Napabucasin: an update on the first-in-class cancer stemness inhibitor
Abstract
Napabucasin (BBI608) is an orally administered small molecule that blocks stem cell activity in cancer cells by targeting the signal transducer and activator of transcription 3 pathway. The signal transducer and activator of transcription 3 pathway is over-activated in many types of cancer and has been shown to be an important pathway in cancer stem cell-mediated propagation of cancer. Cancer stem cells are a subpopulation of cancer cells considered to be the primary source of tumor growth, metastasis, and resistance to conventional therapies, and thus, responsible for cancer relapse. This review describes the clinical development program of this first-in-class cancer stemness inhibitor, including preclinical discovery, early clinical trials, current phase III clinical trial evaluation, and future therapeutic combinations. The therapeutic potential of napabucasin was first reported in a preclinical study that demonstrated the potent anti-tumor and anti-metastatic activity of napabucasin in several different cancer types, both in vitro and in vivo. In mouse models, napabucasin was effective both as a monotherapy and in combination with other agents; in particular, synergy was observed with paclitaxel in vivo. Napabucasin clinical trials have demonstrated encouraging anti-tumor activity as monotherapy and in combination with conventional therapeutics, with no significant pharmacokinetic interactions when used in combination therapies. Adverse events attributed to napabucasin ha…
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A Phase III clinical trial of napabucasin versus placebo in patients with advanced CRC showed no significant difference in unselected patients, with regard to overall survival, progression-free survival, or disease control rate.
“A Phase III clinical trial of napabucasin versus placebo in patients with advanced CRC showed no significant difference in unselected patients, with regard to overall survival, progression-free survival, or disease control rate.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hubbard and Grothey, 2017
Patients with pY-STAT3-positive disease demonstrated significantly improved overall survival when treated with napabucasin (median oxidative stress = 5.1 months) compared with placebo-treated patients (median oxidative stress = 3.0 months).
“However, patients with pY-STAT3–positive disease demonstrated significantly improved overall survival when treated with napabucasin (median oxidative stress = 5.1 months) compared with placebo-treated patients (median oxidative stress = 3.0 months), even though patients with pY-STAT3–positive tumors had a poorer prognosis.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hubbard and Grothey, 2017
Patients with pY-STAT3-positive tumors had a poorer prognosis.
“However, patients with pY-STAT3–positive disease demonstrated significantly improved overall survival when treated with napabucasin (median oxidative stress = 5.1 months) compared with placebo-treated patients (median oxidative stress = 3.0 months), even though patients with pY-STAT3–positive tumors had a poorer prognosis.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hubbard and Grothey, 2017
There currently are three ongoing Phase III clinical trials involving napabucasin in combination with other standard chemotherapy agents in metastatic CRC, metastatic pancreatic ductal adenocarcinoma, and other advanced malignancies.
“There currently are three ongoing Phase III clinical trials involving napabucasin in combination with other standard chemotherapy agents in metastatic CRC, metastatic pancreatic ductal adenocarcinoma, and other advanced malignancies (Hubbard and Grothey, 2017).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hubbard and Grothey, 2017
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- Authors
- Hubbard, J. M., & Grothey, A.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Grothey, Axel
- Venue
- Drugs
- Published
- 2017-06-01
- Volume
- 77
- Issue
- 10
- Pages
- 1091-1103
- ISSN
- 0012-6667 (ISSN-L)
- 1179-1950
- OpenAlex
- W2621051455
- Cited by
- 157
- References
- 4
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 25 · 2023: 15 · 2022: 20 · 2021: 13 · 2020: 25 · 2019: 21 · 2018: 16 · 2017: 4
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drugs (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- napabucasin, cancer stem cells, STAT3 signaling, oral small molecule, combination therapy, paclitaxel, metastasis, tumor recurrence, gastrointestinal adverse effects, clinical development
- MeSH terms
- Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Benzofurans, Clinical Trials as Topic, Disease Models, Animal, Humans, Naphthoquinones, Neoplasms, Neoplastic Stem Cells, STAT3 Transcription Factor
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