Developing genetically modified human ES cells to model human cancers
Cancer is one of the leading causes of death in California. Cancer treatment and cancer patient care cost Californians tens of billions of dollars every year. Despite some improvement in the survival of cancer patient in general, certain cancers such as pancreatic and lung cancers remain highly lethal; the survival rate of pancreatic cancer patients is below 5% and lung cancer below 20% . Therefore, there is an urgent need for new treatments for these human cancers. Pre-clinic cancer models are critical for the development of new cancer therapy. Mouse models for human cancers are valuable physiological tools for studying the tumorigenesis pathways. However, due to clear cellular and physiological differences between mouse and human, mouse models often fail to recapitulate the human tumorigenesis. For example, while cancers developed in mouse are mostly lymphomas and sarcomas, the major types of human cancers are of epithelial origin. These differences also lead to the common dilemma in drug discovery that a cancer therapy works well in mouse models but poorly in human patients. Therefore, there is an increasing need for more physiologically relevant human cancer models for mechanistic studies and drug development. In particular, there is an urgent need for relevant models for some of the most lethal human cancers - pancreatic and lung cancers.
Human ES cells (hESCs), which can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body, present a possible solution to model human cancers. Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, could be useful to model certain human diseases. However, iPSCs are not suitable to model human cancers for several reasons. For example, one of the hallmarks of human cancer is genomic instability. Therefore, iPSCs derived from human cancer cells will harbor extensive unknown genetic abnormalities that are specific for that cancer cell, excluding their use as a disease model. In addition, the common genetic abnormalities in cancer such as the p53 mutations could disrupt proper self-renewal and differentiation of pluripotent stem cells.
With established expertise in sophisticated genetic manipulation of hESCs, we propose to introduce the most common causative cancer mutations found in human pancreatic and lung cancers into hESCs that can be induced in a pancreatic lineage- or lung epithelial-specific manner. By determining the tumorigenesis of primary cells derived from these genetically modified hESCs in vitro and in vivo, we aim to establish a new generation of relevant pre-clinic cancer models that can be useful for both mechanistic studies and drug development.
Cancer is the second leading cause of death in California (behind heart disease), costing California billions of dollar in cancer care and treatment each year. It is estimated that 2 out 5 Californians will be diagnosed with cancer during the lifetime. Pancreatic cancer, diagnosed in thousands of Californians each year, is the most lethal cancer with a survival rate below 5%. Lung cancer, which is one of the most common cancers among Californians, is also highly lethal with a survival rate about 20%. Therefore, despite some improvement in the overall cancer survival during the past decade, there is a critical need to develop new therapies to treat these lethal cancers such as pancreatic and lung cancers. In order to develop new cancer treatment, relevant pre-clinic cancer models are critical for providing the mechanistic insight to design novel treatment and testing the efficacy of the new treatments. The existing mouse models for cancers or mouse xenograft cancer models have many intrinsic deficiencies, leading to the common scenario that drugs work well in these models but poorly in human patients. Our proposed research is aimed to employ sophisticated genetic manipulation technology to genetically modify human ES cells to develop a new generation of physiologically relevant cancer models for human pancreatic and lung cancers. These models will become important tools for studying mechanism of cancer development and developing new treatments for these lethal human cancers.