Dr. Nastiuk is a translational prostate cancer researcher. He studied neurobiology (Oberlin College, B.S. with high honors) and molecular neuroendocrinology (The Rockefeller University, Ph.D.). He completed fellowship training in protein biochemistry (Rockefeller) and prostate cancer genetics (Columbia P&S) prior to joining the Roswell Park Comprehensive Cancer Center faculty in 2015.
The laboratory’s objective is to improve therapy for genitourinary disease while equipping trainees with the knowledge and intellectual rigor to do carry this research forward. Specifically, we are investigating androgen deprivation therapy (ADT) signaling pathways in prostate cancer, and ADT side effects seen in patients.
We are examining the mechanism controlling a co-morbidity of ADT, sarcopenia. The lab developed the first mouse model that recapitulates the clinical syndrome of ADT-induced “obese frailty”, including the phenotypic muscle loss and fat gain, as well as the functional loss of strength. Exploiting this model, we found that muscle regulating TGFß-superfamily cytokines (the myokines) are ADT-regulated. Functionally, pan-myokine blockade abrogates the ADT-induced muscle loss and the functional deficits, indicating that one or more of these myokines may be targets for therapeutic intervention. In mouse models of prostate cancer, we have examined the utility of these myokines as therapeutic targets to ameliorate ADT-induced sarcopenia. Recently, we found that these myokines may regulate tumor volume. To validate and translate these results, we have a clinical study testing whether these myokines are biomarkers of obese frailty and if a nutrition and exercise intervention modulates these frailty biomarkers, and ameliorates the obese frailty.
We developed and employ a variety of innovative imaging modalities to further this research, including ultrasound and MRI. This has allowed investigation of genetically engineered mouse models, as well as autochthonous and xenografted prostate cancer tumor models. We are currently working to develop targeted molecular imaging agents for both MR and photoacoustic imaging of prostate cancer (with Hans Schmitthenner, RIT).
We continue to study the mechanism of ADT-induced cytokine directed apoptosis, and resistance to ADT. In late stage cancers, we find a phenotypic shift, where cFLIP is high and the cytokines TNF and TGFß 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 that induces a pro-migratory (metastatic) phenotype and immunosuppression via selection of stem-like ADT-resistant cells (with John Krolewski). Translating these insights, we have a study open testing whether ADT induces cytokines and MDSCs in patients.
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