Predoctoral trainees are selected on a competitive basis from current graduate students in the following graduate programs at the University of Minnesota:
- Microbiology, Immunology & Cancer Biology (MICaB)
- Molecular, Cellular, and Developmental Biology & Genetics (MCDB&G)
- Biochemistry, Molecular Biology & Biophysics (BMBB)
Students in the MCDB&G and BMBB programs begin their training in a combined program in Molecular, Cellular and Structural Biology (MCSB).These programs provide broad training in core disciplines that are essential to cancer research: biochemistry, cell biology, immunology, microbiology and genetics. The curriculum within each program allows the student and faculty preceptor the opportunity to design a program of training that incorporates core knowledge in these disciplines, while allowing for specialization in a specific area. Specific graduate-level courses in Biology of Cancer and Translational Cancer Research are offered by the MICaB graduate program and are required for all trainees supported by the Cancer Biology Training Grant.
Current predoctoral trainees
Solid tumors consist of malignant cells and a heterogeneous mixture of supporting stromal cells that are essential for tumor growth beyond a few millimeters. This complex and immunosuppressive tumor microenvironment remains a significant challenge to cancer treatment. Non-malignant stromal cells called cancer-associated fibroblasts exist exclusively in the tumor stroma and modulate adaptations to the microenvironment that promote survival and progression of the disease. Castration-resistant prostate cancer (CRPC) has a high stromal composition and the presence of highly reactive stroma enriched with cancer-associated fibroblasts directly correlates with poor prognosis. My work in the laboratory of Dr. Aaron LeBeau aims to address CRPC treatment limitations by developing a stroma- targeted chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy. This approach is based upon the hypothesis that eliminating the aiding and abetting tumor stroma with CAR NK cells will lead to reduction in tumor burden and tumor-mediated immunosuppression. In contrast to healthy tissues, cancer-associated fibroblasts over-express the membrane-bound serine protease fibroblast activation protein alpha (FAP) in the tumor microenvironment. This expression pattern is characteristic of 90% of all epithelial tumors, including CRPC, which makes FAP an attractive target for CAR NK cell immunotherapy. Existing immunotherapies for solid tumors have limited efficacy and more work is needed to understand the intricacies of the tumor microenvironment and to tailor CAR-based therapeutic approaches to these types of cancer. My research will contribute to a better understanding of the interactions among tumor, stromal, and CAR NK cells and could facilitate the development of immunotherapies for other refractory solid tumors containing supportive stromal cells. Because my approach targets genetically-stable stromal tissue, and not antigens expressed on mutation-prone cancer cells, FAP-CAR NK cells could be an effective therapy to kill heterogeneous tumor populations.
Title of Research Project: Role(s) of RAD18 in the regulation of genomic stability Homologous recombination (HR) is a key pathway for the precise repair of DNA double-stranded breaks and other DNA replication-associated lesions. HR promotes repair of lesions by using the non-damaged sister chromatid as a template for repair. Due to its essential role in maintaining genome stability, the HR pathway is tightly regulated and both loss of HR and illegitimate hyper-recombination are associated with genomic instability and carcinogenesis. Our main objective is to understand how the HR pathway is regulated by RAD18, a RING-type E3 ubiquitin ligase that is best known for its role in promoting DNA damage tolerance. This objective is based in part on preliminary data from our laboratory demonstrating that human RAD18 -/- cells exhibit abnormally high levels of sister chromatid recombination and chromosomal radial formations, indicators of genomic instability. Additionally, a survey of The Cancer Genome Atlas (TCGA) revealed that RAD18 inactivating deletions occur in human cancers at high frequencies, with a particularly high prevalence in cervical and renal cell tumors. We aim to understand the molecular mechanism(s) by which RAD18 suppresses hyper-recombination in human cells and protects normal cells from genome instability. This research will provide long sought-after insight into how hyper-recombination is suppressed and should open new therapeutic avenues of treating patients harboring RAD18 mutations.
Dysregulation of protein kinases is associated with cancer development and progression. This makes kinases excellent candidates for molecularly targeted therapies. However, most of the efforts to develop inhibitors has been focused on a small proportion of the human kinome, as the majority of kinases are not well characterized. We need to develop better tools to study poorly characterized kinases in order to find and pursue new therapeutic targets in cancer.
The receptor tyrosine kinase Tyro3 is an example of an understudied kinase with therapeutic potential. Tyro3 belongs to the TAM family of kinases which are associated with a number of different malignancies, but the individual function of Tyro3 remains understudied. Tyro3 is overexpressed in many hematological malignancies and has been linked to resistance against traditional chemotherapies and molecularly targeted therapies.The goal of my research project is to design a specific biosensor to detect and assess Tyro3 activity. To achieve this, the substrate profile of Tyro3 must be determined. The Parker lab uses phosphoproteomics to determine what substrates are preferentially phosphorylated by Tyro3. These substrates are then incorporated into the biosensors. We can determine the phosphorylation state of the biosensor, and thus the activity of the kinase, using both cellular and in vitro assays. This biosensor can then be used to study the role of Tyro3 in cancer and chemoresistance, as well as to develop specific inhibitors of Tyro3, through Parker Lab collaborations. The process can be applied to design new biosensors for any kinases of interest, allowing us to study a greater selection of the kinome.
More predoctoral training opportunities
Opportunities are available for graduate students to obtain rigorous laboratory-based training in the biology of cancer at the Masonic Cancer Center. Research opportunities cover the broad areas of cell metastasis/angiogenesis, immunology and cancer, cancer genetics/etiology, and cancer therapy.
A number of NIH T32 training grants provide financial support and specialized programs of training that will allow graduate students to establish themselves as independent investigators who will pursue research into the etiology and treatment of cancer. In addition, cancer center faculty members are members of a broad array of graduate programs that facilitate training in cancer-related fields.
- Microbiology, Immunology, and Cancer Biology Graduate Program
- Epidemiology Graduate Program
- Biochemistry, Molecular Biology and Biophysics Graduate Program
- Molecular, Cellular, Developmental Biology & Genetics Graduate Program
- Neuroscience Graduate Program
- Pharmacology Graduate Program
- Comparative and Molecular Biosciences Graduate Program
- Combined M.D./Ph.D. Training Program
Allison Hubel, Ph.D., College of Science and Engineering, and David McKenna, M.D., Department of Laboratory Medicine, have received NIH Research Education Program (R25) funding to develop an individualized training program to offer scholars the opportunity to gain experience in the advanced techniques used to process blood and stem-cell based therapies, the sophisticated assays used for product characterization and post-treatment patient assessment, and to learn the regulatory requirements of cell-based therapies. The intent of this integrated education program in development and clinical practice of cell-based therapies is to be instrumental in countering the decline of blood-based investigators and fostering advances in the treatment of hematological and other disease. The program will offer short-term educational experiences in specific techniques to participants in order to further enable their planned research careers in blood research.