Emerging therapies targeting the ubiquitin proteasome system in cancer

Abstract

The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

Disease-proportional proteasomal degradation of missense dystrophins

“…Alternatively, pharmacologic inhibition of the ubiquitination ligases specific to skeletal muscle or even dystrophin could be more effective therapeutics with fewer side effects. Indeed, the cancer biology field, which has been using proteasome inhibitors for treatment of multiple myeloma (51), has recently begun to target the cancer-specific E3 ligases responsible for ubiquitination of p53 and c-Myc (52). Although identifying the specific E1-E2-E3 cascade for a given substrate is a difficult task (53,54), our stable missense dystrophin cell lines provide a high-throughput screening platform ( Fig.…”

The ubiquitin-like modifier FAT10 in cancer development

“…However, since UBA6 is a bispecific E1 activating enzyme for FAT10 and ubiquitin, this option must be handled with care to minimize putative side effects. Targeting the ubiquitin-proteasome system in cancer is already clinically effective at least via inhibition of the proteasome while inhibitors or activators of E3 ligases or DUBs with a better perspective for selectivity are being developed (Weathington and Mallampalli, 2014). The search for FAT10-specific E3 ligases as well as for FAT10-specific deconjugating enzymes is still ongoing and the identification of these enzymes will enable investigations on whether targeting of these enzymes will provide new options for the development of future pharmaceuticals against cancer.…”

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

“…Both E2 and E3 proteins exist as large families: more than 35 E2s and 600 E3s have been identified so far, resulting in highly complex combinations of E2s with different E3 proteins defining the substrate specificity. Defects in this ubiquitin-dependent protein degradation have been implicated in the etiology of neurodegenerative diseases, metabolic disorders, cancer (Weathington and Mallampalli, 2014), developmental deficiency, immunity pathologies (Sakamoto, 2002;Pagano and Benmaamar, 2003) and schizophrenia.…”