Abstract
The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in particular, is a plasma cell malignancy strictly associated with MYC deregulation, suggesting that therapeutic strategies against it would be beneficial in treating this disease. However, targeting MYC was - and, somehow, still is - challenging due to its unique properties: lack of defined three-dimensional structure, nuclear localization and absence of a targetable enzymatic pocket. Despite these difficulties, however, many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition. Different molecules have been tested, in fact, in the context of MM. In this review, we summarize the current status of the different compounds, including the results of their clinical testing, and propose to continue with the efforts to identify, repurpose, redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.
Highlights
Multiple myelomaMultiple myeloma (MM), a rare disease, is the second most common blood cancer[1], with over 54,000 estimated new cases in Europe[2] and 176,000 worldwide in 2020[3]
In support of this hypothesis, a recent Phase I study for the combination of panobinostat with several myeloma standard therapies demonstrated the ability of the combination to resensitize relapsed/refractory MM patients, in the context of resistance to IMiDs, PIs or other novel targets[77]
We try to compile the most recent publications describing the use of different MYC inhibitors in hematologic malignancies, especially MM
Summary
Multiple myeloma (MM), a rare disease, is the second most common blood cancer[1], with over 54,000 estimated new cases in Europe[2] and 176,000 worldwide in 2020[3]. Stein et al.[121] evaluated the safety and efficacy of pinometostat in another Phase I study of acute mixed lineage leukemia and observed that, despite reaching exposure to anticancer levels, it could only display minor clinical activity, suggesting that its combination with standard of care agents would be a better choice In support of this hypothesis, a recent Phase I study for the combination of panobinostat with several myeloma standard therapies demonstrated the ability of the combination to resensitize relapsed/refractory MM patients, in the context of resistance to IMiDs, PIs or other novel targets[77]. The dual PI3K/HDAC inhibitor CUDC-907 showed potent suppressive activity against MYC-dependent tumors[85,127], and, in a Phase II study assessing its safety (NCT02674750), 14% of evaluable relapsed/refractory lymphoma patients achieved an objective clinical response[85] In this same context, Paíno et al.[86] presented a pan-PIM kinase inhibitor, PIM447, able to block all three PIM kinases and act as an mTOR inhibitor, which exhibited cytotoxic effects on myeloma cells and a boneprotective effect in a disseminated mouse model of human myeloma. Caracciolo et al.[148] elegantly explained how MYC contributes to genomic instability, switching the preferential DNA repair mechanisms to the error-prone PARP-mediated alternative non-homologous end joining, and pointed to its potential use as a predictive biomarker for PARPi treatments in MM[148]
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