Dr. Eugene Kandel joined the staff of Roswell Park Comprehensive Cancer Center (Roswell Park) in 2007, as Assistant Member at the Department of Cell Stress Biology.
Dr. Kandel earned an MS degree with honors from the Moscow State University (Moscow, Russia) in 1992 and his PhD from the University of Illinois (Chicago, IL) in 1998. Previously, Dr. Kandel has worked as a Postdoctoral Fellow and a Research Assistant Professor at the University of Illinois at Chicago, and as a Project Scientist and a Staff Scientist at the Cleveland Clinic Foundation in Cleveland, OH. Dr. Kandel also is an Assistant Professor at the State University of New York at Buffalo and the director of Graduate Studies for the Cell Stress and Biophysical Oncology PhD Track (CSBO).
Dr. Kandel's research interest is in the study of signaling pathways in normal and diseased cells. He has authored or co-authored more than 40 journal publications and book chapters. Dr. Kandel has received “Golden Standard” distinction from the US Department of Defense, “Era of Hope” breast cancer research program (1996), “Innovator” Award from the Cleveland Clinic Foundation (2004), and Howard Temin Award from the National Cancer Institute (2005).
The mechanisms of resistance and sensitivity to ischemia-like conditions in normal and malignant cells.
Simultaneous shortage of nutrients and oxygen, as happens under ischemia, is an extremely stressful condition for a mammalian cell. Organ ischemia frequently leads to organ failure. For example, ischemia is a common cause of acute kidney injury, which, in turn, is a major contributor to human mortality and morbidity worldwide. Our recent work utilized an unbiased genetic screen to identify multiple genes whose inhibition can improve survival of kidney cells in ischemia-like conditions. The findings offer insights into the strategies to prevent injury to the kidney and, possibly, other organs and tissues. We are interested in understanding the molecular mechanisms that determine the roles of the discovered genes in stress response, as well as in expanding the list of possible therapeutic targets beyond the candidates from our initial screen. Importantly, the lack of nutrients and oxygen is also an important factor in cancer progression. We are exploring how the various tumor adaptations to such a microenvironmental stress affect the future clinical trajectory of the disease.
The mechanisms of resistance and sensitivity to the inhibitors of MAP kinase cascade in human cancer.
Abnormal activation of the MAP kinase cascade is a common oncogenic event in human malignancies. One of the frequently mutated components of this pathway is a protein kinase encoded by BRAF gene. The recognition of hyperactive BRAF as the driver of many malignancies led to the emergence of therapeutic strategies to suppress its activity. This had a big impact on the management of metastatic melanoma, where BRAF mutations are common and inhibition of BRAF significantly improves survival. Unfortunately, some tumors are unresponsive to these drugs, while others develop resistance in the course of the treatment. We have identified several additional proteins that determine the response of cells to BRAF inhibitors. We are exploring these proteins as the predictors of clinical outcomes and as additional therapeutic targets to enhance the efficacy of anti-BRAF therapy.
Protein kinase Akt as a determinant of stress-resistance and -sensitivity in normal and malignant cells.
Protein kinase B, also known as Akt, is а key regulator of many processes in normal cells. In cancer, Akt gets hyper-activated. This phenomenon contributes to enhanced survival, growth, genetic instability and many other characteristic traits of oncogenically transformed cells. Overall, constitutive activation of Akt is one of the most common biochemical abnormalities in human malignancies. Often, it is a sign of a more aggressive or advanced disease. Importantly, in order to act as an oncogene, Akt depends on cooperation with certain other cellular factors. Furthermore, constitutive activation of Akt is a very stressful event for a normal cell and requires additional adaptations to be tolerated. We are exploring specific dependencies and vulnerabilities associated with oncogenic activation of Akt. Our long-term goal is to use this information to selectively suppress or eliminate cancer cells while sparing normal tissues.
MicroRNAs and their regulation in normal and cancer cells.
MicroRNAs control translation and stability of mRNA and are important determinants of the repertoire and abundance of proteins in mammalian cells, both in health and in disease. We studied and reported the regulation of miRNA expression by NF-kB and FOXO1 transcription factors. More recently, we reported the evidence that a previously unrecognized miRNA can be generated from the transcript of DROSHA gene, and this miRNA may attenuate DROSHA production. Our findings suggest the existence of a negative feedback loop whereby DROSHA keeps its activity in check by producing out of its own mRNA an inhibitor of its translation. Considering that DROSHA is a key enzyme in the classical miRNA biogenesis pathway, it is likely that the proposed mechanism has a global effect on the process of RNA interference in human cells.
Somanath PR, Kandel ES, Hay N, Byzova TV. Akt1 signaling regulates integrin activation, matrix recognition, and fibronectin assembly. The Journal of biological chemistry 2007; 282:22964-76.
Dasgupta M, Agarwal MK, Varley P, Lu T, Stark GR, Kandel ES. Transposon-based mutagenesis identifies short RIP1 as an activator of NFkappaB. Cell Cycle 2008; 7:2249-56.
Dong B, Silverman RH, Kandel ES. A natural human retrovirus efficiently complements vectors based on murine leukemia virus. PLoS ONE 2008; 3:e3144.
Gartel AL, Kandel ES. miRNAs: Little known mediators of oncogenesis. Seminars in cancer biology 2008; 18:103-10.
Kandel ES. NFkappaB inhibition and more: a side-by-side comparison of the inhibitors of IKK and proteasome. Cell Cycle 2009; 8:1819-20.
Lu T, Jackson MW, Singhi AD, Kandel ES, Yang M, Zhang Y, Gudkov AV, Stark GR. Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proceedings of the National Academy of Sciences of the United States of America 2009; 106:16339-44.
