Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It is the fifth most common and third most lethal cancer worldwide. Most HCC patients present symptoms at advanced stages when they are no longer suitable for surgical treatments. Unfortunately, HCC is resistant to conventional radio- and chemo-therapies. Currently, there are five FDA-approved targeted therapies and two immunotherapies for advanced HCC patients but their effects are only modest. Therefore, knowledge on the molecular biology of HCC is warranted for the development of better diagnostic platforms and therapeutic regimens. Our research focuses on three emerging, fundamental, and inter-related aspects in HCC.
Immune microenvironment, immune evasion
Immunotherapies have revolutionized cancer treatment due to recent successful clinical trials with immune checkpoint inhibitors (ICIs) in multiple cancers including HCC. However, only a subset of HCC patients respond to ICIs. Our research aims to characterize the immune landscape of HCC and studies how tumor microenvironmental factors (inflammation, hypoxia, stromal cells, extracellular matrix) intertwine to influence intratumoral immune contexture in HCC, thereby allowing cancer cells to evade from immune surveillance and resist ICIs. Currently, we are investigating new immunotherapies as well as resistance mechanisms to ICIs, with the aim to identify new therapeutic targets to improve their efficacy. Immune cells reside in the same microenvironment and share the same nutrients with cancer cells. Another interesting area that we are exploring is the unique metabolic programs of cancer and immune cells and how they affect the therapeutic responses. Also, we are particularly interested in unraveling the roles of immunometabolites in liver cancer development. Using genome editing tools, we have established a large collection of mouse liver cancer models with different etiologies (NASH, fibrosis, alcoholic liver) and genetic alterations which closely simulate the genetic composition of human liver cancer. We are currently examining the immune landscapes of these tumors and their responses towards different immunotherapies.
Tumor microenvironment (TME) is extremely hostile. Since tumor growth often outpaces the rate of angiogenesis, the lack of blood supply leads to hypoxia, low oxygen level, and inadequate nutrient supply. HCC is one of the most hypoxic and nutrient deprived malignancies. However, by substantially reprogramming the metabolic pathways, apart from adapting to and surviving under these insults, HCC cells become even more aggressive. Conventional wisdom emphasizes that reactive oxygen species (ROS) promote malignancy transformation by inducing genetic mutations. Interestingly, our group demonstrates that excessive ROS accumulation is clearly detrimental to HCC cell survival. To combat oxidative stress, HCC cells undergo metabolic rewiring to prioritize NADPH production to counteract intracellular ROS, thereby maintain survival fitness. We also reported the biological importance of metabolic reprogramming in conferring drug resistance of HCC by state-of-the-art genome-wide CRISPR/Cas9 library screening. On the other hand, HCC cells thrive by strategically enhancing nutrient scavenging under hypoxic conditions. We are actively identifying novel targetable metabolic vulnerabilities and investigating the translational values of potent inhibitors that shed light to more effective therapeutic treatment to ameliorate quality of life of HCC patients.
Our translational research discovered the potentials of novel targeted therapies and combination therapies with FDA-approved treatments for HCC. Currently, we are focusing on the cell cycle inhibitors (centriole biogenesis inhibitor and cell cycle checkpoint inhibitors) and the detailed molecular mechanisms by which they alter the immune landscape and to identify ways to maximize their therapeutic efficacy with immune checkpoint inhibitors. Sorafenib is the first FDA-approved first-line therapy for advanced HCC; however, it can only prolong patients’ survival for three months. We discovered that treatments using auranofin (TXNRD1 inhibitor), methotrexate (antifolate drug), or oxythiamine (TKT inhibitor) can sensitize HCC cells towards Sorafenib, thus improving clinical outcomes of Sorafenib. Nivolumab, or anti-PD-1, was approved by FDA for advanced HCC patients in 2018. Resistance against Nivolumab has been shown clinically. We revealed combination treatments with anti-TIGIT MAb or POM-1 (ENTPD2 inhibitor) can overcome the resistance against nivolumab. POM-1 also increased efficacy of anti-CTLA-4.
Carmen Wong HKU