Pediatric Cancer Biology Program
The Cancer Biology Program is directed by Dr. Michael Cleary. Goals of the Program
The overall research goals of the program are to elucidate the molecular pathogenesis of pediatric cancers and to translate this knowledge into improved treatments. This long-term objective has three major components. The first is to identify the molecular aberrations that induce and sustain the aberrant growth of pediatric cancers. The second is to elucidate the molecular mechanisms by which these aberrations disrupt normal growth control processes. The third is to design therapies that specifically target these molecular abnormalities for treatment of children with cancer and to devise new molecular tools for monitoring the response to therapy in real time.
In the past decade, remarkable progress has been made on the first phase of this long-term objective. Our program, and the field of cancer biology in general, is now primarily focused on the second objective of unraveling the intricate biochemical interactions, which link cancer genes together on molecular pathways that regulate fundamental processes and have gone awry in cancer cells. Cancer genes, and their products, serve as important signposts on these pathways and are key therapeutic targets.
A major insight that has emerged from these investigative efforts is that pediatric cancers are extremely heterogeneous in their molecular pathogenesis. There are many cancer genes that are damaged in human cancers and their diversity and numbers are overwhelming. Fortunately, the myriad mutations in cancer cells appear to disrupt only a handful of fundamental regulatory processes. Nevertheless, the high number of potential molecular targets and low overall incidence of pediatric cancers equates to a small potential market for any single therapeutic agent with molecular specificity. Thus, commercial incentives to develop and validate molecular therapies for childhood cancers are likely to remain low. Major advances in translation of basic research findings to new treatments will primarily depend on investigators in academic centers, not pharmaceutical companies. This reality will continue to serve as a guiding principal in the planning and implementation of our long-term objectives to design more effective and appropriate therapy for childhood cancers.Faculty Research Interests
Michael Cleary, MD
Dr. Cleary’s research interests focus on the molecular pathogenesis of acute leukemias. His laboratory group has discovered several of the major cancer genes that are mutated in childhood leukemias. The identification of these genes has provided some of the most useful prognostic markers for specific subtypes of pediatric leukemias. Current research efforts are directed at two major objectives:
- determine the normal functions for the products of pediatric cancer genes; and
- establish how mutations in pediatric leukemias corrupt these functions.
Dr. Cleary’s research group employs a multi-faceted experimental approach to address these issues using genetic, molecular, and biochemical techniques. Many of the current efforts focus on preclinical mouse models of childhood leukemias. Successful development and use of these models has led to new insights into how pediatric leukemia genes function and also highlighted candidate signaling pathways to be targeted by molecular therapeutics. The preclinical models will continue to be important for testing new therapeutics, thereby allowing expeditious discovery of those with the highest promise to progress to clinical trials in pediatric patients. See laboratory website for more information: http://www.stanford.edu/group/cleary/
Julien Sage, PhD
Research in the Sage laboratory focuses on the retinoblastoma tumor suppressor gene (RB). RB normally works as a negative regulator of cell division, and RB mutation leads to uncontrolled proliferation. Our goal is to take advantage of the central role of RB in cell cycle control and tumorigenesis in order to address basic issues in cancer. In particular, we use mouse models of human cancers associated with loss of RB function to investigate how loss of RB may initiate cancer from stem cell populations. Tumors in mice resemble human tumors in many ways, and design and testing of new therapeutic strategies in mouse models of human cancers will speed anti-cancer therapies. See laboratory website for more information: http://www.stanford.edu/group/sage/
Alejandro Sweet-Cordero, MD
The two most frequent bone sarcomas in children are Osteosarcoma and Ewing’s Sarcoma. Our laboratory is interested in understanding the cell of origin of these tumors. In addition, we are studying the role that tumor-initiating cells (“cancer stem cells”) play in mediating aggressiveness and chemotherapy resistance in these tumors. We are collecting a large bank of primary xenograft samples from both pre and post-chemotherapy patient biopsies to address these questions.
Chromosomal translocations are frequent genetic events in the genesis of many human cancers. They are particularly frequent in tumors common in pediatric patients. In Ewing’s sarcoma, the most common translocation is EWS/FLI-1. We are using a variety of approaches in both mouse and human primary cells to study the mechanism of EWS/FLI-1 mediated oncogenesis. As ets transcription factors such as Fli-1 and Erg are mutated in other tumors in addition to EWS (i.e, erg mutations in prostate cancer) our finding in these model systems may have broader applicability to other tumor types.
In addition to our work in pediatric sarcomas, our laboratory is generally interested in functional genomic approaches to identify novel regulators of oncogenesis. We previously identified a gene expression “signature” for the oncogene Kras. We are using several approaches for identifying effectors and “synthetic lethal” interactions downstream of Kras using siRNA and gene-expression based screening (GE-HTS).
Lablink: http://sweetcorderolab.stanford.edu/
Dr. Matt Porteus
The Porteus lab has developed nuclease mediated genome editing as both a research tool and as a novel and innovative approach to gene therapy for pediatric genetic diseases. Specifically, we are using nuclease mediated genome editing as an approach to cure the hemoglobinopathies, severe combined immunodeficiency and hemophilia. We are using nuclease mediated genome editing as a research tool to induce chromosomal translocations that underlie pediatric cancers and as a way of dissecting important signaling pathways in cells. Finally, we are also interested in the population dynamics of human cancer cells and have developed a novel barcode tracking system to better understand chemotherapy resistance and the evolution of clonal dominance in pediatric leukemias.
Dr. Kathleen Sakamoto
Hematopoiesis is the development of blood cells, which is highly regulated through both intrinsic and extrinsic factors. Transcription factors are critical for normal proliferation and differentiation of blood cells. Growth factors and the bone marrow microenvironment are also critical for normal hematopoiesis. Specific diseases of hematopoiesis result from defects in transcription or protein synthesis.
The overall goal of our laboratory is to understand the molecular regulation of hematopoiesis and how aberrancies result in diseases of hematopoiesis, including leukemia, bone marrow failure, and myeloproliferative disease. We are also developing novel therapies to treat cancer.
Lablink: Sakamotolab.com