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Isaac Kim Laboratory - Research Overview

Prostate cancer is the most common non-cutaneous cancer diagnosed among men and the second leading cause of male cancer death in the United States. In 2018, it is estimated that 29,430 men will die from prostate cancer. Although radiation and surgery are quite effective for localized disease, approximately 30% of men diagnosed with prostate cancer will experience disease recurrence following definitive therapy. More importantly, there is no definitive cure for men who present with metastatic prostate cancer, who have an estimated 5-year survival rate of only 29% according to data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. In patients with metastatic disease, medical (ie, androgen deprivation therapy) or surgical castration is generally the accepted first-line therapy. Yet castration-resistant prostate cancer eventually emerges, limiting life expectancy despite treatment with secondary hormonal agents, such as enzalutamide and abiraterone, targeted to the androgen receptor, as well as immunotherapy and chemotherapy.  

Dr. Kim's laboratory research interests are characterized by studies with near to mid-term translational potential. These studies focus on uncovering molecular mechanisms that govern sensitivity and resistance to anti-androgen therapy in prostate cancer and renal cell carcinoma. Over the past few years, the Kim Laboratory has investigated the role of androgens and anti-androgen therapy in the growth of renal cell carcinoma, the role of Wnt5a and bone-morphogenetic protein-6 (BMP-6) signaling in the development of castration-resistant prostate cancer and, most recently, the potential role of specific neuroendocrine mediators as markers of resistance to the nonsteroidal antiandrogen, enzalutamide, in prostate cancer. 

Dr. Kim and colleagues have shown that increased androgen receptor mRNA expression is associated with poor prognosis in patients with localized renal cell carcinoma (RCC). In addition, results of recent preclinical studies involving androgen receptor-positive RCC have provided support for both androgen biosynthesis in RCC as well as the potential benefits of therapies targeted to androgen signaling pathways in this form of the disease. In the setting of prostate cancer, the Kim Laboratory has provided evidence that release of Wnt5a, a signaling glycoprotein, from bone stroma modulates androgen sensitivity in the context of prostate cancer by triggering expression of BMP-6 and cytokine ligand 2 (CCL2) in androgen-sensitive prostate cancer cells, resulting in the development of castration resistance and enhancement of bone-tumor interactions through macrophage recruitment and regulation. Illustrated in the figure below are features of the proposed mechanism by which release of Wnt5a, as mediated by bone-tumor interactions, may facilitate castration resistance in prostate cancer. 

Isaac Kim Lab - Figure 1

Regarding investigations of possible neuroendocrine markers of resistance to enzalutamide in prostate cancer, Dr Kim was recently awarded $954,000 from the U.S. Department of Defense to pursue these studies. 

Read the news release
 

Laboratory Leadership

Isaac Yi Kim, MD, PhD, MBAIsaac Yi Kim, MD, PhD, MBA received his PhD and MD from Northwestern University in 1996 and 1997, respectively. During this time, Dr. Kim investigated the role of transforming growth factor-β (TGF-β) in prostate cancer, showing that TGF-β gene expression is frequently downregulated in prostate cancer cells, and identifying a specific genetic alteration in TGF-β receptor type I in prostate cancer. He subsequently completed his urology residency at Baylor College of Medicine, a research fellowship in Urologic Oncology at the National Cancer Institute, and a clinical fellowship in endourology, laparoscopy, and robotics at the University of California, Irvine before joining the faculty at the Rutgers Cancer Institute of New Jersey in 2005. During his postgraduate studies, Dr. Kim extended his laboratory research to bone morphogenetic proteins (BMP-6), the largest family in the TGF-β superfamily. This work lead to a main focus of his more recent work and provided evidence that BMP-6 and cytokine ligand 2 (CCL2) can alter prostate cancer progression and sensitivity to anti-androgen therapy, in part by altering the phenotype of tumor-associated macrophages. 
 

Selected Publications

Lee GT, Kwon SJ, Kim J, Kwon YS, Lee N, Hong JH, Jamieson C, Kim WJ, Kim IY. WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages. Br J Cancer. 2018;118(5):670-678. PMID: 29381686; PMCID: PMC5846063.

Lee GT, Han CS, Kwon YS, Patel R, Modi PK, Kwon SJ, Faiena I, Patel N, Singer EA, Ahn HJ, Kim WJ, Kim IY. Intracrine androgen biosynthesis in renal cell carcinoma. Br J Cancer. 2017;116(7):937-943. PMID: 28253524; PMCID: PMC5379152.

Ha YS, Lee GT, Modi P, Kwon YS, Ahn H, Kim WJ, Kim IY. Increased expression of androgen receptor mRNA in human renal cell carcinoma cells is associated with poor prognosis in patients with localized renal cell carcinoma. J Urol. 2015;194(5):1441-8. PMID: 25796113. 

Lee GT, Kang DI, Ha YS, Jung YS, Chung J, Min K, Kim TH, Moon KH, Chung JM, Lee DH, Kim WJ, Kim IY. Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction. Br J Cancer. 2014;110(6):1634-44. PMID:24518599; PMCID: PMC3960605. 

Lee GT, Ha YS, Jung YS, Moon SK, Kang HW, Lee OJ, Joung JY, Choi YH, Yun SJ, Kim WJ, Kim IY. DHCR24 is an independent predictor of progression in patients with non-muscle-invasive urothelial carcinoma, and its functional role is involved in the aggressive properties of urothelial carcinoma cells. Ann Surg Oncol. 2014;21 Suppl 4:S538-45. PMID: 24562935. 

Kwon SJ, Lee GT, Lee JH, Iwakura Y, Kim WJ, Kim IY. Mechanism of pro-tumorigenic effect of BMP-6: neovascularization involving tumor-associated macrophages and IL-1a. Prostate. 2014;74(2):121-33. PMID: 24185914. 

Lee JH, Lee GT, Woo SH, Ha YS, Kwon SJ, Kim WJ, Kim IY. BMP-6 in renal cell carcinoma promotes tumor proliferation through IL-10-dependent M2 polarization of tumor-associated macrophages. Cancer Res. 2013;73(12):3604-14. 

Lee GT, Jung YS, Ha YS, Kim JH, Kim WJ, Kim IY. Bone morphogenetic protein-6 induces castration resistance in prostate cancer cells through tumor infiltrating macrophages. Cancer Sci. 2013 Aug;104(8):1027-32. PMID: 23710822.

Lee JH, Lee GT, Kwon SJ, Jeong J, Ha YS, Kim WJ, Kim IY. CREBZF, a novel Smad8-binding protein. Mol Cell Biochem. 2012;368(1-2):147-53. PMID: 24708639. PMCID: PMC4005471. 

Lee GT, Jung YS, Lee JH, Kim WJ, Kim IY. Bone morphogenetic protein 6-induced interleukin-1β expression in macrophages requires PU.1/Smad1 interaction. Mol Immunol. 2011;48(12-13):1540-7. PMID: 21571370. 

Lee GT, Kwon SJ, Lee JH, Jeon SS, Jang KT, Choi HY, Lee HM, Kim WJ, Lee DH, Kim IY. Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate. 2011;71(14):1525-37. PMID: 21374653. 

Lee GT, Kwon SJ, Lee JH, Jeon SS, Jang KT, Choi HY, Lee HM, Kim WJ, Kim SJ, Kim IY. Induction of interleukin-6 expression by bone morphogenetic protein-6 in macrophages requires both SMAD and p38 signaling pathways. J Biol Chem. 2010;285(50):39401-8. PMID: 20889504; PMCID: PMC2998138. 

 

 

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