STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma
Abstract
:1. Introduction
2. The STAT3 Signaling Pathway
2.1. Activation and Regulation of STAT3
2.2. Crosstalk between STAT3 and NF-κB
3. The Roles of STAT3 in HCC
3.1. Hepatic STAT3 Functions
3.2. Clinical Implication of STAT3 in HCC
3.3. Functions of STAT3 in HCC
4. Clinical Trials of STAT3 Targeting Therapies
4.1. Napabucasin: Cancer Stemness Inhibitor Targeting STAT3-Driven Gene Transcription
4.2. AZD9150: STAT3-Targeted Antisense Oligonucleotide
4.3. OPB Compounds, Pyrimethamine and TTI-101: STAT3 SH2 Domain Inhibitor
4.4. STAT3 Decoy: STAT3-DNA Binding Inhibitor
4.5. Current Status and Future Perspectives of STAT3-Targeted Therapies in HCC
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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NCT No. | Phase | Therapy | Cancer Types | Brief Description | Time | Ref |
---|---|---|---|---|---|---|
NCT 01775423 | Ib | Monotherapy | Advanced solid cancers (n = 41) | Dose escalation achieved | 2009–2019 | [87] |
Ib | Advanced solid cancers (n = 24) | Safety and antitumor activity demonstrated in higher strength capsule | [88] | |||
NCT 01830621 | III | Monotherapy | Advanced CRC (n = 280) | Prolonged OS demonstrated after pSTAT3 stratification | 2013–2016 | [89] |
NCT 03416816 | I | Monotherapy | Advanced solid tumors (n = 90) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity of pro-drug of napabucasin, DSP-0337 | 2018–2020 | / |
NCT 01325441 | Ib/II | Combination | Advanced solid cancers (n = 24) | Safety and antitumor activity demonstrated with paclitaxel, particularly in gastric and GEJ adenocarcinoma | 2011–2020 | [90] |
Ib/II | Advanced gastric and GEJ adenocarcinoma (n = 46) | Safety and antitumor activity demonstrated with paclitaxel, regardless of prior taxane exposure | [91] | |||
Ib/II | Advanced PROC (n = 98) | Safety and antitumor activity demonstrated with paclitaxel, including 3 completes responses | [92] | |||
Ib/II | Advanced PDAC (n = 41) | Safety and antitumor activity demonstrated with paclitaxel, particularly in taxane-naïve group | [93] | |||
Ib/II | Advanced TNBC (n = 35) | Safety and antitumor activity demonstrated with paclitaxel, particularly in taxane-exposed therapy | [94] | |||
NCT 01776307 | Ib/II | Combination | KRAS-wt mCRC (n = 24) | Safety and antitumor activity demonstrated with panitumumab, regardless of prior anti-EGFR exposure | 2012–2019 | [95] |
II | KRAS-wt mCRC (n = 72) | [96] | ||||
NCT 02024607 | Ib/II | Combination | Advanced CRC (n = 63) | Safety and antitumor activity demonstrated with FOLFIRI ± bevacizumab | 2014–2019 | [97] |
III | Advanced CRC (n = 46) | Safety and antitumor activity demonstrated with FOLFIRI ± bevacizumab, regardless of prior FOLFIRI ± bevacizumab exposure and pSTAT3 status | [98] | |||
NCT 02231723 | III | Combination | mPDAC (n = 37) | Safety and antitumor activity demonstrated with gemcitabine and nab-paclitaxel | 2014–2020 | [99] |
NCT 02178956 | III | Combination | Advanced gastric and GEJ adenocarcinoma (n = 680) | To determine if napabucasin in combination with paclitaxel prolongs OS than paclitaxel alone | 2014–2019 | / |
NCT 02279719 | Ib/II | Combination | Advanced HCC (n = 99) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity in combination with sorafenib in comparison with sorafenib alone | 2014–2019 | / |
NCT 02358395 | I | Combination | Advanced HCC (n = 12) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity in combination with sorafenib | 2015–2019 | / |
NCT 02467361 | III | Combination | Advanced cancers (n = 104) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity in combination with immune checkpoint inhibitors | 2015–2019 | / |
NCT 02753127 | III | Combination | mCRC (n = 1253) | To determine if napabucasin in combination with FOLFIRI prolongs OS than FOLFIRI alone | 2016–2020 | / |
NCT 02993731 | III | Combination | mPDAC (n = 1134) | To determine if napabucasin in combination with nab-paclitaxel and gemcitabine prolongs OS than nab-paclitaxel and gemcitabine alone | 2016–2020 | / |
NCT 03416816 | I | Monotherapy | Advanced solid tumors (n = 90) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity | 2018–2020 | / |
NCT No. | Phase | Therapy | Cancer Types | Brief Description | Time | Ref. |
---|---|---|---|---|---|---|
NCT 01563302 | I/II | Monotherapy | Predominantly refractory DLBCL (n = 30) | Safety and antitumor activity demonstrated | 2012–2016 | [105] |
NCT 01839604 | II | Monotherapy | Advanced HCC (n = 58) | Safety, tolerability and pharmacokinetics evaluated but with limited antitumor activity | 2013–2015 | [103] |
Not stated | I | Monotherapy | Advanced lymphoma and solid tumors (n = 25) | Safety and antitumor activity demonstrated | 2015 | [100] |
NCT 02499328 | I & II | Combination | Advanced solid tumors (n = 465) | To evaluate the safety, tolerability and antitumor activity in combination with durvalumab, tremelimumab and AZD5069 | 2015–2020 | / |
NCT 02549651 | 1 | Combination | Relapsed/refractory DLBCL (n = 32) | To evaluate the safety, tolerability and antitumor activity in combination with durvalumab and tremelimumab compared with durvalumab alone | 2016–2019 | / |
