Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy for which novel treatment options are required. Signal Transducer and Activator of Transcription 3 (STAT3) overexpression in MM appears to be mediated by a variety of factors including interleukin-6 signaling and downregulation of Src homology phosphatase-1 (SHP-1). STAT3 overexpression in MM is associated with an adverse prognosis and may play a role in microenvironment-dependent treatment resistance. In addition to its pro-proliferative role, STAT3 upregulates anti-apoptotic proteins and leads to microRNA dysregulation in MM. Phosphatase of regenerating liver 3 (PRL-3) is an oncogenic phosphatase which is upregulated by STAT3. PRL-3 itself promotes STAT-3 phosphorylation resulting in a positive feedback loop. PRL-3 is overexpressed in a subset of MM patients and may cooperate with STAT3 to promote survival of MM cells. Indirectly targeting STAT3 via JAK (janus associated kinase) inhibition has shown promise in early clinical trials. Specific inhibitors of STAT3 showed in vitro efficacy but have failed in clinical trials while several STAT3 inhibitors derived from herbs have been shown to induce apoptosis of MM cells in vitro. Optimising the pharmacokinetic profiles of novel STAT3 inhibitors and identifying how best to combine these agents with existing anti-myeloma therapy are key questions to be addressed in future clinical trials.
Highlights
Major advances have been made in our understanding of the role of Signal Transducer and Activator of Transcription 3 (STAT3) as well as Janus Associated Kinases (JAK)/Signal transducers and activators of transcription (STAT)
The chances of success with STAT3 inhibition in clinical trials maybe enhanced by better selection of patients who may benefit from STAT3 inhibition
The unfavourable pharmacokinetic profiles of some STAT3 inhibitors evaluated far has accounted for their failure in clinical trials [81]
Summary
Multiple myeloma (MM) is the second most common haematological malignancy in adults worldwide [1]. MM is characterised by the accumulation of malignant plasma cells in the bone marrow and is usually associated with a monoclonal protein. Lytic bone lesions, renal impairment and immune paresis are common clinical findings in MM [2]. Translocations (4;14), (14;16) as well as, 17p13 deletion and 1q21 amplification, are associated with an adverse outcome and the optimal management of this group of patients remains to be established [3,4]. Treatment for MM has evolved significantly over the last two decades and patients have access to effective therapeutic agents with acceptable toxicity profiles [5]. MM remains incurable, with relapse occurring in virtually all patients despite novel agent-based therapy [1].
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