Arrhythmic Complications Associated with Cancer Therapies.

Over the last several decades, advancements in cancer screening and treatment have significantly improved cancer mortality and overall quality of life. Unfortunately, non-cancer-related side effects, including cardiovascular toxicities can impact the continued delivery of these treatments. Arrhythmias are an increasingly recognized class of cardiotoxicity that can occur as a direct consequence of the treatment or secondary to another type of toxicity such as heart failure, myocarditis, or ischemia. Atrial arrhythmias, particularly atrial fibrillation (AF) are most commonly encountered, however, ventricular- and bradyarrhythmias can also occur, albeit at lower rates. Treatment strategies tailored to patients with cancer are essential to allow for the safe delivery of the cancer treatment without affecting short- or long-term oncologic or cardiovascular outcomes.

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.

Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma.

Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779-90. ©2017 AACR.

Antileukemic properties of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that act on the mevalonate pathway and inhibit synthesis of cholesterol, geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). In preclinical studies, these agents have been shown to inhibit proliferation, trigger apoptosis and promote cell differentiation of leukemia. Proposed mechanisms include cholesterol deprivation and inhibition of isoprenylation of important signaling molecules. Case reports and early clinical studies suggest a therapeutic potential for statins in acute myeloid leukemia (AML). In the other leukemias there are limited clinical data, but in vitro studies provide a strong rationale for future studies involving statins. The effects of statins on the immune system may lend these agents to a role in allogeneic stem cell transplant. While many of the studies are early, statins have the future potential to be integrated into conventional chemotherapy regimens with limited side effects.

Microwave spectra of the deuterium isotopologues of cis-hexatriene and a semiexperimental equilibrium structure.

Microwave transitions and ground state rotational constants are reported for five newly synthesized deuterium isotopologues of cis-1,3,5-hexatriene (cHTE). These rotational constants along with those of the parent and the three (13)C species are used with vibration-rotation constants calculated from an MP2/cc-pVTZ model to derive an equilibrium structure. That structure is improved by the mixed estimation method. In this method, internal coordinates from good-quality quantum chemical calculations (with appropriate uncertainties) are fit simultaneously with moments of inertia of the full set of isotopologues. The new structure of cHTE is confirmed to be planar and is stabilized by an interaction between the hydrogen atoms H2 and H5, which form a bond and participate in a six-membered ring. cHTE shows larger structural effects of π-electron delocalization than does butadiene with the effects being magnified in the center of the molecule. Thus, strong structural evidence now exists for an increase in π-electron delocalization as the polyene chain lengthens.