

confidence: 92%

NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy

Koerdel

Spitzner²,

Meyer

et al. 2021

Cancers

View full text Add to dashboard Cite

Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.

show abstract

Section: Discussionsupporting

confidence: 92%

NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy

Koerdel

Spitzner²,

Meyer

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…The promising novel STAT3 inhibitor Napabucasin has undergone several preclinical studies ( Hubbard and Grothey, 2017 ; Li et al, 2020 ; Nagaraju et al, 2020 ). Considering that the classic STAT3 trigger point of the immune system was also a significant signal in bone homeostasis ( Li, 2013 ; Yang et al, 2019 ), we had good reason to be concerned that long-time anti-tumor treatment with Napabucasin would also affect the skeletal system of patients, which has never been reported to our knowledge.…”

Section: Discussionmentioning

confidence: 99%

“…Napabucasin (also known as BBI608), the focus of this investigation, is a novel small molecule shown to inhibit gene transcription driven by STAT3 ( Hubbard and Grothey, 2017 ). Based on the promising effects observed in animal xenograft models ( Li et al, 2015 ; Zhang et al, 2016 ), several preclinical studies were conducted in patients with advanced or metastatic cancers ( Li et al, 2015 , 2020 ; Bekaii-Saab et al, 2017 ; Grothey et al, 2017 ; Nagaraju et al, 2020 ). In fact, when this manuscript was written, there were 27 preclinical studies listed in the ClinicalTrials.gov database.…”

Section: Introductionmentioning

confidence: 99%

Napabucasin Induces Mouse Bone Loss by Impairing Bone Formation via STAT3

Huang

Jin

Wang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The novel small molecule Napabucasin (also known as BBI608) was shown to inhibit gene transcription driven by Signal Transducer and Activator of Transcription 3 (STAT3), which is considered a promising anticancer target. Many preclinical studies have been conducted in cancer patients examining the selective targeting of cancer stem cells by Napabucasin, but few studies have examined side effects of Napabucasin in the skeleton system. In the present study, we found treating bone marrow mesenchymal stem cells (BMSCs) with Napabucasin in vitro impaired their osteogenic differentiation. In terms of mechanisms, Napabucasin disrupted differentiation of BMSCs by inhibiting the transcription of osteogenic gene osteocalcin (Ocn) through STAT3. Moreover, through micro-CT analysis we found 4 weeks of Napabucasin injections induced mouse bone loss. Histological analysis revealed that Napabucasin-induced bone loss in mice was the result of impaired osteogenesis. In conclusion, this study provided evidence for the effect of Napabucasin on mouse bone homeostasis and revealed its underlying mechanisms in vivo and in vitro.

show abstract

“…A Phase III clinical trial involving napabucasin in combination with other standard chemotherapeutic agents is currently underway for several advanced malignancies [21]. In rectal cancer, napabucasin reduced not only pSTAT3 levels but also angiogenesis through a ROS-mediated effect [165].…”

Section: Napabucasinmentioning

confidence: 99%

An aberrant STAT pathway is central to COVID-19

Matsuyama

Kubli

Yoshinaga³

et al. 2020

Cell Death Differ

263

275

View full text Add to dashboard Cite

COVID-19 is caused by SARS-CoV-2 infection and characterized by diverse clinical symptoms. Type I interferon (IFN-I) production is impaired and severe cases lead to ARDS and widespread coagulopathy. We propose that COVID-19 pathophysiology is initiated by SARS-CoV-2 gene products, the NSP1 and ORF6 proteins, leading to a catastrophic cascade of failures. These viral components induce signal transducer and activator of transcription 1 (STAT1) dysfunction and compensatory hyperactivation of STAT3. In SARS-CoV-2-infected cells, a positive feedback loop established between STAT3 and plasminogen activator inhibitor-1 (PAI-1) may lead to an escalating cycle of activation in common with the interdependent signaling networks affected in COVID-19. Specifically, PAI-1 upregulation leads to coagulopathy characterized by intravascular thrombi. Overproduced PAI-1 binds to TLR4 on macrophages, inducing the secretion of proinflammatory cytokines and chemokines. The recruitment and subsequent activation of innate immune cells within an infected lung drives the destruction of lung architecture, which leads to the infection of regional endothelial cells and produces a hypoxic environment that further stimulates PAI-1 production. Acute lung injury also activates EGFR and leads to the phosphorylation of STAT3. COVID-19 patients' autopsies frequently exhibit diffuse alveolar damage (DAD) and increased hyaluronan (HA) production which also leads to higher levels of PAI-1. COVID-19 risk factors are consistent with this scenario, as PAI-1 levels are increased in hypertension, obesity, diabetes, cardiovascular diseases, and old age. We discuss the possibility of using various approved drugs, or drugs currently in clinical development, to treat COVID-19. This perspective suggests to enhance STAT1 activity and/or inhibit STAT3 functions for COVID-19 treatment. This might derail the escalating STAT3/PAI-1 cycle central to COVID-19.

show abstract

Napabucasin (BBI 608), a potent chemoradiosensitizer in rectal cancer

Cited by 22 publications

References 45 publications

NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy

NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy

Napabucasin Induces Mouse Bone Loss by Impairing Bone Formation via STAT3

An aberrant STAT pathway is central to COVID-19

Contact Info

Product

Resources

About