Chulabhorn Research Institute had been collaborating with Chulabhorn hospital, the National Cancer Institute (Thailand), Khon Kaen University, and Chiang Mai University with the aim to alleviate the suffer of liver cancer patients and the tumor biobank for liver cancer was set up to provide resource for future investigations. Since 2008, CRI, participating Thai institutions and the National Cancer Institute (Bethesda, USA) has established the Thailand Initiative on Genomics and Expression Research for Liver Cancer (TIGER-LC) consortium. The goal is to perform a comprehensive large scale genome-wide and candidate association study to identify and validate genome factors and tumor biology that affect liver cancer risk progression and response to therapy. The MOU signing ceremony of TIGER-LC between CRI and collaborators The study aims to include 6,000 volunteers which are 1,000 HCC cases; 2,000 CCA cases, 2,000 patients with chronic liver diseases arising from hepatitis B and or hepatitis C infection, alcoholic cirr hosis, and liver fluke carriers which are considered high risk non-carrier cases, as well as a sample of 1,000 healthy population-based controls recruited at our collaborating institutions and Chulabhorn hospital. Information from questionnaire, clinical data and specimens such as blood, urine, saliva and tissue were collected with the same efficiency and standard and delivered to CRI. The biobank and database system are set up at CRI to accommodate a...

The main focus of the research is to understand the relationship among genetics, environmental exposures, and the etiology of primary liver cancer through the establishment of a large clinical cohort consisting of well-defined case-control and case-case individuals. Recognizing the molecular features and genetic mutations of liver cancer from Thai patients could lead to more effective treatment options for this population. These findings may point researchers toward new strategies for drug development. Through integrative analysis approaches, the research also aims to identify clinically-relevant biomarkers that may be useful for risk assessment, cancer early detection, tumor subtype classification, prediction of tumor relapses and responses to therapy which could potentially lead to more effective treatment of liver cancers. Using biospecimens collected in the biorepository, the researchers studied multi-omics data arising from tissue of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patients from Thailand. Genome sequences, gene activity and metabolic profiles data of 398 tissue samples were analyzed and the researchers were able to identify molecular subtypes of either type of liver cancer which are closely resembles each other’s. These common subtypes of HCC and CCA showed similar gene expression pattern, tumor biology and clinical outcome. The follow up study focused on metabolic profile of Thai HCC patients, the researchers discovered that certain metabolic genes, tissue metabolites and serum metabolites can independently stratify HCC patients...

Biologics, or biopharmaceutical drugs, are promising treatments with low side effects for several diseases including cancer, immunological disorder and infectious disease. The high cost of biologics treatment causing the low drug accessibility and affordability. Each year Thailand imports approximately 500-1,000 million Baht of these products from many foreign sources. CBRD is focusing on translating fundamental scientific research to solve national and global health issues using multidisciplinary cutting-edge technology. Since the pandemic of bird flu in 2004 in Thailand, Her Royal Highness Princess Chulabhorn realized that Thailand was in an urgent need of national health security for self-reliance on therapeutics. Biologics or biological products consist of variety classes of bioactive agents including vaccines, blood products, tissue therapy, cell therapy, gene therapy, and recombinant proteins. CBRD main focus is currently on development of recombinant proteins and biologics with potential to be therapeutics, vaccines, diagnostics, and research reagents. Current focus is primarily but not limited to monoclonal antibody, virus like particle, and recombinant peptide hormone. To ensure the seamless transition and preparation of product pipeline, CRI has integrated all necessary steps required for biologics drug development, which are lead screening, lead identification, lead optimization, characterization assay establishment, efficacy demonstration, process development, and proof of concept study. With the lighting speed of technology shift nowadays, CRI has been invested in state-of-the-art technology for...

A variety of large bioreactor scales have been utilized ranging from pilot-scale 50L and production scale 200L and 1000L. The downstream process optimizations including chromatography, virus inactivation, tangential flow filtration and normal flow filtration are performed in parallel with upstream process optimization to expedite the timeline for the best benefit for Thai patients.

To elucidate mechanisms through which chemical and biological agents in the environment induce pathogenesis. To study the association between environmental and occupational exposures and effects of toxicants, particularly carcinogenic compounds in air and water, in selected populations. To study the effects of environmental pollutants and industrial chemicals as modifiers of physiological and pathological status, and the influence of host factors, such as nutritional status and disease states, on toxicity and carcinogenicity of chemicals.

