Towards rational design of combination therapeutic targets
- Towards rational design of combination therapeutic targets
List of Collaborating Institutions
- Children’s Hospital of Philadelphia
University of Pennsylvania
St. Jude Children’s Research Hospital
Major research efforts have focused on the development of targeted monotherapeutic agents that can maintain high rates of cure, yet minimize toxicities. Given the prevalence of crosstalk among oncogenic pathways and disease heterogeneity, it has become increasingly apparent that combination therapies are required to achieve long-term cure and to minimize development of resistance mutations and escape pathways. The majority of existing combination therapies are developed in an ad hoc fashion, namely one agent at a time, without systematic consideration of potential complex interactions among the gene targets by leveraging disease-specific omics data. Moreover, the existing combination therapies are based on targets of existing drugs, which only represent a small portion of the human proteome. To this end, we hypothesize that systematic identification of synergistic key regulators represents a promising approach for nominating targets of combination therapy. Towards this goal, we will forward engineer a platform for identifying synergistic regulatory nodes in a cancer gene regulatory network as the targets for combination therapy. We will generate disease-specific multi-omics data to construct an integrative gene regulatory network, a pre-requisite for understanding the deregulated gene network in the cancer cells and for developing effective and lasting therapy. We will focus our study on Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) as a proof-of-principle. Ph-like ALL is a recently-recognized high-risk subtype of B-cell ALL (B-ALL) characterized by various genetic alterations that deregulate multiple cytokine receptor and kinase signaling pathways and poor clinical outcomes in both children and young adults. New therapeutic strategies incorporating kinase inhibitors are just entering clinical testing, but remain inadequately studied. Our team proposes a novel approach to this problem by leveraging the unique strengths of the investigators in systems biology, genomics, proteomics, and translational research, as well as the large cohort of patient samples available at our institutions. If successful, the proposed framework would be a tremendous advance and paradigm shift to understand genetic interactions among oncogenic pathways for eventual therapeutic intervention, either through genetic medicines or small molecule treatment.
Kai Tan, PhD is Professor of Pediatrics, Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania. Dr. Tan is a systems biologist with over 15 years of experience of studying transcriptional and epigenetic regulation. His laboratory has pioneered a number of approaches for modeling transcriptional regulatory networks. Using these approaches, they have been dissecting the gene regulatory networks controlling embryonic hematopoiesis, T cell differentiation, and leukemogenesis. Dr. Tan serves as co-leader of the Pediatric Oncology program at the Abramson Cancer Center and director of the Center for Pediatric Tumor Cell Atlas where they are using a range of single-cell and imaging assays to characterize the heterogeneity and microenvironment of pediatric cancers.
Sarah K Tasian
Sarah K Tasian, MD is Assistant Professor of Pediatrics, Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania. Dr. Tasian is a pediatric oncologist and physician-scientist who is interested in development of molecularly-targeted therapeutics for children with high-risk leukemias. Her bench-to-bedside and bedside-back-to-bench translational laboratory research program focuses upon testing of kinase inhibitors and chimeric antigen receptor (CAR) T cell immunotherapies in genetic subsets of childhood ALL and AML. Dr. Tasian has leadership roles in the Children’s Oncology Group (COG) ALL and Myeloid Diseases committees, is the COG Developmental Therapeutics committee Vice-Chair of Biology for Hematologic Malignancies, and leads or co-leads several national or institutional early phase clinical trials testing precision medicine therapies in children with high-risk leukemias.
Junmin Peng, PhD is Full Member (Professor) in the Departments of Structural Biology and Developmental Neurobiology, and Director of the Center for Proteomics and Metabolomics at St. Jude Children’s Research Hospital in Memphis. The Peng group develops high-throughput mass spectrometry-based proteomics, phosphoproteomics, metabolomics and systems biology approaches, and uses the approaches to investigate proteome turnover, cancer and Alzheimer’s disease. Beyond omics analysis of clinical samples, his group also develops cellular and animal models to validate derived hypotheses.