Somanath PR, Vijai J, Kichina JV, Byzova T, Kandel ES. The role of PAK-1 in activation of MAP kinase cascade and oncogenic transformation by Akt. Oncogene 2009; 28:2365-9.
Kandel E. Tumor-associated oncogenes go on (phage) display. Oncotarget 2010; 1:84-5.
Kichina JV, Goc A, Al-Husein B, Somanath PR, Kandel ES. PAK1 as a therapeutic target. Expert Opin Ther Targets 2010; 14:703-25.
Morrison C, Miecznikowski J, Darcy KM, Dolce JM, Kandel E, Erwin DO, Liu S, Shepherd L, Cohn D, McMeekin DS, Block AW, Nowak NJ, Maxwell L. A GOG 210 aCGH study of gain at 1q23 in endometrioid endometrial cancer in the context of racial disparity and outcome. Genes Chromosomes Cancer 2010; 49:791-802.
Singhal R, Deng X, Chenchik AA, Kandel ES. Long-distance effects of insertional mutagenesis. PLoS ONE 2011; 6:e15832.
Yang J, Battacharya P, Singhal R, Kandel ES. Xenotropic murine leukemia virus-related virus (XMRV) in prostate cancer cells likely represents a laboratory artifact. Oncotarget 2011; 2:358-62. (in the news)
Das Gupta J, Luk KC, Tang N, Gaughan C, Klein EA, Kandel ES, Hackett J, Jr., Silverman RH. Absence of XMRV and closely related viruses in primary prostate cancer tissues used to derive the XMRV-infected cell line 22Rv1. PLoS ONE 2012; 7:e36072.
Kandel ES. Mutations in circulating mitochondrial DNA: Cassandra of oral cancer? Oncotarget 2012; 3:664-5.
Singhal R, Kandel ES. The response to PAK1 inhibitor IPA3 distinguishes between cancer cells with mutations in BRAF and Ras oncogenes. Oncotarget 2012; 3:700-8.
Singhal R, Bard JE, Nowak NJ, Buck MJ, Kandel ES. FOXO1 regulates expression of a microRNA cluster on X chromosome. Aging (Albany NY) 2013; 5:347-56. (in the news)
Zynda E, Jackson MW, Bhattacharya P, Kandel ES. ETV1 positively regulates transcription of tumor suppressor ARF. Cancer biology & therapy 2013; 14:1167-73.
Zucker SN, Fink EE, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner PN, Wawrzyniak JA, Foley C, Leonova KI, Grimm MJ, Moparthy K, Ionov Y, Wang J, Liu S, Sexton S, Kandel ES, Bakin AV, Zhang Y, Kaminski N, Segal BH, Nikiforov MA. Nrf2 amplifies oxidative stress via induction of Klf9. Molecular cell 2014; 53:916-28.
Zynda ER, Matveev V, Makhanov M, Chenchik A, Kandel ES. Protein kinase A type II-alpha regulatory subunit regulates the response of prostate cancer cells to taxane treatment. Cell Cycle 2014; 13:3292-301.
Mechtler P, Singhal R, Kichina JV, Bard JE, Buck MJ, Kandel ES. MicroRNA analysis suggests an additional level of feedback regulation in the NF-kappaB signaling cascade. Oncotarget 2015; 6:17097-106.
Zynda ER, Schott B, Gruener S, Wernher E, Nguyen GD, Ebeling M, Kandel ES. An RNA interference screen identifies new avenues for nephroprotection. Cell Death Differ 2015. (in the news)
Babagana M, Johnson S, Slabodkin H, Bshara W, Morrison C, Kandel ES. P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells. Molecular carcinogenesis. 2017;56(5):1515-25.
Bianchi-Smiraglia A, Rana MS, Foley CE, Paul LM, Lipchick BC, Moparthy S, Moparthy K, Fink EE, Bagati A, Hurley E, Affronti HC, Bakin AV, Kandel ES, Smiraglia DJ, Feltri ML, Sousa R, Nikiforov MA. Internally ratiometric fluorescent sensors for evaluation of intracellular GTP levels and distribution. Nature methods. 2017;14(10):1003-9.(in the news)
Mechtler P, Johnson S, Slabodkin H, Cohanim AB, Brodsky L, Kandel ES. The evidence for a microRNA product of human DROSHA gene. RNA Biol. 2017;14(11):1508-13.
Bagati A, Bianchi-Smiraglia A, Moparthy S, Kolesnikova K, Fink EE, Kolesnikova M, Roll MV, Jowdy P, Wolff DW, Polechetti A, Yun DH, Lipchick BC, Paul LM, Wrazen B, Moparthy K, Mudambi S, Morozevich GE, Georgieva SG, Wang J, Shafirstein G, Liu S, Kandel ES, Berman AE, Box NF, Paragh G, Nikiforov MA. FOXQ1 controls the induced differentiation of melanocytic cells. Cell Death Differ. 2018;25(6):1040-9.
Bianchi-Smiraglia A, Bagati A, Fink EE, Affronti HC, Lipchick BC, Moparthy S, Long MD, Rosario SR, Lightman SM, Moparthy K, Wolff DW, Yun DH, Han Z, Polechetti A, Roll MV, Gitlin, II, Leonova KI, Rowsam AM, Kandel ES, Gudkov AV, Bergsagel PL, Lee KP, Smiraglia DJ, Nikiforov MA. Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma. The Journal of clinical investigation. 2018;128(10):4682-96.
Fink EE, Moparthy S, Bagati A, Bianchi-Smiraglia A, Lipchick BC, Wolff DW, Roll MV, Wang J, Liu S, Bakin AV, Kandel ES, Lee AH, Nikiforov MA. XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response. Cell reports. 2018;25(1):212-23.