Cholangiocarcinoma (CCA) is malignancy arising from cholangiocyte in the biliary tract and is the second most common type of primary liver cancer. This type of cancer is associated with poor prognosis and limited treatment options. The major risk factors of this cancer associate with chronic inflammation, cellular injury in the bile duct, and partial obstruction of bile flow caused by various conditions such as primary sclerosing cholangitis (PSC), hepatolithiasis and infestation by liver fluke (Opisthorchis viverrini) (Kubo, Kinoshita, Hirohashi, & Hamba, 1995; Sirica, 2005; Watanapa & Watanapa, 2002). Recent studies attempt to investigate the molecular pathogenesis of this disease, including etiology and molecular alterations. Genetics and epigenetics changes in cholangiocarcinoma have been identified from a number of studies. Alterations of several cellular functions including self-sufficiency and proliferation, apoptosis resistance, escape from senescence, and tumor invasiveness and metastasis, are proposed to contribute the onset of cholangiocarcinoma (Lazaridis & Gores, 2005). The uncontrolled proliferation of cells due to harboring of genes mutations causes cancer development. Cell cycle progression is a highly regulated process that involves several steps including DNA replication and cell mitosis. At present, understanding the mechanisms involved in cholangiocarcinoma cells development and finding the indicators of the response to cancer treatment is beneficial to the treatment option of this cancer. Recent research conducted by the Thailand Initiative in Genomics and...

Photodynamic therapy (PDT) has proven to be an effective and minimally invasive modality for cancer treatment, which can be used alone or together with other conventional treatments. PDT requires three harmless key components: photosensitizer, light and oxygen. The treatment protocol is based on the activation of a photosensitizer by using a suitable wavelength of light in the presence of tissue oxygen, which then results in the generation of singlet oxygen or other reactive oxygen species (ROS) to destroy cancer cells. PDT also offers significant benefits to overcome a variety of cancers. Many photosensitizers are hydrophobic and show tendency to aggregate in aqueous solutions, so that encapsulation in drug delivery system may improve their PDT performance. Recently, our laboratory successfully prepared polymer-lipid hybrid nanoparticles with good biocompatibility to deliver the hydrophobic photosensitizers that expand the therapeutic applications of PDT to multidrug resistant (MDR)lung cancer cells. The formulated nanoparticles have the potential to improve the solubility of photosensitizer. Also, nanoparticles may augment in vitro PDT efficacy by effectively increasing the accumulation of photosensitizer in MDR cells without being affected by the MDR mechanisms, leading to enhanced light-induced generation of singlet oxygen and superoxide anion, which finally causes apoptotic cell death. Cancer immunotherapy is another area of interest. Some cancer cells have partner proteins that bind to...

It is now widely accepted that the tumor microenvironment influences the fate and behavior of cancer cells and plays crucial roles in regulating tumor progression and therapeutic responses. The microenvironment of cells cultured in vitro on traditional plastic substrata does not account for cell interactions with the extracellular matrix (ECM) and is thus a less reliable approach to analyze cellular activity. However, most studies are performed with cancer cells grown in two-dimensions on plastic plates, leading to high failure rate of drug discovery and development. Culture conditions that recreate the appropriate microenvironment for cells should provide a better model for studying cellular activity and discovery of anticancer drugs. We thus developed cell culture models that more closely resemble in vivo tumor biology and investigated its consequences on cellular activity and responses to anticancer compounds. The results of an in vitro 3D model showed that 3D cultured cells on Matrigel showed cellular dormancy (G0/G1 cell cycle arrest), decreased cell migration and invasion, and were resistant towards a variety of chemotherapeutic agents.Further investigation of the molecular mechanisms implicated in tumor dormancy and drug resistance led to the identification of a key mediator involved in the development of chemoresistance in 3D cultures which may offer the potential of developing effective targeted therapies for cancer.

Metastasis and drug resistance of cancer cells are major problems in cancer therapy. Metastasis is the spread of cancer cells in the body, from primary tumor site to distant organs, where the cancer cells remain dormant for months to years as micrometastases, and then regrow to become recurrent tumors. We have explored the effect of chemicals and drugs on metastasis of cancer cell lines. A common environmental contaminant, perfluorooctanoic acid (PFOA), enhanced the metastatic potential of FTC133 thyroid cancer cells, while sub-lethal doses of the drug, doxorubicin, increased metastatic potential of low-invasive HepG2 liver cancer cells. On the other hand, vanillin, the vanilla flavoring agent, was found to reduce the metastatic potential of 4T1 mouse breast cancer cells and to suppress metastasis in an animal model, orally given vanillin for a month. Vanillin and its structure-related compound, apocynin, decreased metastatic potential of A549 lung cancer cells by inhibiting the PI3K/Akt signaling pathway. Homodimers of vanillin and apocynin were more potent than their monomers in inhibiting invasion of HepG2 liver cancer cells, and protein focal-adhesion kinase (FAK) was identified as a target of the dimeric compounds. Chrysin, found in Thai propolis, also showed anti-metastatic potential by reducing tumor recurrence, through suppressing growth of breast cancer micrometastases after spreading to the lungs of mice.With chrysin, STAT3 inhibition was the mechanism for inhibiting...

