TARGETTING ACHILLES HEELS IN MYELOMA

Kenneth C. Anderson

Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA

Abstract

Multiple myeloma (MM) is a model for using in vitro and in vivo models of the tumor in its bone marrow (BM) microenvironment to target tumor cells, tumor-host interactions, and the BM milieu in novel therapeutics. To date proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), histone deacetylase (HDAC) inhibitors, and monoclonal antibodies (MoAbs) have translated from the bench to the bedside and FDA approval, extending the survival of patients 3 to 4 fold. Further progress is advancing in novel strategies to target protein homeostasis, novel immune therapies, and treatments targeting genomic anomalies. PIs trigger apoptosis in MM cells, modulate adhesion molecule expression on tumor and BM cells, and regulate cytokine secretion in the BM milieu. The also promote osteoclast apoptosis and promote new bone formation. Ubiquitin proteasome receptor inhibitor and ubiquitylating agent inhibitors target the ubiquitin proteasome pathway upstream of the proteasome and can overcome PI resistance. HDAC6 selective inhibitors block aggresomal protein degradation and synergize with PIs. IMiDs bind and activate cereblon ubiquitin 3 ligase activity, with degradation of IZF1/3 in MM cells. Excitingly, prototype degronimids bind to ubiquitin ligase complexes including cereblon, VHL, or MDM2; as well as bind and selectively target substrates for degradation.

Multiple immune therapies are promising in MM. IMiDs activate T, NK, and NK-T cells and target regulatory T cells, at least in part related to degradation of alios/ikaros and thereby stimulating IL-2 transcription and secretion. IMiDS also bind a novel substrate p-53 related protein kinase (PRPK) and mediate cereblon-independent MM cytotoxicity. MoAbs targeting SLAMF7 and CD38 have moved rapidly from the bench to the bedside, with enhanced activity in combination with IMiDs or PIs. B cell maturation antigen (BCMA) is a selective plasma cell antigen currently targeted with immunotoxin and bispecific antibodies, as well as by targeting its ligands BAFF and APRIL to downregulate growth and survival signaling. Checkpoint inhibitors are expressed on MM cells, as well as immune effector cells and accessory cells (myeloid derived suppressor cells and plasmacytoid dendritic cells), which promote MM cell growth and drug resistance. Importantly, checkpoint inhibitors can overcome the effect of these accessory cells and trigger autologous cytotoxicity of patient MM cells. Moreover, IMiDs can enhance checkpoint inhibitor-induced cytotoxicity. Vaccination of patients with smoldering MM with peptide-based vaccines can trigger autologous anti-MM immunity, which is enhanced by IMiDs and shifted to a central memory phenotype by HDAC 6 inhibitor. Finally, BCMA CART cell therapies are achieving complete responses even in MM refractory to all other therapies. Combinations of these immune approaches offer the most promise.

Finally, MM is very genetically heterogeneous, with ongoing DNA damage. RAS mutations are most common, with transient responses to MEK/ERK inhibitor therapy. Patients with t (11:14) MM and overexpression of BCL-2 can respond to venetoclax. Ongoing efforts are presently delineating mechanisms underlying the extensive constitutive and ongoing DNA damage, including Homologous recombination, APEX nuclease activity, Pan nuclease activity, and APOBEC activity, in order to develop selective inhibitors. Other strategies target the consequences of the genetic heterogeneity, such as targeting STK4 activity to restore p73-mediated apoptotic signaling in MM with decreased YAP1 copy number. Additionally, MM with MYC amplification has high levels of replicative stress and reactive oxygen species (ROS); ATR inhibitors to block replicative stress response in combination with agents to increase ROS triggers synergistic MM cytotoxicity. Finally, targeting fast-forward loops or regulatory loops in MM, such as KDM3A-KLF2-IRF4 axis, offers great promise to target both the tumor and its microenvironment.