Musculoskeletal events associated with the management of endocrine-responsive breast cancer

Musculoskeletal symptoms have been reported in patients treated with third generation aromatase inhibitors (AIs) and with blockers of hypothalamic–pituitary gonadal axis. AIs act by suppressing postmenopausal estrogen biosynthesis through inhibition of the enzyme aromatase, which is responsible for the conversion of androgens to estrogens in many tissues. Maximal estrogen and/or androgen deprivation is beneficial for cancer growth suppression but could be associated with side effects such as accelerated bone loss and osteoporotic fractures which are extensively reported. Musculoskeletal events, another group of adverse events, have been studied to a lesser extent and are usually commonly reported as arthralgia and myalgia. Furthermore, the pathogenesis and anatomical findings of musculoskeletal symptoms have not been adequately elucidated. In this communication, we review recent information related to musculoskeletal symptoms in breast cancer and speculate on possible explanations for musculoskeletal pain related to hormone deprivation. We outline treatment options for control of arthralgia and myalgia due to hormonal therapy. More knowledge about the etiology and management of musculoskeletal adverse effects breast cancer during endocrine therapy is needed because discontinuation of the treatment due to intolerant symptomatology may result in disruption of the treatment schedule

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM