# Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $556,316

## Abstract

Project 2 - SUMMARY/ABSTRACT
While surgical resection is potentially curative for early stage hepatocellular carcinoma (HCC), care of
advanced stage disease is limited to treatment with sorafenib, regorafenib, or nivolumab which increase
survival by 3-4 months. Even in patients who undergo resection, recurrence within 5 years occurs in ~70%.
Therefore, there is an urgent need for new therapeutic strategies to treat advanced disease and to prevent
postoperative recurrence. Our long-term translational goal is to improve outcomes in patients with advanced
stage HCC and in post-operative HCC patients. More than 90% of HCC cases arise in the setting of hepatic
injury and inflammation, which involve production of several cytokines, notably hepatocyte growth factor (HGF)
and IL-6 that activate signal transducer and activator of transcription (STAT) 3. STAT3 is a master regulator of
most of the key hallmarks and enablers of cancer and its activation occurs in approximately 60% of HCCs
where it is a predictor of tumor recurrence and contributes to immune resistance in HCC by regulating the
development, recruitment, and the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs).
Our group, in collaboration with a clinical-stage pharmaceutical firm (Tvardi Therapeutics, Inc.), used
computer-based docking and lead-compound optimization strategies to identify TTI-101 (C188-9), a potent,
non-toxic and orally bioavailable inhibitor of STAT3. Administration of TTI-101 to mice that develop liver
steatosis and fibrosis followed by HCC (hepatocyte-specific Pten knockout mice) led to arrest of tumor growth,
as well as marked reduction in liver injury and fibrosis. A Phase I study of patients with solid tumors, including
HCC, at MD Anderson showed no toxicity through dose level (DL) 3 and resulted in a partial clinical response
after two cycles at DL2 in the first HCC patient entered into the trial. Tvardi collaborated with the Department of
Pathology at MD Anderson to develop a clinical laboratory improvement amendments (CLIA)-certified IHC test
and score for pY-STAT3 levels by immunohistochemistry (IHC), which was further developed into a pY-STAT3
score for HCC tumors. We hypothesize that STAT3 contributes to HCC tumor growth and immune resistance,
as well as HCC development in the setting of liver inflammation and fibrosis. We hypothesize further that use
of a STAT3 inhibitor, such as TTI-101, will be more effective at treating advanced HCC when combined with
standard therapy (nivolumab) than nivolumab alone and will prevent postoperative recurrence. In Aim 1, we
will determine the safety and early effectiveness of TTI-101 when used in combination with nivolumab in
patients with surgically non-resectable HCC. In Aim 2, we will determine the utility of the pY-STAT3 score of
HCC patient tumors or adjacent non-tumoral liver in predicting postoperative recurrence. In Aim 3, we will
determine if TTI-101 adjuvant therapy reduces HCC recurrence. The impac...

## Key facts

- **NIH application ID:** 10246497
- **Project number:** 5P50CA217674-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** David John Tweardy
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $556,316
- **Award type:** 5
- **Project period:** 2019-09-25 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246497

## Citation

> US National Institutes of Health, RePORTER application 10246497, Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC (5P50CA217674-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10246497. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*