| Popis: |
Cancer is the second leading cause of death worldwide with an estimated 9.6 million deaths in 2018 [4]. Cachexia is characterized by the depletion of skeletal muscle with or without fat loss and can be associated with a variety of tumor types, but is most commonly observed in cancers of the upper gastrointestinal tract, up to 83%, and lung cancers, up to 60% [5]. Decreased lean body weight as a result from cachexia can lead to functional deficits, increased risk for toxicities and lower tolerance to chemotherapies, ultimately decreasing overall survival. With an estimated 30% of all cancer patients being affected by cachexia and no approved therapies, there is a critical unmet need to develop novel and effective targeted therapeutic strategies [6]. Histone deacetylases (HDACs) are known to be overexpressed in a variety of cancers and are an expanding class of anticancer therapeutics that induce growth arrest, differentiation and apoptosis of malignant cells [46, 110]. For this reason, HDAC inhibitors (HDACis) are being clinically developed and preclinically investigated across multiple cancer types and non-oncologic diseases, such as cachexia. However, their promising preclinical activity has yet to be observed in the same magnitude in clinical development, with only a portion of patients responding to therapy. In this study, we explored preclinical applications of a novel histone deacetylase inhibitor, AR-42, in cancer-cachexia and retrospectively analyzed AR-42’s disposition in phase I cancer trials. The variety of biological effects observed from HDACis can be attributed to each compound’s unique chemical structure and molecular profile, leading to the application of HDACis in both malignant and non-malignant diseases. However, like many anticancer agents, HDACis can exhibit a broad toxicity profile and have only shown modest activity in clinic as monotherapy anticancer agents. We evaluated AR-42 alone and in combination with anabolic therapies as a novel combinational strategy in preclinical models of cancer cachexia and identified IL6 signaling through STAT3 as a plausible mechanism for AR-42’s anti-cachectic efficacy in skeletal muscle. As our understanding of the role of epigenetics in disease evolves, the use of epigenetic therapies in combinational regimens is becoming increasingly popular and highlights the need to better understand their molecular targets and pharmacokinetic properties in an effort to individualize treatment regimens and minimize toxic side effects of multidrug approaches. We additionally performed retrospective analyses of AR-42’s clinical data from two phase one cancer trials and identified lean body mass as a potential source of inter-individual variability among patients. Through PopPK analyses we concluded AR-42’s first-in-human dosing regimen was appropriate, however, identified the absorption profile as potential contributor to variability. Together, these results support further evaluation of the novel HDACi to identify biomarkers pertinent to its antitumor and anti-cachectic activity, as well as identifying minimal biologically effective doses for its potential use as a combinational therapy. |
