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
Carlos Perez Kerkvliet
Carlos Perez Kerkvliet
Therapeutic options for triple-negative breast cancer (TNBC) are limited. This subtype of breast cancer (BC) lacks expression of molecules currently exploited for targeted therapy, including steroid hormone receptors: estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor 2 receptor (HER2). TNBC is the most aggressive, metastatic, and deadly form of BC, and it accounts for 20-30% of all BC cases. Although lacking these receptors, there is an emerging role of the glucocorticoid receptor (GR) in promoting progression and chemotherapy resistance in TNBC. Our main objective is to understand the role of oncogenic molecular signaling associated with GR. Our preliminary data indicates that TGFβ and 14-3- 3ζ modulate the activity of the GR, presumably via phosphorylation and direct interaction. Notably, both TGFβ and 14-3- 3ζ have been shown to be elevated in TNBC. We hypothesize that TGFβ and 14-3- 3ζ act in concert with GR to promote oncogenesis. To address this hypothesis, we will identify the mechanisms of phospho-Ser134 GR and 14-3- 3ζ interactions in TNBC progression. Additionally, we will test whether phospho-Ser134 GR is critical for proliferation and metastasis of TNBC cells in vivo. This project is relevant to public health because phospho-Ser134 GR and its associated signaling factors are excellent drug targets and possible biomarkers that will assist in better detection, diagnosis and management of TNBC.
The APOBEC3 (A3) subfamily of cytosine deaminase enzymes is a powerful source of mutagenic capacity in the human body. While these enzymes help to restrict foreign, invasive nucleic acids (i.e., viral genomes during an infection), they can also act as a major source of endogenous damage in the human genome. Much of this damage can be corrected by cellular repair machinery, yet a subset persists and is embedded as mutations. These mutations can contribute to disease progression in multiple cancer types, including cervical, lung, head and neck, and breast cancers. Additionally, A3 genes have considerable natural variation ranging from a 29.5 kb deletion of the full A3B gene to a wide range of single nucleotide polymorphisms. This variation leads to a differential contribution of APOBEC enzymes in cancer progression, with A3B and A3H-haplotype I showing the most significant causalities. However, the allele frequencies of these genes are geographically skewed, and thus a diverse international cohort of cancer samples is required to fully understand APOBEC contribution in cancer. My work in the lab of Dr. Reuben Harris aims to identify the distinct signatures that make up the diverse mutational profile responsible for cancer initiation and progression. To accomplish this goal, we have established multiple international collaborations to collectively sequence tumor samples from geographically distinct areas in order understand mutational profiles across varying A3B/A3H-haplotype I genotypes. Furthermore, we are working to develop tractable cell system to interrogate the APOBEC mutational process across multiple clonal generations of model breast cancer cell lines. A crucial component to this analysis involves the implementation of cutting-edge molecular engineering and gene editing techniques in conjunction with advanced bioinformatic and biostatistical tools to resolve the APOBEC signature in the presence of existing mutational backgrounds and other mutagenic factors. By defining these composite signatures, we can begin to understand the regulation and specificity of endogenous and exogenous mutagenic agents that often synergize to promote disease, with the ultimate goal of predicting cancer patient response to therapeutic intervention.
Paclitaxel, which targets microtubules (MTs), is the most widely prescribed drug for the treatment of breast and ovarian cancer, the second most commonly diagnosed and most lethal women’s cancers, respectively. Unfortunately, the inability to predict and influence how cancer patients will respond to paclitaxel and the onset of paclitaxel resistance represent major obstacles for long term disease remission. The exact mechanisms through which rapidly cycling cancer cells survive paclitaxel treatment remain elusive. The goal of my research is to investigate a member of the UCS (UNC-45/CRO1/She4p) protein family, UNC-45A, as a novel MT-interacting protein with MT-destabilizing activity whose overexpression in cancer cells antagonizes the effect of paclitaxel. We aim to define how UNC-45A modulates MT dynamics and determine whether it can serve as 1) a biomarker to stratify patients based on their likelihood of paclitaxel sensitivity and/or 2) as a therapeutic target for paclitaxel-resistant human cancers.
Sepsis strikes 750,000 Americans annually, and ~33% of these patients die – far more than from prostate cancer, breast cancer, and AIDS combined. Patients who survive severe sepsis often display prolonged immune system dysfunction with deficits in innate and adaptive immune responses. Cancer is the most common comorbidity in septic patients with nearly 93,000 cases annually. Importantly, cancer is also the comorbidity associated with the highest risk of death in patients with sepsis. The objective of my predoctoral research is to study the mechanisms responsible for the functional impairment in innate and adaptive immune cells that contribute to enhanced tumor growth and metastasis using the cecal ligation and puncture (CLP) model of sepsis. This objective is based in part on published data from the lab showing sepsis compromises the host’s ability to mount optimal CD4 and CD8 T cell responses to newly introduced antigens. The central hypothesis of my thesis project holds that alterations in the number and function of T cells and DC after sublethal CLP-induced sepsis are responsible for the suppressed immunity that leads to increased mortality from cancer induction in sepsis survivors. Our rationale for these studies is that once we understand how cells within the adaptive and innate arms of the immune system are affected during sepsis, we will be able to develop new and innovative therapeutic approaches to restore immune cell numbers and function in sepsis survivors.
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.