Developing CAR T Cell Therapies to Target Tumor Heterogeneity in Advanced Prostate Cancer Therapies that inhibit androgen biosynthesis and target the androgen receptor are the mainstay of treatment for patients with advanced prostate cancer. However, most men will eventually develop resistant disease that is called castration-resistant prostate cancer (CRPC). Metastatic CRPC is not curable and treatments at this stage are aimed at extending and improving quality of life. CRPC is a heterogeneous disease composed of at least two subtypes including prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC). Both CRPC subtypes are found together in many lethal, treatment-resistant prostate cancers. New and potent therapies that account for and eliminate the heterogeneity of CRPC are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a revolutionary advance in oncology that combines precision targeting with powerful killing of tumor cells. In this approach, a patient?s own immune T cells are collected from the blood, genetically engineered to recognize and kill his/her specific cancer and reintroduced into the patient. This technology has the potential to transform the treatment of cancer including those that have been considered incurable. Our group has pushed forward the first CAR T cell therapy for metastatic CRPC to a clinical trial by building on a series of scientific accomplishments. We discovered that prostate stem cell antigen (PSCA) is a protein expressed on the surface of the majority of prostate adenocarcinomas, developed antibodies that bind specifically to PSCA, and extensively engineered and tested PSCA CAR T cell therapy in laboratory models of prostate cancer. Recently, we have also found that another protein, carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5), is expressed on the surface of most NEPCs. In the proposed research, we will initiate a phase I clinical trial to evaluate our PSCA CAR T cells in patients with metastatic CRPC, and interrogate patient specimens to elucidate mechanisms of treatment resistance with particular attention given to the emergence of NEPC. We will also engineer and evaluate CARs aimed at safely and specifically targeting CEACAM5 in laboratory models of NEPC. Lastly, we will determine whether a strategy combining PSCA CAR T and CEACAM5 CAR T cells can safely address tumor heterogeneity in CRPC by eradicating both prostate adenocarcinoma and NEPC.
The research is aimed at developing novel chimeric antigen receptor T cell immunotherapy strategies for late- stage prostate cancer with a specific emphasis on defining and overcoming an underlying tumor resistance to therapy. Knowledge obtained from these studies will ultimately be applied to reduce the burden of disease and lengthen life in men with advanced, treatment-resistant prostate cancer.
|Miller, Eric T; Salmasi, Amirali; Reiter, Robert E (2018) Anatomic and Molecular Imaging in Prostate Cancer. Cold Spring Harb Perspect Med 8:|
|Navarro, Héctor I; Goldstein, Andrew S (2018) HoxB13 mediates AR-V7 activity in prostate cancer. Proc Natl Acad Sci U S A 115:6528-6529|
|Mitra, Mithun; Ho, Linda D; Coller, Hilary A (2018) An In Vitro Model of Cellular Quiescence in Primary Human Dermal Fibroblasts. Methods Mol Biol 1686:27-47|
|Li, Jiayun; Speier, William; Ho, King Chung et al. (2018) An EM-based semi-supervised deep learning approach for semantic segmentation of histopathological images from radical prostatectomies. Comput Med Imaging Graph 69:125-133|
|Kang, Jung J; Reiter, Robert E; Kummer, Nicolas et al. (2018) Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy. Am J Clin Oncol 41:1-5|
|Lee, Ha Neul; Mitra, Mithun; Bosompra, Oye et al. (2018) RECK isoforms have opposing effects on cell migration. Mol Biol Cell 29:1825-1838|
|Aggarwal, Rahul; Huang, Jiaoti; Alumkal, Joshi J et al. (2018) Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol 36:2492-2503|
|Cheng, Larry C; Li, Zhen; Graeber, Thomas G et al. (2018) Phosphopeptide Enrichment Coupled with Label-free Quantitative Mass Spectrometry to Investigate the Phosphoproteome in Prostate Cancer. J Vis Exp :|
|Park, Jung Wook; Lee, John K; Sheu, Katherine M et al. (2018) Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science 362:91-95|
|Tan, Nelly; Shen, Luyao; Khoshnoodi, Pooria et al. (2018) Pathological and 3 Tesla Volumetric Magnetic Resonance Imaging Predictors of Biochemical Recurrence after Robotic Assisted Radical Prostatectomy: Correlation with Whole Mount Histopathology. J Urol 199:1218-1223|
Showing the most recent 10 out of 339 publications