Immunogenomics and PDX models for precision medicine on CRC

This project is to develop early detection and preclinical tests for precision medicine of metastatic colorectal cancer (mCRC), using both immunogenomics (iG) and patient-derived xenograft (PDX) mouse technology. Under the support of MOHW, our team of NHRI, TMUH, and VGH-TPE has made a significant progress in the past year, and on this basis, we wish to extend this project in the next two years to reach the point of clinical application. mCRC is a major health issue affecting nearly 20% of the 15,000 new cases each year in Taiwan. Depending on the genetic profiles, target therapy with anti-EGFR (Cetuximab, Erbitux) or anti-VEGF (Bevacizumab, Avastin) can be administered to the patients on top of chemotherapy using folinic acid, 5-FU, oxaliplatin or irinotecan. Recently, regorafenib (Stigvaga), an oral multikinase inhibitor, has been approved by US FDA for treating advanced mCRC patients that failed the standard treatment. To cope with the increasing demands and healthcare expenditure, precision medicine, which deals with stratification of patients according to the genomic profiles, we propose to combine genomics, immunology, animal models, and pharmacology to improve cancer survival and reduce the disease burden by individualized treatment. This project include the following three components: Core competence in genomics and zebra fish model for chemoresponse will be established at NHRI to achieve the following goals: 1. to identify the mutations in the cancer genome, regarding point mutation, insertion and deletion, copy number change, and chromosomal rearrangement. 2. to investigate tumor heterogeneity and clonal evolution of the cancer genome; 3. to develop a robust system for routine test for prioritizing treatment options. PDX mouse will be applied to maintain the tumors of the mCRC cases in the mice. This in-vivo passage of mCRC will allow us not only to predict the efficacy of chemotherapeutics with various drugs, also the system can generate cancer cells for additional experiments using the zebrafish system or the tissue culture. The aims include: 1. to further improve the success rate and robustness of the system; 2. to investigate the correlation with clinical outcome; 3. to predict the chemoresistance patterns in mCRC. Immunogenomics is the technology that analyzes the immunoglobin and T-cell receptor diversity by next generation sequencing. We wish to achieve the following goals: 1. to investigate the range of diversity of the immune repertoires (iR) in the B and T cells; 2. to study the dynamic changes of iR after surgery and during treatment; 3. to identify common iR signatures in CRC. Given the urgency for treatment management of mCRC and the genomic complexity of the cancer genome, we consider it necessary to combine clinical and research expertise to develop a genomic medicine program for precision medicine. As our team has a long-standing collaboration and the pilot study (of the past year) is promising, we hope this extension study will further develop the potential of the collaborative research for advancing our knowledge and improving the care of this common cancer in Taiwan.