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Kidney cancer ranks as the seventh most common cancer in US. In 2016, it is estimated that over 62,000 and 14,000 Americans will be diagnosed with and succumb to kidney cancer. In California, approximately 7,000 new cases of kidney cancer is diagnosed each year. Risk factors for this cancer include smoking tobacco, which doubles the risk. Men are 2-3 times more likely to develop this disease than women. African Americans and Hispanics also have higher risk. Clear cell renal cell carcinoma (ccRCC) is the most common subtype, accounting for 80 percent of all cancers of the kidney. Clinical course of ccRCC is remarkable for a high frequency of dissemination (metastasis) to the lung. Patients with lung metastasis have very poor outcome with 5 year survival chance of around 10 percent. A unique genetic feature of ccRCC is that greater than 70 percent of cases involved a mutation or deletion of the VHL gene. But the precise role of VHL in the development or the dissemination of ccRCC is unclear. Recently, we created a new ccRCC model in mouse by deleting the VHL gene in cancer cell lines. This model revealed a completely new process that tumor dissemination occurs. In our model, if we grafted VHL-positive or VHL-negative tumor cells alone, tumor will grow in the kidneys but no metastasis will occur. If we graft a combination of VHL-positive and VHL-negative together, large number of metastases develop rapidly in the lungs. The VHL-negative tumor cells are the driver of metastasis, even if they are a small proportion of tumor. Our model suggest that tumor cells are not uniform. In fact, different subpopulations might be cross-talking and cooperating with each other to advance the cancer. This new concept highlights the importance of finding the key driver populations in the tumor and that more effective treatments will be to target this driver population. The research strategies of this current TRDRP proposal are three folds. First, we plan to use freshly isolated clinical specimens of ccRCC (40 cases in 2 years) to fully characterize the crosstalks between distinct VHL-negative and VHL-positive population in the tumors. Second, we will use the freshly isolated tumors to establish new tumor grafts in animal models, which will enable us to study the signal crosstalk and the metastatic process in detail in animals. Thirdly, we will test a new therapeutic strategy on the newly developed animal models. We will evaluate the efficacy of STF-31 an inhibitor of glucose transporter, which is known to preferentially target the VHL-negative tumor cells. If successful this treatment will negate the function of the driver population, and halt lung metastasis. The key objectives of this project are to use clinical specimens to verify the new cooperative concept of metastasis we discovered and also to develop new tumor models from patient specimens. In turn, we will test a new approach to inhibit the lethal metastatic process by taking aim at the driver population in the tumor. The long term benefit of this project is to gain a better understanding of how metastasis occurs and to devise appropriate and effective treatment to gain an upper hand on metastasis, the known lethal stage of kidney cancer and many other solid tumors. |
