Mechanisms of Src activation and its role in latent bone metastasis of breast and

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DESCRIPTION (provided by applicant): Metastasis represents a major threat to the lives of cancer patients. Although most solid tumors can be surgically removed, metastatic relapses may occur years or decades later, usually accompanied with resistance to adjuvant therapies. My long-term goal is to understand the biological mechanism underlying metastasis latency and the associated drug-resistance. The immediate aims proposed in this application focus on the role of an oncogene, Src, in mediating latent bone metastasis of breast and prostate cancers. I have recently found that Src activity associates with latent bone metastasis in gene expression datasets of breast tumors. In experimental models, inhibition of Src decreased survival of cancer cells in the bone marrow. Mechanistically, I showed that Src mediates survival response of cancer cells to cytokines that are specifically enriched in bone metastases. These results indicated that Src plays an important role in metastasis latency and have provoked considerable interests of clinicians at Memorial Sloan Kettering Cancer Center (MSKCC). A clinical trial that aims to determine the effect of FDA-approved Src inhibitors on the level of cancer cells in the bone marrow is being designed and will soon be carried out. The experiments proposed in this application are based on the above finding as well as some provocative preliminary data. I plan to reveal mechanisms that activate Src and consequently confer cancer cells ability to survive in the bone marrow. Moreover, I will also explore the possibility that Src connects latent metastasis with resistance to adjuvant therapies in specific subtypes of breast tumors. I will then extend my studies to prostate cancer, another cancer type that exhibits a strong proclivity to develop latent bone metastasis. The main approach I will employ to study metastasis will be xenograft models (implanting human tumor cells to immunodeficient mice). RNAi technology and pharmacological inhibition will be used to intervene the activities of Src and related molecules. I believe the research described here is timely, feasible and important for the public health. The Pathway to Independence Award would greatly facilitate my success in performing these studies by providing opportunities for additional training and a smooth career transition. I obtained my bachelor degree with the highest honors from Fudan University in 2000. In the same year I entered Columbia University to pursue a PhD degree in biology. My graduate training focused on pre-mRNA splicing, a fundamental process in gene expression. I took an integrative approach combining the power of bioinformatics and molecular biology. Such approach not only led to a series of important findings but also equipped me with interdisciplinary expertise. In 2006, I graduated from Columbia University and was awarded "Distinction to the Dissertation". I then joined Dr. Joan Massagui's lab and started my postdoctoral career in the field of cancer biology and metastasis. In the past three years, I have complemented my previous skills by absorbing a large set of technical and conceptual approaches to metastasis research. I have performed a series of sophisticated analyses in gene expression profiles or array CGH data of human tumors and made several important discoveries including the Src-metastasis latency connection. Moreover, I have been exposed to a large amount of knowledge of clinical oncology and human pathology. All of this experience has fostered my development into a cancer biologist with broad expertise and integrative thinking. My future career goal is to obtain a faculty position and establish an independent research program on metastasis. In seeking a K99/R00 award, I aim to gain more comprehensive skills in studying metastasis and to successfully extend my research to the field of prostate cancer. To this end, I will continue my training in Dr. Massgue's Lab, one of the world-leading programs in metastasis research. In addition, I have also invited Drs. Larry Norton and Neal Rosen to be my co-mentors. Their expertise in clinical oncology and translational studies will help me to direct the project toward a clinical relevant angel. To obtain clinical samples essential for my research goals, I have established collaboration with Dr. Edi Brogi and Dr. John Foekens. A major challenge during my career development will be to extend the research to prostate cancer, which requires specific techniques and insights. Drs. Charles Sawyers and Howard Scher have agreed to help me establish this expertise. I will gain hands-on experience and obtain relevant reagents from their laboratories. Moreover, they are willing to be potential collaborators after I gain dependence. My career transition will also involve various training activities including Responsible Conduct of Research, mentoring, grant writing, presentation, and lab management. All of this training as well as my scientific research will take place at MSKCC, an ideal environment with state-of-art core facilities and highly interactive scientific community. MSKCC provides a robust bridge between scientific research and clinical practice and gathers outstanding scientists and clinicians. At this transitional stage of my career, I will continue to benefit from this research-intensive and clinical-oriented environment. The K99/R00 award would foster my interaction with the diverse expertise in this community, facilitate my maturation as an independent researcher and enable a smooth transition toward the next stage of my career. PUBLIC HEALTH RELEVANCE: In certain cancers, metastasis may occur years or decades after the removal of primary tumors, usually accompanied by resistance to adjuvant therapies. The proposed study will investigate the activation mechanisms of Src and explore its role in latent bone metastasis and therapeutic resistance in breast and prostate cancers. Because of the availability of FDA-approved Src inhibitors, this study will carry significant clinical implications and may suggest novel therapeutic strategies that can be immediately subject to clinical trials.