Multiple myeloma (MM) is a cancer that effects tens of thousand of people in the United States alone. Similar to other cancers, there is no cure for MM requiring patients to receive treatment for the rest of their lives which can be both tiresome and expensive. Currently, proteasome inhibitors are used as a first-line treatment to combat this disease. The proteasome plays a key role in degradation of proteins that the cell no longer needs; proteasome inhibitors take advantage of the malignant cells’ characteristic overproduction and reliance on the proteasome by blocking this degradation pathway, resulting in cell death. However, as with other chemotherapies, patients often develop resistance to proteasome inhibitors. A key contributor to this resistance mechanism is the overexpression of histone deacetylase-6 (HDAC6) and upregulation of the aggresome pathway as a means of protein removal. When proteins are not degraded by the proteasome, they form aggregates that are transported with the help of HDAC6 to aggresomes for storage and later removal by the lysosome through autophagy. Though involvement in the aggresome pathway is limited to HDAC6 and not other members of the HDAC family, the four FDA approved inhibitors are all pan-inhibitors and consequently, cause adverse reactions in patients such as cardiotoxicity; selective inhibition of the HDAC6 isozyme may result in reduced cytotoxic effects while maintaining therapeutic efficacy. Likewise, HDAC6 knockdown mice have been seen to grow and develop normally, making it an ideal therapeutic target. This project focuses on implementation of a polypharmacologic strategy of tethering the pharmacophores for both a proteasome inhibitor and an HDAC6 selective inhibitor to develop one drug molecule for treatment of proteasome inhibitor resistant MM. There are many advantages to polypharmacology compared to combination treatments, most notably a synergistic therapeutic effect due to simultaneous delivery of both pharmacophores to the tissues of need. Additionally, these strategies limit drug-drug interactions and are predicted to increase patient compliance. For these reasons, we hypothesize that our dual proteasome/HDAC6 inhibitors will deliver greater therapeutic efficacy than the combination treatment of the corresponding proteasome and HDAC6 inhibitor in resistant patients.

Paradigm shift in treating multiple myeloma: Incapacitation of proteasome and aggresome pathways with polypharmacological agents

ACS Fall 2021

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