New Class of Renal Cell Carcinoma Identified
Two studies by James Brugarolas, MD, PhD, Assistant Professor of Internal Medicine, Hematology-Oncology, and Developmental Biology at UT Southwestern, represent important steps forward in kidney cancer research.
In a paper, published online in Nature Genetics on June 10, Dr. Brugarolas and his team define a new class of renal cell carcinoma. Using a novel approach to study cancer genetics, they report the identification of a type of renal cancer characterized by mutations in the BAP1 gene. BAP1-deficient tumors account for 15 percent of all kidney tumors.
Dr. Brugarolas found that tumors with mutations in BAP1 tend not to have mutations in another gene previously discovered to be mutated in renal cancer, PBRM1. Tumors with PBRM1 mutations account for 50 percent of all renal cancers. Whereas PBRM1-mutated tumors are usually benign, tumors with BAP1 mutations have features of very aggressive cancers.
The team also developed a test can be applied to any patient tumor to determine whether BAP1 is defective. This test, an immunohistochemistry test, was developed Payal Kapur, MD, Associate Professor of Pathology. Using these tests patients can now determine whether their tumor lacks BAP1 or not.
“The significance of these findings lies in that mutations drive cancer and thus a classification of kidney cancer based on mutations is likely to pave the way to better treatments,” Dr. Brugarolas said. “Furthermore, preliminary results suggest that BAP1-deficient tumors may be more sensitive to radiation, which normally doesn’t work for kidney cancer.”
In another study, Dr. Brugarolas and his lab have shown that human kidney cancer grown in mice can behave like kidney cancer in patients. In a study, published June 6, in Science Translational Medicine, tumors responded to drugs that are active against kidney cancer in humans, such as sunitinib, and were resistant to drugs that do not work for kidney cancer in humans, such as erlotinib, a lung cancer drug. This provides an ideal platform in which to study drugs before they move to human trials.
To learn more about the findings of his Science Translational Medicine paper, we asked Dr. Brugarolas to explain the impact of his findings:
You found that tumors implanted into mice retained their “human” features. Why is this significant?
In as much as the properties of human tumors are preserved in the tumors implanted in mice, mice with human tumors can be used to develop new drugs against kidney cancer. Traditionally, 90 percent of anti-cancer drugs tested in clinical trials fail. What this goes to show is that preclinical (pre-human) testing is inadequate. The toll in patient lives and economical, as you can imagine, is enormous. Thus, novel paradigms are needed. What we report here is a paradigm that could be used to determine whether a drug should or should not go forward into human testing.
What sets this study apart from other studies on the same topic?
This the first report to show that human tumors in mice reproduce genetics, gene expression, and, most importantly, treatment responsiveness of kidney cancer in patients.
We know this is an early finding, and we certainly try to avoid hype, but what are the implications of your findings for cancer patients?
Two-fold. First, these mice can be used to pre-screen drugs before they go into clinical trials. Hopefully, we can do better than a 90 percent failure rate. Second, the platform may also be used for personalized cancer medicine. With the advent of genomics we have learned every tumor is different. Because of this, it is unpredictable whether a specific patient will respond to this or that drug. However, their tumor could be implanted into a mouse and the mouse (instead of the patient) could be tested.
This personalized angle has several challenges, however. First, only 16 percent of tumors grow in mice. On the other hand, these are the most aggressive tumors. Second, since it may take up to 6 months for the tumors to grow in the mice, it is best to generate the mouse when the tumor is first diagnosed and before metastases appear.