Wang, Mei

The Clinician Scientist Awards (CSAs)

Spotlighted by Vitalscience : “Assistant Professor Mei Wang and her team have had a paper published in Oncogene, a leading cancer research journal, on July 12, 2010. Their studies have shown that inhibiting an enzyme called Icmt induces a highly regulated process termed autophagy, or “self digesting”. Significantly, the much elevated autophagy leads to cancer cell death. Assistant Professor Wang and her team found that the new inhibitor not only induces cell death in cultured cancer cells through autophagy induction, but also in human tumours grown in mice. “We are working to find out exactly how this new class of drugs regulates… self-digestive activity, and its link to cancer cell death,” said the study authors. “By doing so, we hope not only to advance the basic understanding of autophagy and cancer cell death, but also to accumulate needed information for further clinical development of new experimental anticancer drugs." “Assistant Professor Mei Wang and her team have had a paper published in Oncogene, a leading cancer research journal, on July 12, 2010. Their studies have shown that inhibiting an enzyme called Icmt induces a highly regulated process termed autophagy, or “self digesting”. Significantly, the much elevated autophagy leads to cancer cell death. Assistant Professor Wang and her team found that the new inhibitor not only induces cell death in cultured cancer cells through autophagy induction, but also in human tumours grown in mice. “We are working to find out exactly how this new class of drugs regulates… self-digestive activity, and its link to cancer cell death,” said the study authors. “By doing so, we hope not only to advance the basic understanding of autophagy and cancer cell death, but also to accumulate needed information for further clinical development of new experimental anticancer drugs."

Recent Award: “The Clinician Scientist Awards (CSAs), which come packaged together with major research funding, have been won by Assistant Professor Mei Wang…..”. “Assistant Professor Wang and colleagues will continue to investigate the pharmacological actions of these experimental drugs in the laboratory, information that is crucial before clinical trials can be initiated.”

CSAs are an integral component of a talent funding program of the country’s Biomedical Sciences (BMS) Initiative. Funded by the National Research Foundation and administered by the National Medical Research Council of the Ministry of Health (MOH), the program aims to provide clinician-scientists in Singapore with a conducive environment for medical research that can eventually be moved into clinical practice.”

Research Interests:

Oncogenic transformation by Ras and Rho oncoproteins depends largely on the appropriate post-translational modification at their C-termini. In this regard, many key regulatory proteins involved in oncogenic signaling processes possess the C-terminal CAAX sequence which destines them for prenylation modification. Protein prenylation is a three step process which involves the addition of an isoprenoid lipid by one of the two prenyltransferases, a proteolytic step by Rce1 protease, and the carboxymethylation by an enzyme termed Icmt.

Oncogenic transformation by Ras and Rho oncoproteins depends largely on the appropriate post-translational modification at their C-termini. In this regard, many key regulatory proteins involved in oncogenic signaling processes possess the C-terminal CAAX sequence which destines them for prenylation modification. Protein prenylation is a three step process which involves the addition of an isoprenoid lipid by one of the two prenyltransferases, a proteolytic step by Rce1 protease, and the carboxymethylation by an enzyme termed Icmt. Because of the functional dependency of CAAX proteins on the prenylation modification, targeting these oncoproteins through inhibition of the prenylation process has been a subject of intense study. Genetic and pharmacologic blockade of both the steps of isoprenoid lipid addition and of carboxymethylation have profound consequences on oncogenic transformation. Research in this lab focuses on (1) the basic science, particularly the impact on cell signaling, by perturbing the protein prenylation process, and (2) preclinical development of inhibitors of prenylation.

The focus of the basic research aspect of the lab is to advance the understanding of the role(s) that specific prenylated proteins play in cellular signaling and cancer development. In this setting, inhibitors of prenylation serve as useful tools in identifying important players in cell signaling. We have found that inhibition of Icmt, the enzyme for the last step of prenylation modification, induced excessive autophagy and cell death, in addition to G1 cell cycle arrest. Suppression of autophagy rescues cancer cells from cell death, suggesting that autophagy induction by inhibiting Icmt promotes cancer cell death (Wang et al., J.Biol.Chem.2008 Jul 4; 283(27):18678-84). Since evading apoptosis is an important part of tumorigenesis, inducing cancer cell death through an alternative route such as autophagic cell death can be a novel approach therapeutically. Considerable effort in the lab is focused on the identification of the CAAX protein(s) through which the efficacy of Icmt inhibition is mediated by induction of autophagy and cell death.

The focus of the translational aspect of our research is to further advance the preclinical evaluation of potent and selective small molecule inhibitors of Icmt and one of the enzymes involved in the isoprenoid addition step, protein geranylgeranyltransferase I (GGTase-I), as anticancer agents. The scope of the research includes: (i) the investigation of the in vivo efficacy against proliferation and metastasis of these compounds using animal models; to this end, our studies have shown that cysmethynil has in vivo antiproliferative efficacies against multiple human cancers using a xenograft mouse model (Figure 3), (Wang et al, 2008; Wang et al., under review). (ii), the identification of new and better inhibitors in collaboration with our colleagues in NUS (SIN Pat. Appl. No. 200907728-0; manuscripts under review); and (iii), the investigation of the pharmacokinetics and ADME/Tox properties of these small molecule inhibitors (Wang et al., J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Feb 15:877(5-6):553-7.).