A research duo from the University of Texas MD Anderson Cancer Center in Houston, Texas – Dr. Eric Jonasch, an oncologist and professor in the department of Genitourinary Medical Oncolgy, and Dr. Guang Peng, an associate professor of Clinical Cancer Prevention – received a 2019 Advanced Discovery Award.
The team plans to investigate how the novel tumor suppressor gene NPRL2 functions by studying how it triggers innate immune response in renal cell carcinoma (RCC) by impairing S-phase DNA damage response (S-DDR). NPRL2 is frequently deleted from chromosomes in clear cell RCC and the research team will also explore treatment strategies exploiting this deficiency.
In this Q & A, Dr. Jonasch and Dr. Peng discussed their work and its impact on patients.
In the application, we aim to understand molecular determinants of immunoresponsiveness in RCC through exploring DNA damage control mechanisms involved in DNA replication. We hypothesize that endogenous damaged DNA resulted from defective DNA replication control mechanisms may serve as signaling molecules to promote anti-tumor innate immunity, a complementary immune response network to neoantigen-dependent adaptive immunity.
We believe the new information about NPRL2 identified from our project will provide molecular insights into two key questions in RCC: first, Loss of a major RCC tumor suppressor VHL is not sufficient to initiate tumorigenesis. NPRL2 is localized in the genomic region of VHL. It is deleted in more than 10% of RCC patients. The new function of NPRL2 in regulating DNA damage response may help us understand how NPRL2 deficiency cooperates VHL loss in RCC development. Second, Loss of NPRL2 activates mTOR signaling pathway and alters immunoresponsiveness of RCC, which provide mechanistic basis for stratifying patients for immune therapy and developing new treatment regimens.
Our study is expected to identify NPRL2 as a potential biomarker to identify RCC patients who are likely going to benefit from immune therapy using immune checkpoint blockade (ICB). In addition, it may also be used for stratifying patients to identify ICB-insensitive tumors, for the combination of mTOR inhibitors with ICB.
This project not only provides basic mechanism insight into the etiology of RCC driven by loss of VHL, but also help identify a new molecular pathway (DNA replication damage control pathway) as a potential predictor for immunoresponsiveness in RCC.
Immune therapy using IBC has shown promising clinical results in RCC treatment. However only a subpopulation of RCC patients respond to the treatment. In general, RCC tumors contain low mutation load compared to other cancer types. Mutation load may not be a sensitive marker to predict treatment responses. Thus the goal of our research is to help identify biomarkers more specific for RCC tumors due to unique genetic alterations in RCC to predict immunoresponsiveness and responses to immune therapy.
NPRL2 as a new tumor suppressor may connect the activation of mTOR pathway, the defect in genome maintenance mechanisms and altered immune landscape in RCC. The molecular consequences of NPRL2 deficiency may create therapeutic opportunities to use both pathway-targeting (mTOR pathway, DNA damage pathway) and immune-based (IBC) approaches.
We have worked together previously on different projects involved in DNA repair and RCC. As a basic scientist, Dr. Peng focuses on studying genome maintenance mechanisms and the impact of altered DNA repair and DNA damage response on immunoresponsiveness. As a physician-scientist, Dr. Jonasch focuses on translational and clinical studies of RCC etiology and therapy. NPRL2 was identified from a genetic screen designed to identify novel regulators of DNA replication damage control. From cancer patient data in [The Cancer Genome Atlas Program], we surprisingly discovered its clinical significance in RCC. Results from our studies motivated us to collaborate on this project by combining our research expertise.
We are grateful to this unique funding mechanism to support collaboration between bench and clinical scientists. It will definitely help move basic research findings/insights to address urgent clinical questions. It will also tremendously help bench scientists to understand RCC from a patient perspective, and thus focus and guide the basic research towards actionable endpoints.
The challenge is to establish the opportunities and platforms that permit efficient communication between bench and clinical scientists. Our institution provides an outstanding environment for establishing the continuum of cancer research from basic, translation to clinical studies.
Cancer is not just a biological question, a medical disease. It is also a social problem. Witnessing its impact on the lives of patients and their families motivates us to work as scientists and clinical investigators. It is our hope that with the new technologies, new biological concepts, we can contribute to help cancer patients prolong their fighting against cancer and eventually win the battle.