Many proteins are chemically modified after synthesis. These Post-Translational Modifications (PTMs), such as phosphorylation and O-GlcNAcylation, play an important role in regulating metabolic processes. Our studies show that the levels of O-GlcNAcylation and O-GlcNAc transferase (OGT), an enzyme catalyzing the addition of a single GlcNAc residue to target proteins, were up-regulated in breast and colon cancer tissues and cell lines. Using mass spectrometry, many O-GlcNAc-modified proteins were identified in these cancers, for example pyruvate kinase M2 (PKM2). O-GlcNAcylation of PKM2 affects its phosphorylation as well as its activity, thus indicating the crosstalk between these two PTMs. We also demonstrated that OGT knockdown led to a significant reduction of colony formation in breast and colon cell lines, suggesting it plays vital roles in tumor progression. Phosphorylation is another regulatory mechanism, but identification of phosphoproteins can sometimes be difficult due to possible digestion by phosphatase enzyme. We have therefore isolated exosomes, extracellular vesicles (EVs) of 30-100 nm size, from the conditioned media of isogenic cholangiocarcinoma cell lines with different metastatic potential. More than 40 phosphoproteins were identified with significant change in phosphorylation level. Heat Shock Protein 90 was confirmed as showing differential phosphorylation in relation to tumor invasiveness, so aberrant phosphorylation of exosomal proteins may be useful for development of a metastatic cancer biomarker. Indeed, since EVs contain many functional biomolecules, such...

Cancer is a disorder resulting from autonomous, uncontrolled cell growth and differentiation, and with malignant behavior, is capable of invasion and metastasis. Carcinogenesis is initiated by non-lethal genetic damage, followed by a multi-step process involving both phenotypic and genetic changes. Regulatory genes such as the proto- oncogenes, the tumor suppressor genes, and genes regulating apoptosis are important targets of genetic damage, as well as the DNA repair genes. Mutational damage to these genes will result in activation or inactivation of the functions of their gene products, resulting in uncontrolled proliferation with abnormal differentiation and acquisition of the capability for invasion or metastasis. Because of our longstanding interests in proteins, we are exploring the protein changes that occur in human cancer. Initially, we collaborated with the Department of Pathology, Phramongkutklao Hospital, Bangkok to analyze changes in protein in human cancer tissues, using surgical specimens of tumor tissue and normal tissue, characterized in terms of pathology. Our group was the first research group in Thailand to use the proteomic approach in 1997, at that time using two-dimensional gel electrophoresis to compare the proteome patterns (or the total protein present at any tissue at any given time) between normal and cancer tissue. Thus, study of thyroid disease demonstrated increased expression of certain proteins, such as cathepsin B and prohibitin, in neoplastic thyroid diseases...

Our early studies on genetic diseases, since 1987 and earlier, focused on the hemoglobinopathies, which occur frequently in Thailand and consist of two types. Thalassemia results from lack or decreased synthesis of one or more globin chains, while abnormal hemoglobins consist of mutations altering the amino acid sequence of globin chain(s). However, as research in the hemoglobinopathies developed in Thailand, we shifted our interest to Inborn Errors of Metabolism, which can cause severe clinical manifestations, such as mental retardation or developmental abnormalities. Generally, inborn errors arise from deficiencies in enzymes of various metabolic pathways, such as the urea cycle, pathways for degradation or synthesis of specific amino acids, or mucopolysaccharide degradation. Such disorders may be due to mutations leading to dysfunctional or poorly functioning enzyme or may result from lowered expression or absence of these enzymes. Such enzyme deficiencies are typically detected by an accumulation of the substrate of the enzyme reaction and/or a decrease in the level of metabolites, which occur after the enzyme reaction. Typically, each inborn error of metabolism occurs with low frequency, but there are many defects, so cumulatively, inborn errors of metabolism are significant problems. In many cases, the devastating effects can be avoided through proper treatment, such as in phenylketonuria, which may be treated with diets low in phenylalanine. So, it is important to...