This project is designed to develop a new approach to cancer treatment through the study of growth, survival, and metastasis regulatory signal transduction events that identify molecular targets for anticancer drug development. Our work is divided into basic research and translational research through the Preclinical Development Research Core, a translational drug development facility that we have established. Our work is currently focused on (1) the molecular mechanisms of hematopoietic cell regulation by beta-catenin and the identification of beta-catenin as a target in hematologic malignancies (2) development and implementation of novel pharmacodynamic assays, including assays for antiangiogenic therapy, histone deacetylase inhibitors, and Hsp90 inhibitors. (1) While studying the anticancer action of lovastatin, a drug that was brought to Phase I clinical trial at the NCI as a direct translation of our research, we found that a critical determinant of sensitivity to the proapoptotic activity of lovastatin was the integrity of beta-catenin protein. This led us to examine the role of beta-catenin in apoptosis. We used hematologic malignancies as our model and found that beta-catenin plays an unexpectedly vital role in these cells. Our data demonstrated that beta-catenin regulates leukemia cell survival, proliferation, and adhesive properties. These data were the first to identify beta-catenin as a target for anticancer drug development in hematologic malignancies (Chung et al. Blood 100:982-990, 2002). To pursue our hypothesis that beta-catenin signaling is deregulated in hematologic malignancies, and that each malignancy is associated with a characteristic mechanism of deregulation, in collaboration with Tomohiro Kajiguchi of the Urologic Oncology Branch we have studied beta-catenin in two forms of leukemia, mast cell leukemia and FLT3 AML. We found that beta-catenin is a substrate for the tyrosine kinase c-kit, which is deregulated in mast cell leukemia. This study demonstrated that c-kit upregulates Wnt signaling in human mast cell leukemia, and that beta-catenin is a novel target for the treatment of mastocytosis and mast cell leukemia (Leuk. Res. 32:761-770, 2007). FLT3 activation via mutation or overexpression plays a key role in myeloid leukemogenesis. We demonstrated that FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and target gene expression in FLT3-positive AML cell lines and primary leukemia cells (Leukemia 21:2476-2484, 2007). We have established a collaboration with Drs. John Janik and John Morris of the Metabolism Branch, NCI to investigate the mechanism of beta-catenin signaling in adult T-cell leukemia patients on Metabolism Branch protocols. Acute ATL has a very poor prognosis, despite the fact that it has been known for decades that the etiologic agent of ATL is the HTLV-1 virus, and that HTLV-1-encoded Tax plays a key role in HTLV-1-induced malignant transformation. Although Tax plays a critical role in the initial transformation process, Tax expression is frequently undetectable in acute ATL. Thus, targeting of Tax would not appear to present a viable strategy in the most advanced and rapidly progressive form of ATL. We have discovered that (1) primary acute ATL cells express beta-catenin, (2) beta-catenin expression occurs in the absence of the Tax oncoprotein, (3) beta-catenin protein localizes to the cell nucleus in Tax-negative ATL cells, and (4) transcriptional analysis of primary ATL patient samples by our collaborator John Brady using Affymetrix arrays demonstrates high levels of expression of the beta-catenin transcriptional partner TCF4 and the beta-catenin/TCF4 target gene survivin. Our collaborative project was published in Blood in 2009 (Blood 113:4016-4020, 2009). Recently survivin has been shown to be the most negative prognostic factor in ATL. We have succeeded in transfecting primary ATL cells, and have used this technique to transfect wild-type beta-catenin and a panel of constructs that block nuclear beta-catenin signaling as well as control siRNA and beta-catenin siRNA. These experiments demonstrated that in primary ATL cells survivin and the potent antiapoptotic gene Bfl-1 are under the transcriptional control of beta-catenin. Analysis of the pathways leading to beta-catenin overexpression and activation in primary ATL cells demonstrated a complex pattern of deregulatory events that stabilize beta-catenin and upregulate beta-catenin nuclear localization including Akt phosphorylation and CD45 silencing. Recently it has been demonstrated that NSAIDs such as celecoxib significantly down-regulate nuclear beta-catenin levels and block