The Experimental Therapeutics (ET) Program contributes to more effective treatment of neoplastic diseases through a spectrum of basic and translational research.
The Aims are to 1) define cellular pathways involved in survival and proliferation in order to improve understanding of response to established treatments and identify new therapeutic targets; 2) elucidate biological, biochemical, and pharmacological aspects of the action of novel anti-cancer agents and identify biochemical properties that contribute to tumor cell resistance; 3) evaluate potential genetic and genomic contributions to efficacy and toxicity of anticancer treatments; and 4) conduct early phase clinical trials, based on research in this Program and others, with hand off to disease- specific clinical Programs for phase II testing after initial assessment of safety, pharmacokinetics, pharmacogenetics, and biological effects in the clinical setting. The Program is jointly led by Zhenkun Lou, PhD, Scott Kaufmann, MD, PhD, and Alex Adjei, MD, PhD, who have expertise in DNA repair, cellular signaling, cellular pharmacology, and the conduct of early phase clinical trials. The ET Program has 46 members from 13 departments and divisions, with total direct funding of $12.6M ($8M peer-reviewed, with 88% from NCI). Since the last competitive renewal, the Program has generated 777 publications (129 published in journals with impact factor ?10, 42 with impact factor ?20) with 21% and 50% of these publications reflecting intra- and interprogrammatic collaborations, respectively. Notable accomplishments include 1) the demonstration that protein kinase C? transforms lung adenocarcinoma through the hedgehog pathway and ovarian cancer through the Hippo/YAP pathway; 2) preclinical work showing that CDK4/6 inhibitors alter the epithelial-to-mesenchymal transition and metastasis of breast cancer cells, leading to a CDK4/6 inhibitor/aromatase inhibitor phase II trial in the Women's Cancer Program; 3) demonstration that ZNF423 regulates BRCA1 expression, and allelic variation in this pathway affects the chemopreventive efficacy of tamoxifen; and 4) completion of phase I trials of endoxifen and PARP inhibitors as well as initiation of early phase trials of ATR inhibitors. The Program makes extensive use of Shared Resources, especially the Microscopy and Cell Analysis, Proteomics, Pathology Research, Genome Analysis, Pharmacology, and Pharmacy facilities as well as the Clinical Research Office. The Program adds value to the Mayo Clinic Cancer Center (MCCC) by i) bringing together investigators with a shared emphasis on the preclinical and early clinical study of small molecule therapeutics, alone or in conjunction with immuno-oncology agents, and ii) serving as a resource for early phase clinical trials for MCCC Programs. Future goals of the program include 1) further preclinical work on deubiquitinases and their inhibitors as modulators of DNA repair pathways, 2) expansion of our emphasis on metabolic targets in cancer, and 3) translation of ongoing work on DNA repair, metabolic targets, and chemotherapy/immunotherapy combinations into novel clinical trials.
|DuBois, Steven G; Mosse, Yael P; Fox, Elizabeth et al. (2018) Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 24:6142-6149|
|Farber, Benjamin A; Lalazar, Gadi; Simon, Elana P et al. (2018) Non coding RNA analysis in fibrolamellar hepatocellular carcinoma. Oncotarget 9:10211-10227|
|Lu, Yingchang; Beeghly-Fadiel, Alicia; Wu, Lang et al. (2018) A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Res 78:5419-5430|
|Dasari, Surendra; Newsom, Sean A; Ehrlicher, Sarah E et al. (2018) Remodeling of skeletal muscle mitochondrial proteome with high-fat diet involves greater changes to ?-oxidation than electron transfer proteins in mice. Am J Physiol Endocrinol Metab 315:E425-E434|
|Nowsheen, Somaira; Aziz, Khaled; Aziz, Asef et al. (2018) L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage. Nat Cell Biol 20:455-464|
|Razidlo, Gina L; Burton, Kevin M; McNiven, Mark A (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293:11143-11153|
|Wu, Dongyan; Yang, Haitao; Winham, Stacey J et al. (2018) Mediation analysis of alcohol consumption, DNA methylation, and epithelial ovarian cancer. J Hum Genet 63:339-348|
|Leon-Ferre, Roberto A; Polley, Mei-Yin; Liu, Heshan et al. (2018) Impact of histopathology, tumor-infiltrating lymphocytes, and adjuvant chemotherapy on prognosis of triple-negative breast cancer. Breast Cancer Res Treat 167:89-99|
|Jahanseir, Khadijeh; Xing, Deyin; Greipp, Patricia T et al. (2018) PDGFB Rearrangements in Dermatofibrosarcoma Protuberans of the Vulva: A Study of 11 Cases Including Myxoid and Fibrosarcomatous Variants. Int J Gynecol Pathol 37:537-546|
|Painter, Jodie N; O'Mara, Tracy A; Morris, Andrew P et al. (2018) Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses. Cancer Med 7:1978-1987|
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