Ji Luo, Ph.D.
Our lab focuses on understanding the biology of cancer with mutations in the Ras oncogene. In particular, we are using functional genomics to dissect genetic dependencies and delineate mechanisms of non-oncogene addiction in Ras mutant cells. We are currently investigating the role of SUMO ligases, RNA splicing factors, and certain transcriptional factors support the malignancy of cancer cells with Ras mutation. In addition, we are developing new RNAi and CRISPR tools to identify druggable target combinations in KRAS mutant cells. Lastly, we have developed pharmacological synthetic lethal screens to discovery new therapeutic strategies that can be rapidly translated into clinical trials.
Our long-term goal is to understand the mechanisms of tumorigenesis and identify new therapeutic strategies for cancer treatment. In particular, we focus on understanding the biology of Ras mutant cancer and identifying new treatment approaches for Ras tumors. Research in the lab focuses on the follow areas:
Synthetic Lethal Partners of the KRAS Oncogene
We have previously conducted RNAi screens to identify synthetic lethal partners of the KRAS oncogene (Luo et al., Cell, 2009). Our current effort is focused on elucidating the molecular mechanisms by which these genes support Ras-driven oncogenesis. In particular, we are studying how RNA splicing factors (Weng et al., PNAS, 2012) and SUMO ligases (Yu et al., submitted) supports the oncogenic activity of KRAS and how these pathways might be exploited for therapeutic gain. Investigation of other candidate synthetic lethal partners of KRAS is also underway. Our analysis indicates that cancer cells exhibit non-oncogene addiction to a broad network of genes that act to alleviate oncogenic stress and enable cancer cell survival. Therapeutic approaches that exploit non-oncogene addiction should provide new avenues to target cancer cells. We are studying bioactive molecules and developing small-molecule inhibitors that target non-oncogene addiction to assess their potentials in cancer therapy.
Genetic Dissection of Cancer Using RNAi and CRISPR
We are developing new RNAi and CRISPR tools to enable genetic screens with improved penetrance and reduced off-target effects. Recently, we have developed new RNAi tools for a combinatorial siRNA screen to identify optimal drug target combinations against KRAS mutant cancer cells (Yuan et al., Cancer Discovery, 2014). We are also developing new vector systems that allow the introduction of complex genetic alternations in cells to better model the genetic complexities seen in human cancer.
We are investigating new therapeutic modalities against Ras cancers. We have developed a new chemical screening platform for discovering compounds that can destabilize KRAS protein (Carver et al., PLOS One, 2014). As part of the CCR Major Opportunities Initiative, we have developed a pharmacological synthetic lethal screen to identify, from a collection of FDA-approved and clinical-stage compounds, drug combinations that show selective toxicity in KRAS mutant cells. Our goal is to translate these findings into early stage clinical trials within a few years.
Positions: To inquire about potential postdoctoral and postbaccalaureate openings, please e-mail a cover letter and C.V. to Dr. Luo.
Selected Recent Publications
- Cancer Discovery. 4(10): 1182-1197, 2014. [ Journal Article ]
Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells.Proc. Natl. Acad. Sci. U.S.A. 109(52): E3659-67, 2012. [ Journal Article ]
- Science. 337(6090): 104-109, 2014. [ Journal Article ]
- Science. 335(6066): 348-353, 2011. [ Journal Article ]
- Cell. 137(5): 835-848, 2009. [ Journal Article ]
Ji Luo received his B.A. in Natural Sciences from the University of Cambridge, UK in 1998. He completed his Ph.D. training as an HHMI Predoctoral Fellow in the laboratory of Dr. Lewis Cantley at Harvard University, Boston. His Ph.D. research focused on the role of PI 3-kinase in development, diabetes and cancer. Ji Luo undertook his postdoctoral training as an AACR Fellow in the laboratory of Dr. Stephen Elledge at Harvard Medical School, Boston. His postdoctoral research focused on the development of bar-coded shRNA library technologies for genome-wide RNAi synthetic lethal analysis in cancer cells.
|Fehad Khan||Postbaccalaureate Fellow (CRTA)|
|Chih-Shia Lee Ph.D.||Research Fellow|
|Shinjen (Sean) Lin Ph.D.||Postdoctoral Fellow (CRTA)|
|Xiang Wang Ph.D.||Special Volunteer|
|Haibo Zhang Ph.D.||Postdoctoral Fellow (Visiting)|