Utilizing TGF-β inhibitors for a Novel Approach to Hepatocellular Carcinoma
Joel Ravichandran
Introduction: Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death in the world due to its high-rate of metastasis and reoccurrence1,2. The most common cause is due to hepatitis B virus mediating cellular pathways and proteins in hepatocytes. Unfortunately, HCC is highly resistant to traditional chemotherapy and is often detected when the cancer is in an advanced stage, leaving it past the ability of surgical options to cure it. Needing a novel method of treating HCC, TGF-β, a cytokine used by cancer to suppress the immune system’s cytotoxic mechanisms, is being studied to see if inhibition could increase immune removal of HCC3,4.
Methods: Clatherin heavy chains, associated with increased levels of TGF-β, were studied using immunochemistry and RT-PCR in human and mice model HCC1. Secondarily, a clinical trial with 47 patients with HCC were given sorafenib, a common kinase inhibitor, and galunisertib, a TGF-β inhibitor, to assess safety margins and effectiveness at reducing HCC. Tertiarily, hepatocytes were treated with TGF-β and ROS was measured by flow cytometric studies. Finally, POSTN genes were knocked out using restriction enzymes2,3.
Results: Clatherin coated pits had an essential role in inhibiting TGF-β induced apoptosis and inducing autocrine signaling of TGF-β upregulated clatherin coated pits. Models that had higher TGF-β and clatherin coated pits had lower survivability and a worse prognosis; however, patients saw greater effect from TGF-β inhibitors when there were high expressed TGF-β and clatherin coated pits. Galunisertib showed acceptable safety and prolonged overall survivability of HCC by 4.1 months. Hepatocytes showed increased ROS generation leading to apoptosis when exposed to high levels of TGF-β. When POSTN genes were knocked out, TGF-β increased greatly and HCC invasion was increased in mouse models
Conclusion: TGF-β inhibitors, while still needing further clinical trials, is a promising option for treating HCC. Physicians should consider assessing the levels of clatherin coated pits in patients with HCC, for its well-established correlation to effectiveness of TGF-β inhibitor drugs4. A new avenue of gene therapy could be used to knockout POSTN genes, decreasing TGF-β and reducing the ability of HCC to hide from the host immune system5.
Works Cited:
1: Caballero-Díaz D, Bertran E, Peñuelas-Haro I, et al. Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer. J Hepatol. 2020;72(1):125-134. doi:10.1016/j.jhep.2019.09.012
2 : Chen G, Wang Y, Zhao X, et al. A positive feedback loop between Periostin and TGFβ1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation. J Exp Clin Cancer Res. 2021;40(1):218. Published 2021 Jun 30. doi:10.1186/s13046-021-02011-8
3: Sánchez A, Alvarez AM, Benito M, Fabregat I. Apoptosis induced by transforming growth factor-beta in fetal hepatocyte primary cultures: involvement of reactive oxygen intermediates. J Biol Chem. 1996;271(13):7416-7422. doi:10.1074/jbc.271.13.7416
4 : Kelley RK, Gane E, Assenat E, et al. A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma. Clin Transl Gastroenterol. 2019;10(7):e00056. doi:10.14309/ctg.0000000000000056Galunisertib, a TGF B1 receptor type inhibitor, lead to results in controlling hepatocellular carcinoma
5: Kim DH, Kim WD, Kim SK, Moon DH, Lee SJ. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis. 2020;11(5):406. Published 2020 May 29. doi:10.1038/s41419-020-2618-6