Laboratory of Cancer Gene Therapy
|Head of Lab:
||Paula Y.P. LAM
Associate Professor, Dept of Physiology, National University of Singapore
Associate Professor, Duke-NUS Graduate Medical School
||Guan Shou Ping (PhD)
Chong Siao Ting
Catherine Kok Yen Li
The main focus our laboratory is to develop/engineer an effective cancer cell targeted gene delivery system. We aim to characterize the induction and biological effects of these therapeutic modalities in the tumor milieu and channelled the acquired knowledge to develop improved therapeutic regimens against the treatment of cancers. The overall goal of our laboratory is to provide an understanding and insight into the development of cancers, hence, translating the findings to the clinics.
Cancer is characterized by uncontrolled cellular proliferation. We capitalized upon this unique property of cancer cells and developed a transcriptional targeted strategy whereby the transcription of the therapeutic gene is only activated in rapidly proliferating cells in the context of viral vectors or tumor homing stem cells armed to express cell cycle-dependent therapeutic genes. Apart from exploring these innovative approaches, we are also keen to study the biological effects of various agents in preclinical cancer mouse models. These agents include small molecule inhibitors, gap junction inhibitor, metal ions chelators, and SOD mimics to study the essential balance required to protect and help normal cells to recover while inducing maximal cytotoxicity to tumor cells and tumor initiating cells. We believe this is achievable through targeted therapies which involve the understanding of specific molecular targets and their signal transduction pathways during the progression of cancer as exemplified below, and how cancer cells acquired resistance against treatment over time.
Glioblastoma multiforme (GBM) is among the most lethal of all cancers. Standard of care includes surgical resection, radiation therapy, and concomitant and adjuvant chemotherapy with temozolomide. Typically, gliomas consist of the central core and the infiltrative zone at the peripheral rim. The central core of the tumor divides rapidly while the peripheral rim of the tumor tends to invade to the normal parenchymal, and paves the path to tumor recurrence. This phenomenon is known as “To Go or Grow” theory where an inverse correlation of glioma cell motility and proliferation has been established. We have identified molecular targets that modulate the transition between GBM invasion and proliferation, and these candidates may serve as putative targets for anti-cancer therapies.
Figure 1 Development of various treatment modalities for targeted cancer therapy
1. Lazennec G and Lam PY. “Recent discoveries concerning the tumor - mesenchymal stem cell interactions” In press, BBA-Reviews on Cancer
2. Endaya BB, Lam PY, Meedeniya A, Neuzil J. “Transcriptional profiling of dividing tumor cells detects intratumor heterogeneity linked to cell proliferation in a brain tumor model”. Molecular Oncology, 10; 126-137, 2016
3. Yulyana Y, Tovmasyan A, Ho IAW, Sia KC, Newman JP, Ng WH, Guo CM, Hui KM, Batinic-Haberle I* and Lam PY*. “Redox-active Mn porphyrin and potent SOD mimic, MnTnBuOE-2-PyP5+, enhances carbenoxolone-mediated TRAIL-induced apoptosis in glioblastoma multiforme”. Stem Cell Reviews and Reports, 12; 140-155, 2016
4. Chong DQ, Toh XY, Ho IAW, Sia KC, Newman JP, Yulyana Y,Ng WH, Lai SH, Ho MF, Tham CK*, Lam PY*. “Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status” BMC Cancer, 15:255
5. Yulyana Y, Ho IAW, Sia KC, Newman JP, Toh XY, Berwini B Endaya, Chan J, Gneicchi M, Huynh H, Chung AY, Kiat Hon Lim, Leong HS, Iyer GN, Hui KM, Lam PY “Human fetal mesenchymal stem cells inhibit hepatocellular carcinoma growth through IGF-1R/PI3K/Akt”, Mol Therapy, 23(4), 746-756, 2015
6. Lv M, Fraefel C, Sia KC, Newman JP, Shafiq Ali Bin Mohamed Bashir , Ng WH and Lam PY. The potential application of regulatable oncolytic herpes simplex virus in treating human cancers, British Journal of Cancer 110(1), 94-106, 2014
7. Ho IAW, Yulyana Y, Sia KC, Newman JP, Guo CM, Hui KM, Lam PY. “Matrix metalloproteinase-1 mediated mesenchymal stem cells tumor tropism is dependent on crosstalk with stromal derived growth factor-1/C-X-C chemokine receptor-4 axis” FASEB J 28(10), 4359-4368, 2014
8. Chan JKY and Lam PY. Human mesenchymal stem cells and its paracrine factors for the treatment of brain tumors, Cancer Gene Therapy, 20(10): 539-543, 2013
9. Sia KC, Huynh H, Chung AYF, Ooi LLPJ, Lim KH, Hui KM and Lam PY. Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model, Molecular Cancer Therapeutics, 12(8): 1651-1654, 2013
10. Ho IAW, Toh HC, Teo YL, Guo CM, Hui KM and Lam PY “Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis”, Stem Cells. 31(1): 146-155, 2013
11. Sia KC, Huynh H, Chinnasamy D, Hui KM, Lam PY “Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging.” Gene Ther. 19(5): 532-42, 2012
12. Ho IA, Chan KWY, Ng WH, Guo CM, Hui KM, Cheang P, and Lam PY. “Matrix metalloproteinase 1 is necessary for the migration of human bone marrow-derived mesenchymal stem cells”, Stem Cells 27(6): 1366-1375 2009