Keynote Speakers

About a decade ago, in an insightful assay that projected how biology would increasingly stimulate the creation of qualitatively new realms of mathematics, Cohen(2004, PLoS Biology) pointed out that “ In biology, ensemble properties emerge at each level of organization from the interactions of heterogeneous biological units at that level and at lower and higher levels of organization.”, and that “New mathematics will be required to cope with these ensemble properties and with the heterogeneity of the biological units that compose ensembles at each level.”. However, in contrast to the explosive volume of data generated by more and more advanced high throughput biotechnologies including the next generation sequencing, statistical methods of coping with ensemble properties are still in their infancies. While heterogeneity is the key issue for quantitative study in cancer biology, it has a number of facets to cover, including patient-to-patient heterogeneity and heterogeneity of cancer cell subpopulations in the tumor tissue and its microenvironment. The explosion of genomics data, like other realm of data science, calls for deep analytics to guide the logics in delineating a complex system. In this talk, I will convey an approach based on the statistical concept of liquid association for a five way co-analysis of the complex regulatory pattern between mRNA expression, microRNA expression, DNA copy number variation, point mutation, and DNA methylation.

Through genome-wide analysis of more than 1,500 clinical cancer samples, we identified a number of novel molecular targets that can have an oncogenic function and be applicable to development of anti-cancer drugs (molecular-targeting drug, cancer vaccine, and antibody). Using such information, our group has developed two monoclonal antibodies, one against FZD10 that was expressed exclusively in synovial sarcoma and the other against CDH3 that was expressed in many types of cancer. The phase I clinical trial for synovial sarcoma using 90Y-conjugated anti-FZD10 antibody was over. We together with OncoTherapy Science have isolated nearly 100 peptides (HLA-A02 or HLA-A24 restricted), corresponding to a part of oncoproteins, which are able to induce cytotoxic T lymphocytes that would specifically kill cancer cells in an HLA-restricted and antigen-dependent manner. In addition, we have developed novel small molecular compounds targeting two kinases, MELK (maternal embryonic leucine zipper kinase) and TOPK (T-LAK cell-originated protein kinase), both of which are highly and frequently transactivated in various cancer tissues, including AML as well as lung and triple-negative breast cancers. MELK was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. TOPK plays a critical role in the mitosis of cancer cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTS167 with IC50 of 0.41 nM as well as TOPK inhibitors, OTS 514 and OTS964, with IC50 values of 2.6 nM and 28 nM, respectively. OTS167 suppressed sphere formation of breast cancer cells and small cell lung cancer cells more effectively than the attached cells, caused drastic reduction of MELK autophosphorylation, enhanced MELK degradation, and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, pancreas cancer and AML cells in mice by both intravenous and oral administration. Similar to the knockdown effect of TOPK siRNAs, TOPK inhibitors caused a cytokinesis defect and the subsequent apoptosis of cancer cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. Furthermore, treatment of AML cells with TOPK inhibitor resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients who relapsed after FLT3-inhibitor treatment. Our results suggest that the inhibition of MELK and/or TOPK may be viable therapeutic options for the treatment of various human cancers.

Precision medicine is a concept to take individual variability into account in disease prevention and treatment. It has become possible because of the recent development of human genome sequencing and pan-omics technologies as well as the application of large-scale biologic databases to characterize patients and guide clinical practice. It has significantly improved treatment outcome of human diseases including cancers. Here I use lung cancer as an example to show how precision medicine has improved the patients’ treatment outcome. Lung cancer is the leading cause of cancer mortality worldwide. Since the identification of EGFR activating mutations in 2004 and the discovery of specific targeting agents, the treatment of lung cancer has entering a new era of precision therapy. The mutated EGFR may function as an oncogenic driver in more than 50% of Asian and 10-15% of Caucasian lung adenocarcinomas. Patients harboring activating EGFR mutants, most commonly L858R or Ex19Del, usually present good initial responses to EGFR-TKIs and survival improvement, but eventually develop disease progression after a median of 12 months. T790M mutation accounts for 60% of these resistant cases. Other resistant mechanisms include the activation of alternative oncogenic pathways or small cell transformation. There are several strategies to overcome EGFR-TKIs resistance including a switch to chemotherapy; turn off the compensatory oncogenic pathways; dual inhibition with anti-EGFR antibodies and TKIs; development of new generation EGFR TKIs (AZD9291, CO-1686); and knockdown of EGFR by siRNA or specific T790M DNAzyme. Promising new approaches include immunotherapy with checkpoint inhibition by anti-PD-1/PD-L1 antibodies, adoptive T cell and cancer stem cell (CSC)/microenvironment directed therapy. We have developed aptamer based immune checkpoint inhibitors against PD-1, PD-L1 and CTLA4, which showed potential for development of cancer immunotherapy. We established CSC culture and screening platform to identify new drug against CSC and cancer microenvironment. The recent study by Lung Cancer Mutation Consortium confirmed that multiplexed gene testing is feasible for precision lung cancer therapy. Taiwan established national reference laboratory to provide standardized gene-testing platform for all lung cancer patients. Taiwan National Health Insurance reimbursed Gefitnib and Erlotinib for first line therapy of EGFR mutant lung cancer patients since 2011. With the implementation of nation-wide gene testing and personalized therapy, the overall 5-year survival for NSCLC has improved from 16% to 32%. The precision medicine has significantly improved the treatment outcome for NSCLC.

The Cancer Genome Atlas (TCGA), a collaboration between the National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI), aims to generate comprehensive, multi-dimensional maps of the key genomic changes in major types and subtypes of cancer. A three-year pilot project initiated in 2006 confirmed that an atlas of changes could be created for specific cancer types. It also showed that a national network of research and technology teams working on distinct but related projects could pool the results of their efforts, create an economy of scale and develop an infrastructure for making the data publicly accessible. Importantly, it proved that making the data freely available would enable researchers around the world to make and validate important discoveries. The success of the pilot led the National Institutes of Health to commit major resources to TCGA to collect and characterize additional tumor types. TCGA finalized tissue collection with matched tumor and normal tissues from 11,000 patients, allowing for the comprehensive characterization of 33 cancer types and subtypes, including 10 rare cancers. This talk will present the latest update on the project as well as future directions  and an overview of the newest repository of genomics data: The NCI Genomics Data Commons.