napabucasin (BBI608)

Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level...Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.

In vivo studies confirmed significant tumour-suppressive effects upon oral administration of NW16 along with favourable tolerability in a colorectal cancer xenograft model. These results indicate that NW16 could be a promising candidate for developing targeted therapy for colorectal cancer because of its multifaceted mechanism.

Some of them such as TTI101 and BBI608 have been approved by the FDA for the treatment of certain cancers. All in all, STAT3 plays an important role in cancer progression and becomes a potential target for cancer treatment.

For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.

In this study, the anti-proliferative and apoptotic effects of NP and the chemotherapy agent doxorubicin (DX), a natural compound, on glioblastoma cells (U87) were investigated. Since it can suppress Jak2/Stat3, an important cancer cell proliferation pathway in glioblastoma, the combination of NP and DX can be used as an alternative treatment agent. But no synergistic effect of NP and DX on the U87 cells of the glioblastoma cell line was observed.

As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.

NP showed that it suppresses the proliferation of neuroblastoma cells. Due to its inhibitory effect on Jak2 and Stat3, it can be used to prevent invasion of SH-SY5Y cells. NP, which can inactivate Jak2/Stat3, can be used as a treatment agent by combining with DX in proliferation pathway in neuroblastoma.

Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized...Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.

P3, N=668, Ongoing, 1Globe Health Institute

Furthermore, tumor cell stemness are inhibited by napabucasin, which can help CTLs to achieve comprehensive tumor killing. Collectively, the proposed strategy of cDC1 in situ recruitment and activation combined with stemness inhibition provides great immune response and anti-tumor potential, providing new ideas for clinical tumor vaccine design.

Therefore, high-MUC1 tumors may have a better outcome to Napabucasin therapy. We report how MUC1 regulates STAT3 activity and provide a new perspective on repurposing the STAT3-inhibitor Napabucasin to improve clinical outcome of epithelial cancer treatment.

PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.

We also found that napabucasin increased the AUC and AUC of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.

Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.

BBI608 pretreatment protects the liver and suppresses the alcohol-triggered premetastatic niche formation. In conclusion, under the extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironment.

These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.

The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo...We found that JAK-STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + Kras tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC, who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

BOL-resistant (BR) cell lines, HCT116 and HCA7, were equally sensitive to standard CRC therapeutic agents and known STAT3 inhibitors but resistant to homoharringtonine (HHT), a known protein synthesis inhibitor...Of note, BOL did not inhibit protein synthesis in normal human colon epithelial cells whereas HHT and napabucasin remained effective in these normal cells...Treatment with the most potent analog, 5c, resulted in significant inhibition of cell proliferation and protein synthesis at nanomolar concentrations. These quassinoid analogs may represent a novel class of protein synthesis inhibitors for the treatment of human CRC.

Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC. The Sumitomo Pharma Oncology, Inc.

Flow cytometric analysis demonstrated that the drug combination shows a synergistic effect in producing excess mitochondrial and cellular ROS, causing apoptosis and in inducing cell cycle arrest in both BPH-Cd and DU145 cells. Taken together, our study demonstrates that NCX 4040 and Napabucasin in combination could be a potential anti-PCa therapy which warrants further evaluation for its clinical application.

Based on meta-analysis and computational approach, NQO1 is a viable biomarker and targeted molecule in CRC. In vitro results showed that inhibiting NQO1 with the drug BBI 608 decreased cell proliferation in both CRC cell lines. Knockout or overexpression or site directed mutagenesis is essential for a better understanding about BBI 608 targeted NQO1 and its amino acids.

As a combined diagnostic and therapeutic nanoprobe, N-TMPs@NAP could successfully conduct PET/CT imaging, suppress CSCs, and synergistically stimulate anticancer immune responses. Additionally, this nanoprobe might someday be employed in clinical situations because TMPs for it can be produced from human tissue and NAP has FDA approval.

Napabucasin and 2'-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC = 9.57 and 18.10 μM) and HEL (IC = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.

Furthermore, napabucasin significantly inhibited cisplatin-resistant SCLC cell xenograft growth in vivo by downregulating SOX2 and inducing apoptosis. These data demonstrate that napabucasin may be a novel drug for the clinical treatment of cisplatin-resistant SCLC.

Cancer and myCAF crosstalk increases myCAF maintenance and cancer cell stemness. In this study using human breast and liver cancer cell lines, maintenance of the OPN-induced myCAF phenotype also requires cancer stemness. This indicates that the myCAF phenotype requires two distinct signaling pathways: initiation and maintenance.

Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance.

Results show for the first time that NB exerts an anti-cancer activity through the direct interaction to Akt and mTOR proteins. The methyl moiety of acetyl group of NB is required for its potent anti-cancer activities. These data encourage further development of NB compounds for Akt and mTOR driven cancers.

In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1...Significantly, the anti-tumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3-induced ICD in HCC, and confirm STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.

Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.

Inhibition of STAT3 signaling was achieved by RNAi or the small-molecule inhibitor napabucasin...Importantly, genetical and pharmacological perturbation of the IL-6/STAT3 pathway resulted in CRT sensitization specifically in those cell lines, in which STAT3 activity was augmented by IL-6. In conclusion, our data underscore the general importance of IL-6/STAT3 signaling for CRT resistance and suggest that pathway inhibition may represents a putative treatment strategy in order to increase the fraction of patients with PDAC who are candidates for surgical approaches.

Importantly, augmented NPC43 cell death was observed in combined treatment (47.1±2.1%) compared to single treatment (NK alone: 9.2±6.5%; Napabucasin alone: 25.0±4.5%). In summary, this work demonstrated encouraging therapeutic potential of both NK therapy and in combination with STAT3 inhibitor Napabucasin for NPC treatment.

The combination of BBI608 with gemcitabine plus irradiation creates higher cytotoxicity (decreased proliferation, clonogenicity and increased Annexin V positive cells; p<0.001) in PDAC cell lines and the mice bearing subcutaneous PANC-02 and MIA PaCa-2 model. Collectively, this investigation offers mechanistic insight into the cytotoxicity initiated by BBI608 and suggests further investigation of its utility for PDAC therapy is warranted.

P1/2, N=55, Terminated, Takayuki Yoshino | Trial completion date: Feb 2020 --> Aug 2021

In vivo experiment, STAT3 inhibitor further suppressed the size of NSCLC tissues, and further down-regulated the expression of ROR1 and ABCB1 while up-regulated the expression of p53 in NSCLC tissues. In conclusion, STAT3 inhibitor enhanced the antitumor effect of gefitinib on EGFR-mutated NSCLC cells through regulating ROR1/ABCB1/P53 pathway.

Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.

P1/2, N=565, Completed, Sumitomo Dainippon Pharma Oncology, Inc | Active, not recruiting --> Completed

A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC, and to napabucasin...This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable.

Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9)...No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.