Manjeet Rao, PhD
Associate Professor of Cellular & Structural Biology
President's Distinguished Junior Scholar Award
Manjeet Rao, Ph.D., joined the Greehey Children's Cancer Research Institute in January of 2007 with major faculty responsibilities as a Principal Investigator in Molecular Oncogenesis and Associate Professor in the Department of Cellular and Structural Biology. Dr. Rao completed his post-doctoral research at The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA. Dr. Rao pioneered the in vivo RNA-interference (RNAi) approach that can be used to silence virtually any gene in a tissue-specific manner. The simplicity of his RNAi approach will facilitate the generation of mouse models mimicking human conditions caused by various degrees of genetic hypomorphism, such as ectodermal dysplasia, T-cell immunodeficiency, autosomal dominant polycystic kidney diseases, and various types of cancer. Selective expression of siRNAs may be crucial to effective therapy, as undesired toxicity is a major problem of gene therapy.
Research in my laboratory is directed towards understanding the role of microRNAs in the oncogenesis of adult cancers (breast and ovarian cancer) and pediatric tumors (pediatric renal tumor and acute lymphoblastic leukemia). Our current projects on using microRNAs as novel biomarkers and therapeutic adjuvants for the diagnosis/prognosis and treatment of drug-resistant breast cancers and pediatric brain tumors build logically on our recent discovery (Imam et al., 2010, Oncogene) of a potent tumor suppressor microRNA that sensitizes resistant cancer cells to TRAIL (tumor necrosis factor related apoptotic inducing ligand), a new generation of cancer therapeutic agents currently in clinical trials, which induces apoptosis in cancer cells, while sparing normal cells. We have used unbiased high-throughput screening approach to identify candidate miRNAs and genes that regulate drug sensitivity in breast cancer cells. Our recent research achievements of safe and efficacious delivery of microRNA using lipid and FDA-approved nanoparticle-based systemic delivery approaches to treat drug-resistant metastatic breast cancers in mouse tumor model paves the way for a phase I clinical trial in the near future.
Therapeutic potential of miRNA. Injection of LANCER-conjugated miR-204 suppressed breast cancer lung metastasis. A. Live bioluminescence images of mice injected with miR-204 or miR-204 mutant (neg. control;) oligos using the Xenogen In Vivo Imaging System. B. Lung tumor metastasis volume was assessed starting from day10 until animals were sacrificed at day 60 after TNBC cell introduction (via tail vein). Using ROI analysis tumor light intensity was calculated in photon/sec, which directly corresponds with number of live cells in vivo. C. Representative lung images showing GFP+ve metastatic foci (red circle) in neg. control (cntrl) groups, while there is no detectable foci in miR-204 injected mice. D. Sections of liver from miR-204 injected mice show no signs of hepatotoxicity.
One of our other research interests involves understanding the mechanism by which cancer stem cell self-renewal is regulated. Besides well established gate keeper genetic changes in cancer, epigenetic alterations including global DNA hypomethylation, hypermethylation of specific tumor suppressor genes as well as histone modifications have emerged as common characteristics of many cancers. Recent developments suggesting an epigenetic progenitor origin of human cancers further underscore the importance of epigenetic regulation in tumorigenesis. We believe that the identification and validation of novel molecular targets regulating early epigenetic changes in normal cells will be key to the development of effective therapeutic regimens for treating cancer. To accomplish that, we are currently using a loss-of-function RNA interference screen to identify molecular effectors that are in a synthetic lethal relationship with specific polycomb proteins, which are best known as epigenetic regulators and are implicated in the maintenance of normal stem cell pluripotency and the pathogenesis of several human cancers.