James T. Dalton
University of Michigan
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Featured researches published by James T. Dalton.
Current Oncology Reports | 2016
Jeffrey Crawford; Carla M. Prado; Mary Ann Johnston; Richard J. Gralla; Ryan P. Taylor; Michael L. Hancock; James T. Dalton
Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm’s effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (nu2009=u2009150) or enobosarm 3xa0mg (nu2009=u2009150) orally once daily for 147xa0days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10xa0% improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484, NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1.
Cancers | 2016
Ramesh Narayanan; James T. Dalton
Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer.
Cancer Research | 2018
Kinsie E. Arnst; Yuxi Wang; Dong Jin Hwang; Yi Xue; Terry Costello; David Hamilton; Qiang Chen; Jinliang Yang; Frank Park; James T. Dalton; Duane D. Miller; Wei Li
Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small-molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nmol/L. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation, and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.Significance: These findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation antitubulin drug for cancer therapy. Cancer Res; 78(1); 265-77. ©2017 AACR.
Molecular and Cellular Endocrinology | 2017
Ramesh Narayanan; Christopher C. Coss; James T. Dalton
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.
Investigational New Drugs | 2016
Christopher C. Coss; Amanda Jones; James T. Dalton
SummaryGTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23xa0% and the area under the curve (AUC∞) by 43xa0%. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC∞) were increased by co-administration of the UGT inhibitor (50 and 112xa0%, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.
British Journal of Clinical Pharmacology | 2017
James T. Dalton
Numerous selective androgen receptor modulators (SARMs) with differing chemical structures and nearly ideal pharmacological and pharmacokinetic properties have been developed that are well tolerated and selectively increase lean body mass in humans. However, definitive demonstration of the linkage between lean body mass and physical function in a relevant, large patient population has remained elusive for a SARM. The clinical endpoints serving as their basis of approval have shifted with time and clinical indication and are likely to continue to do so as the field matures with additional safety and efficacy data pertaining to the relationship between lean body mass and physical function, regulatory decisions with SARMs and other agents, and yet unexplored clinical indications.
Archive | 2015
Ramesh Narayanan; James T. Dalton
Sex hormones, androgens and estrogens, are critical not only for the physiology and development of secondary sexual organs, but also for neuronal development, cognition, bone and muscle development and maintenance, adipose tissue physiology, lipid and carbohydrate homeostasis. The phenotypes of transgenic animals in which the synthesis of androgens and estrogens or their ubiquitously expressed receptors (androgen receptor (AR, NR3C4) and estrogen receptor (ER, NRC3A1/2) has been abolished provide unequivocal evidence of their essential roles. Likewise, imbalances due to hypo- or hyperactivity of the AR and ER are associated with a variety of human diseases, including osteoporosis, sarcopenia and breast, ovarian and prostate cancers, to name a few, making steroidogenic enzymes and steroid receptors attractive therapeutic targets. Despite their endogenous roles, testosterone and estradiol are often not the first choice of treatment due to their steroidal pharmacophore and lack of tissue selectivity. Advances in the understanding of AR and ER biology and synthetic chemistry efforts to identify small molecule modulators of ER and AR that elicit favorable effects on target tissues without effects on off-target tissues led to the advent of selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs). This chapter discusses the pharmaceutical development, pharmacological characteristics, therapeutic functions, and molecular mechanisms for tissue selectivity of SERMs and SARMs.
Archive | 1998
Duane D. Miller; Leonid I. Kirkovsky; James T. Dalton; Arnab Mukherjee
Archive | 2002
Duane D. Miller; Leonid I. Kirkovsky; James T. Dalton; Arnab Mukherjee
Archive | 2003
James T. Dalton; Duane D. Miller; Mitchell S. Steiner; Karen A. Veverka