Kathleen Kelly, Ph.D.

Dr. Kelly’s program investigates mechanisms of prostate cancer tumorigenesis and progression. A major area of focus addresses the roles of oncogenotype, tumor heterogeneity/cancer stem cells, and metabolism in the development of therapeutic responses, especially for castrate resistant prostate cancer. Additional research investigates signal transduction pathways that influence prostate cancer bone metastasis. As chief of LGCP, Dr. Kelly advances integration with the clinical prostate cancer program to carry out mechanism-based translational studies using a variety of pathological, genomic, and patient-derived live culture approaches.
1) prostate cancer, 2) organoid cultures, 3) drug response and resistance, 4) metabolism and imaging, 5) cancer stem cells, 6) oncogenomes
Contact Info
Center for Cancer Research
National Cancer Institute
Building 37, Room 1068
Bethesda, MD 20892
Ph: 240-760-6827
kellyka@mail.nih.gov
Research Interests
Our laboratory focuses on understanding the mechanistic consequences of specific genetic alterations that lead to the development of prostate cancer (PC), especially as related to progression. Prostate cancer (PC) is the most frequently diagnosed non-cutaneous cancer in men, and although organ confined PC is highly treatable with surgery and/or radiation, metastatic disease is incurable and leads to significant morbidity and mortality. Our goal is to improve detection and treatment of prostate cancer through understanding genomic and biochemical mechanisms of disease progression.
We use two complementary approaches, patient-derived xenografts/organoids and genetically engineered mouse models (GEMMs). A strength of our laboratory is our ability to employ a wide variety of in vivo models and imaging modalities. We use the large cohort of LuCaP patient-derived CRPC xenografts established by our collaborators at the University of Washington. The LuCaP cohort represents the genotypic and phenotypic heterogeneity of advanced prostate cancer clinical samples. To facilitate experimental manipulations, including genetic modifications and high throughput screening assays, we optimized organoid methods for establishing and maintaining in vitro cultures of LuCaP xenograft tumor cells. In addition to the LuCaP organoids, we also have developed a number of organoid cultures from NIH clinical center CRPC patient biopsy samples. Together these organoid cultures in combination with matching PDX tumors provide an extensive, clinically-relevant experimental platform. One major effort is focused upon high throughput screens to determine therapeutic sensitivity and metabolic characteristics (including imaging tools) as they relate to molecular characteristics. A second effort addresses the genetic and epigenetic mechanisms of CRPC dedifferentiation and neuroendocrine transdifferentiation that occurs in response to androgen deprivation.
GEMMs are particularly useful for the availability of genetically-defined tumor tissue, the ability to longitudinally investigate various stages of prostate cancer progression, and the ease of manipulating the hormone environment. Models of aggressive CRPC in mice have provided insight into poorly differentiated tumors enriched for cancer stem/progenitor cells. Combined PTEN/TP53 mutations occur in ~30% of clinical CRPC. Our characterization of a Pten/Tp53 null prostate cancer GEMM model revealed that the amplification and plasticity of luminal prostate cancer progenitor cells contributes to the aggressive and castration resistant nature of the disease. Ongoing investigations are focused upon the signaling pathways that promote self-renewing cancer stem cells and their relationship to castration indifference.
Selected Recent Publications
- Clinical Cancer Research. In Press: 2018. [ Journal Article ]
- Cell Reports. 23(3): 808-822, 2018. [ Journal Article ]
- Oncogene. 36(4): 525-533, 2017. [ Journal Article ]
- Cell Reports. 13(10): 2147-2158, 2015. [ Journal Article ]
- Mol. Cell. Biol. 32: 941-53, 2012. [ Journal Article ]
Dr. Kelly received her Ph.D. from the University of California, Irvine. She completed her postdoctoral training in the laboratory of Philip Leder, Harvard Medical School, and she has maintained an independent research program at the NCI since 1984. Dr. Kelly's interests have focused on the genetic regulation of cell growth, cancer progression and metastasis.
Name | Position |
---|---|
Remi Adelaiye-Ogala Ph.D. | Postdoctoral Fellow (Visiting) |
Supreet Agarwal, Ph.D. | Research Fellow |
Aian Neil Alilin | Animal Technician (Contr.) |
Wardah Tahir Bajwa | Postbaccalaureate Fellow (CRTA) |
Michael L. Beshiri, Ph.D. | Research Fellow |
Danielle N. Burner | Postbaccalaureate Fellow (CRTA) |
Emily A. Kolyvas | Predoctoral Fellow (Medical Student) |
Sonam Raj Ph.D. | Postdoctoral Fellow (Visiting) |
Ilya S. Senatorov Ph.D. | Postdoctoral Fellow (CRTA) |
Margaret White Ph.D. | Postdoctoral Fellow (CRTA) |
Ivy Yin, Ph.D. | Research Biologist |
From Left Back Row: Ross Lake, Keith Jansson, Aian Neil Alilin, Dmitry Grigoryev, Lechen (Frank) Li, Supreet Agarwal, Mike Beshiri
From Left Front Row: Lei Fang, Hong Pan, Crystal Tran, Kathy Kelly, Juanjuan (Ivy) Yin, Miriam Breaugh