01-02-2017 | Image
Agents approved or under development for MM target key biological pathways that drive MM cell proliferation and survival. (a) Approved agents include proteasome inhibitors (proteasome inhibitors target the proteasome, which plays a role in the normal degradation and clearance of intracellular misfolded and unfolded proteins. This inhibition leads to protein accumulation and eventual apoptosis), IMiDs (the CRBN E3 ubiquitin ligase complex marks protein with ubiquitin for degradation. The binding of an IMiD to this complex leads to the degradation of two key proteins, Aiolos (IKZF3) and Ikaros (IKZF1), ultimately killing MM cells) and DAC inhibitors (DAC inhibitors target proteins in the nucleus and cytoplasm. HDACs deacetylate target nuclear proteins implicated in gene regulation, including histones and tumor suppressor genes. DACs, which target cytoplasmic proteins, namely HDAC6, play a role in protein metabolism through the formation of aggresomes that transport proteins to be degraded by lysosomes. DAC inhibitors target HDAC6, blocking aggresome formation and subsequent protein degradation, thus leading to protein accumulation and apoptosis). (b) Agents under development: CAR-T cells (CAR-T cells are engineered to recognize target tumor cells and induce cell death), mAbs (mAbs utilize antibody-dependent cellular toxicity (targeting of cell surface proteins such as CS1 and CD38) to induce apoptosis; antibody drug conjugates (e.g., indatuximab ravtansine) target cells expressing the recognized receptor, leading to receptor internalization and release of cytotoxic chemotherapy and cell death), oncolytic virotherapy (viruses stimulate MM apoptosis through many complex mechanisms, including direct virus-mediated cytotoxicity and indirect enhancement of immune responses) and KSP inhibitors (KSPs facilitate early mitosis by separating microtubules. KSP inhibitors block this process, thereby serving as antimitotic agents in rapidly dividing MM cells). Adapted with permission from Novartis Pharmaceuticals Corporation. A=antigen; ADCC=antibody-dependent cell-mediated cytotoxicity; CAR=chimeric antigen receptor; CRBN=cereblon; HDAC=histone deacetylase; HSP90=heat-shock protein 90; i=inhibitor; IMiD=immunomodulatory drug; KSP=kinesin spindle protein; mAb=monoclonal antibody; MM=multiple myeloma; MOA=mechanism of action; NK=natural killer; TCR=T-cell receptor.