Director, Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research

President's Chair in Developmental Immunology, Microbiology, Immunology & Molecular Genetics

Distinguished Professor, Microbiology, Immunology & Molecular Genetics

Co-Leader, Pilot and Collaborative Translational Clinical Studies Program

Professor, Institute for Molecular Medicine, Molecular & Medical Pharmacology

Member, ACCESS Program: Dept. of Microbiology, Immunology, & Molecular Genetics, Internal Advisory Board, JCCC Genitourinary Oncology Program Area, JCCC Tumor Immunology Program Area, NanoBiotechnology and Biomaterials, CTSI, California NanoSystems Institute

Faculty, Molecular Biology IDP

Investigator, Howard Hughes Medical Institute

We are interested in the development of the immune response, growth regulation mechanisms used in leukemias and during metastasis of certain epithelial cancers to the bone marrow, and the application of new quantitative processes of whole-animal imaging. We have used positron emission tomography (PET) reporter gene strategies to mark populations of lymphocytes reactive to antigens on solid tumors and follow lymphocyte homing and expansion in living mice. Many of these techniques may be suitable for evaluation of human anti-tumor responses. Our laboratory has contributed major findings in the following areas: (i) Therapeutic Strategies for Ph Chromosome?Positive Leukemias. Human chronic myelogenous leukemia (CML) is associated with the Philadelphia chromosome, which produces the BCR-ABL tyrosine kinase oncogene. Our laboratory demonstrated that this kinase is critical for the leukemic phenotype of CML and related types of leukemia. Targeted drug therapy for CML (Gleevec and other drugs) that inhibits the enzymatic activity of BCR-ABL has been very successful for treatment of the chronic phase of CML but has been less effective for the blast crisis stage of CML or the initial treatment of Ph-positive ALL. In both of these aggressive leukemias, additional genetic changes complement the action of BCR-ABL and the malignancy continues to grow in the face of the kinase-targeted therapy. Although some of this lack of responsiveness is due to mutations in the kinase that render the drug less effective, in other cases the combination of genetic changes allows the bypass of cell killing by the drug. (ii) Lymphoid Development and Immune Monitoring by Positron Emission Tomography. A family of PET probes based on FAC has been developed, and these can be used to predict the uptake of closely related chemotherapy agents; this may aid in selecting specific patients for more-personalized chemotherapy regimens. Early-phase clinical testing of the FAC family probes has been initiated, in collaboration with Caius Radu and Johannes Czernin (UCLA). (iii) Prostate Cancer Pathogenesis. To develop a system where the prostate gland could be studied analogously to blood, we adapted a previously described tissue recombination model to reconstruct prostatic tissue from dissociated single cells when combined with an inductive stromal source and transplanted into immune-deficient mice. This system allows for the purification of cells that generate prostatic structures, and also provides a way to define specific oncogenic insults or combinations capable of transforming naïve prostate epithelium. Building on our expertise in the mouse system, we asked if we could purify distinct subsets of cells from the human prostate, using surface markers CD49f and Trop2 to define basal and luminal cells isolated from primary benign human prostate tissue. Basal cells, defined as CD49fhiTrop2+, could self-renew in vitro and generate prostatic ducts in vivo. Introduction of three oncogenes?AKT, ERG, and AR?in basal cells, but not luminal cells, was sufficient to initiate prostate adenocarcinoma. The resulting cancer had a luminal phenotype, demonstrating that a stem-like basal cell can serve as a cell of origin and differentiate into a malignant cell with a mature marker profile.