Dr. Nastiuk is a translational cancer researcher who joined the Roswell Park Cancer Institute faculty in 2015. He studied neurobiology (B.S. with high honors) at Oberlin College and molecular neuroendocrinology (Ph.D.) at The Rockefeller University. He completed fellowship training in protein biochemistry (Rockefeller) and prostate cancer genetics (Columbia P&S) before developing his research program examining the mechanism of endocrine therapy in prostate cancer at UC Irvine. Prior to coming to Roswell, he initiated investigations into the mechanism of therapy induced progression and developing enhanced specificity in imaging of localized prostate cancers at the University of Rochester.
The Nastiuk lab’s overarching goal is to improve therapy for genitourinary disease. Specifically, we are investigating androgen deprivation therapy (ADT) signaling pathways changed in benign prostatic hyperplasia and prostate cancer.
(#1 & #2): I found that in normal prostate and early cancer, an anti-apoptotic protein (cFLIP) is down-regulated by ADT, while pro-apoptotic cytokines (TNF and TGF) are up-regulated. We continue to study the mechanism of ADT-induced cytokine directed apoptosis. In late stage cancers, we find a phenotypic shift, where cFLIP is high and the cytokines appear to have paradoxical pro-tumorigenic activities, which may be an adaptive response of the prostate microenvironment leading to therapy resistance. We are dissecting this interaction between epithelial cells (tumor) and stromal cells (microenvironment) both in vitro and in vivo. We find that in more advance prostate cancer cells, ADT induces TNF, but rather than autocrine signaling of apoptosis, there is paracrine signaling to the surrounding stroma that induces the monocyte chemoattractant CCL2. This chemokine also appears to be, via paracrine signaling, pro-migratory/metastatic for the tumor cells (with Chawnshang Chang, Univ. Rochester and John Krolewski, RPCI). We are also interested in mechanisms and markers of ADT resistance, examining the roles of androgen synthesis (HSD3B1) and a tumor suppressor (PLZF/ZBTB16) (with G. Xiao, Univ. Rochester and D. Wu, Tongji Univ.).
(#3): We are examining an additional therapy response, the co-morbidity of “Obese Frailty”, a combination of sarcopenia (muscle loss) and fat gain, frequently seen in patients during long-term ADT for prostate cancer control. Unlike other cancer patients, these patients rarely show the fat loss and overall wasting characteristic of generalized tumor-induced cachexia. In mice undergoing ADT, we find that the expression of a subset of the TGFß superfamily (myostatin and other BANGs) change over time related to loss of strength and muscle mass. In mouse models of prostate cancer we expect to elucidate these BANGs’ role as biomarkers for, as well as targets of therapy for the sarcopenia resulting from androgen signaling blockade in prostate cancer patients.
(#4): We are testing whether we can recapitulate the pro-apoptotic activities of ADT in intermediate-stage diseases that may have acquired resistant androgen receptor mutations in preclinical models of prostate cancer (prostate PTEN deletion) and BPH (tg Pb-PRL). In collaboration with Dr. Young Kwon (Pharmaceutical Sciences, UC Irvine), we are developing targeted, chimeric nanoparticles for gene therapy using the ADT downstream effector genes, above, that simultaneous express the pro-apoptotic cytokine and knock-down cFLIP.
(#5): Furthering this research is a series of innovative applications of small animal pre-clinical imaging. This has allowed investigation of genetically engineered mouse models, as well as autochthonous and xenografted prostate cancer tumor models. We previously developed a high resolution MRI technique with spectroscopic enhancement for increased resolution and anatomic differentiation (with Orhan Nalcioglu, UC Irvine). More recently, we have optimized high frequency ultrasound imaging for rapid volumetric reconstruction and image guided-injection (with Ron Woods, Univ. Rochester). We are currently working to develop targeted molecular imaging agents for photoacoustic imaging of prostate cancer (with Hans Schmitthenner and Naval Rao, RIT, and Vikram Dogra, Univ. Rochester).
Dogra, V, Chinni, B, Singh, S. Schmitthenner, H, Rao, N, Krolewski, JJ, Nastiuk, KL (2016) Photoacoustic imaging with an acoustic lens detects prostate cancer cells labeled with prostate specific membrane antigen-targeting near infrared dye conjugates. J Biomed Opt 21(6), 066019 http://www.ncbi.nlm.nih.gov/pubmed/27367255.
Singh, S, Pan, C, Yeh, C-R, Wood, R, Yeh, S, Sha, K, Krolewski, JJ, and Nastiuk, KL (2015) Quantitative volumetric imaging of normal, neoplastic and hyperplastic mouse prostate using ultrasound. BMC Urology (2015) 15:97. http://www.ncbi.nlm.nih.gov/pubmed/26391476.
Nastiuk, KL, Krolewski, JJ. (2016) Opportunities and challenges in combination cancer gene therapy. Advanced Drug Delivery Reviews 2016 Mar 1;98:35-40. http://www.ncbi.nlm.nih.gov/pubmed/26724249.
Wu, G, Huang, S, Nastiuk, KL, Li, Gu, J, Wu, M, Zhang, Q, Lin, H, Wu, D. (2015). Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer. The Prostate, 75:777-82. http://www.ncbi.nlm.nih.gov/pubmed/25731771.
Sha, K, Nastiuk, KL, Chang, C, and Krolewski, JJ. (2015) TNF blockade suppresses the enzalutamide induced metastatic phenotype of prostate cancer and microenvironment cell co-cultures. Oncotarget 2015 Sep 22;6(28):25726-40. http://www.ncbi.nlm.nih.gov/pubmed/26327448