Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone.

Engineered microscale hydrogels for drug delivery, cell therapy, and sequencing.

Engineered microscale hydrogels have emerged as promising therapeutic approaches for the treatment of various diseases. These microgels find wide application in the biomedical field because of the ease of injectability, controlled release of therapeutics, flexible means of synthesis, associated tunability, and can be engineered as stimuli-responsive. While bulk hydrogels of several length-scale dimensions have been used for over two decades in drug delivery applications, their use as microscale carriers of drug and cell-based therapies is relatively new. Herein, we critically summarize the fundamentals of hydrogels based on their equilibrium and dynamics of their molecular structure, as well as solute diffusion as it relates to drug delivery. In addition, examples of common microgel synthesis techniques are provided. The ability to tune microscale hydrogels to obtain controlled release of therapeutics is discussed, along with microgel considerations for cell encapsulation as it relates to the development of cell-based therapies. We conclude with an outlook on the use of microgels for cell sequencing, and the convergence of the use of microscale hydrogels for drug delivery, cell therapy, and cell sequencing based systems.