NCT 02546661 | I | Combination | MIBC (n = 156) | To evaluate the safety, tolerability and antitumor activity of durvalumab in combination with AZD9150 or other novel anticancer agents compared with durvalumab alone | 2016–2020 | / |
NCT 02983578 | II | Combination | Advanced pancreatic, lung, colorectal cancer (n = 75) | To evaluate the antitumor activity and tumor-based biomarkers in combination with durvalumab | 2017–2021 | / |
NCT 03334617 | II | Combination | Advanced non-small cell lung cancer (NSCLC) (n = 260) | To evaluate the safety, tolerability and antitumor activity of different combinations of anticancer agents | 2017–2021 | / |
NCT 03394144 | I | Combination | Advanced solid tumors (n = 110) | To evaluate the safety, tolerability and antitumor activity in combination with durvalumab compared with AZD9150 alone | 2018–2019 | / |
NCT 03421353 | I & II | Combination | Advanced solid tumors (n = 110) | To evaluate the safety, tolerability and antitumor activity in combination with durvalumab and chemodrugs compared with AZD9150 alone; to compare its bioavailability of subcutaneous and intravenous formulations | 2018–2020 | / |
NCT 03742102 | Ib/II | Combination | mTNBC (n = 110) | To evaluate the safety, tolerability and antitumor activity of durvalumab and paclitaxel in combination with AZD9150 or other novel anticancer agents | 2018–2020 | / |
NCT 03819465 | Ib | Combination | Advanced NSCLC (n = 200) | To evaluate the safety, tolerability and antitumor activity of durvalumab in combination with AZD9150 or other novel anticancer agents +/- chemotherapy | 2018–2020 | / |
NCT 03527147 | I | Combination | Relapsed/refractory non-Hodgkin lymphoma (n = 88) | To evaluate the safety, tolerability and antitumor activity of different combinations of targeted agents | 2018–2021 | / |
NCT No. | Phase | Therapy | Cancer Types | Brief Description | Time | Ref. |
---|---|---|---|---|---|---|
OPB-31121 | ||||||
NCT 00955812 | I | Monotherapy | Advanced solid tumors (n = 14) | Unfavorable pharmacokinetic profile and antitumor activity demonstrated, leading to discontinuation of compound development | 2009–2012 | [109] |
OPB-111077 | ||||||
NCT 01711034 | I | Monotherapy | Advanced solid tumors (n = 145) | Safety, tolerability and antitumor activity demonstrated, including one PR in DLBCL | 2012–2015 | [110] |
NCT 01942083 | I | Monotherapy | Advanced HCC (n = 33) | Safety and tolerability demonstrated but no antitumor response was observed | 2013–2017 | [111] |
NCT 02250170 | I | Monotherapy | Advanced solid tumors (n = 47) | To evaluate the safety, tolerability and antitumor activity | 2014–2019 | / |
NCT 03197714 | Ib | Monotherapy | Relapsed/refractory AML (n = 15) | To evaluate the safety, tolerability and antitumor activity | 2017–2018 | / |
NCT 03158324 | IIa | Monotherapy | NPC/refractory tumors (n = 52) | To evaluate the safety, tolerability and antitumor activity | 2017–2020 | / |
NCT 03063944 | I | Combination | AML (n = 12) | To evaluate the safety, tolerability and antitumor activity in combination with decitabine | 2017–2023 | / |
NCT 04049825 | I | Combination | Relapsed/refractory DLBCL (n = 65) | To evaluate the safety, tolerability and antitumor activity in combination with bendamustine and rituximab | 2019–2021 | / |
OPB-51602 | ||||||
NCT 01184807 | I | Monotherapy | Refractory solid tumors (n = 51) | Better tolerability for intermittent than continuous dosing; antitumor activity demonstrated, including 2 PRs in EGFR mutation-positive NSCLC prior anti-EGFR exposure | 2009–2013 | [112] |
NCT 01423903 | I | Monotherapy | Advanced cancers (n = 45) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity | 2010–2013 | / |
NCT 01344876 | I | Monotherapy | Relapsed/refractory hematological malignancies (n = 20) | Safety and tolerability demonstrated but long-term administration at higher doses was difficult with daily dosing and no antitumor response was observed, leading to termination of study | 2011–2014 | [113] |
NCT 01867073 | I | Monotherapy | Advanced solid tumors (n = 20) | To evaluate the pharmacokinetic profile in relation to pSTAT3 expression in peripheral mononuclear blood cells and single nucleotide polymorphisms in patient tissues | 2011–2015 | / |
NCT 02058017 | I | Monotherapy | Advanced NPC (n = 9) | Poor tolerability, leading to termination of study | 2013–2015 | [114] |
Pyrimethamine | ||||||
NCT 01066663 | I & II | Monotherapy | Relapsed CLL/SLL (n = 26) | To evaluate the safety, tolerability, pharmacokinetic profile and antitumor activity | 2010–2024 | / |
TTI-101 | ||||||
NCT 03195699 | I | Monotherapy | Advanced cancers (n = 30) | To evaluate the safety, tolerability and pharmacokinetic profile | 2017–2020 | / |
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Lee, C.; Cheung, S.T. STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma. Cancers 2019, 11, 1646. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111646
Lee C, Cheung ST. STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma. Cancers. 2019; 11(11):1646. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111646
Chicago/Turabian StyleLee, Carol, and Siu Tim Cheung. 2019. "STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma" Cancers 11, no. 11: 1646. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111646