nuclear beta-catenin signaling. We screened a panel of NSAIDs against primary ATL cells and HTLV-1-infected cell lines and found that celecoxib had the most-favorable ratio of potency to toxicity, inhibited beta-catenin nuclear signaling and induced cell death. Together these data identify nuclear beta-catenin as a novel therapeutic target in advanced, Tax-independent ATL. We are implementing our studies of beta-catenin signaling in ATL as co-investigators on one open ATL trial and on two protocols currently being written for inhibitors of the beta-catenin target gene survivin. (2) The Preclinical Development Research Core has been working with intramural, extramural and industry investigators on a range of phase I and phase II clinical trials. I am an associate investigator on 18 clinical trials. For each of these trials we work with the PI to develop novel pharmacodynamic endpoints, including analysis of circulating endothelial progenitor cells, mature endothelial cells, and a wide range of rare immune subsets. This year we have analyzed over 120 patients for these parameters. Our basic research on signal transduction pathways that can inhibit the growth of hormone-refractory prostate cancer cells led us to the identification of histone deacetylase as a critical target in this neoplasm. We have developed a novel pharmacodynamic assay for assessment of HDAC inhibitor activity in vivo. The NCI has applied for a patent on our work, which is uniquely capable of analyzing HDAC inhibitor activity in as little blood as in a finger-stick, and can look at combination therapy pharmacodynamic responses by examining 10 parameters simultaneously. We have implemented this technology in several published clinical trials (Gojo et al. Blood 109:2781-2790, 2007 and Kummar et al., Clin. Cancer Res. 13:5411-5417, 2007). We have established a collaboration with Drs. Jay Bradner and Stuart Schreiber of the Broad Institute to use our technology to develop new HDAC inhibitors, and a collaboration with Dr. Michael Palladino of Nereus Pharmaceuticals to study HDAC inhibitors in combination with the novel Nereus proteasome inhibitor NPI-0052. This year we have a CRADA agreement with Syndax Pharmaceuticals to support HDAC inhibitor research in the lab. We have analyzed recent progress in HDAC as a molecular target in an invited review in Current Opinion in Oncology. As an outgrowth of our lovastatin phase I trial, together with Fred Mushinski and other intramural and extramural investigators, we identified a new antimetastasis gene, MxA. We then identified a relevant mechanism of activity and designed and implemented a high-throughput drug discovery screen for MxA induction. This project was published in 2009 (J. Biol. Chem. 284:15206-15214, 2009), and the NIH has filed for patent protection for the hits we have identified in our primary and secondary screens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICSC006743-16
Application #
7970167
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2009
Total Cost
$737,847
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Balasubramaniam, Sanjeeve; Redon, Christophe E; Peer, Cody J et al. (2018) Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. Anticancer Drugs 29:457-465
Neckers, Len; Blagg, Brian; Haystead, Timothy et al. (2018) Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development. Cell Stress Chaperones 23:467-482
Yuno, Akira; Lee, Min-Jung; Lee, Sunmin et al. (2018) Clinical Evaluation and Biomarker Profiling of Hsp90 Inhibitors. Methods Mol Biol 1709:423-441
Tang, Sai-Wen; Thomas, Anish; Murai, Junko et al. (2018) Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors. Clin Cancer Res 24:1944-1953
Christenson, Jessica L; Trepel, Jane B; Ali, Haythem Y et al. (2018) Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer. Horm Cancer 9:82-94
Thomas, Anish; Redon, Christophe E; Sciuto, Linda et al. (2018) Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol 36:1594-1602
Berzofsky, Jay A; Terabe, Masaki; Trepel, Jane B et al. (2018) Cancer vaccine strategies: translation from mice to human clinical trials. Cancer Immunol Immunother 67:1863-1869
Kijima, Toshiki; Prince, Thomas L; Tigue, Megan L et al. (2018) HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation. Sci Rep 8:6976
Lee, Jung-Min; Nair, Jayakumar; Zimmer, Alexandra et al. (2018) Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study. Lancet Oncol 19:207-215
Moses, Michael A; Kim, Yeong Sang; Rivera-Marquez, Genesis M et al. (2018) Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer. Cancer Res 78:4022-4035

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