ß-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer.

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent ß-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific ß-catenin-containing complexes, and the epigenome. On chromatin, ß-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, ß-catenin bound histone methyltransferase EZH2. SF1/ß-catenin and EZH2/ß-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/ß-catenin from chromatin and favored EZH2/ß-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities. SIGNIFICANCE: Oncogenic ß-catenin can use tissue-specific partners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for ß-catenin-driven cancers.

Synergy between inhibitors of two mitotic spindle assembly motors undermines an adaptive response.

Mitosis is the cellular process that ensures accurate segregation of the cell's genetic material into two daughter cells. Mitosis is often deregulated in cancer; thus drugs that target mitosis-specific proteins represent attractive targets for anticancer therapy. Numerous inhibitors have been developed against kinesin-5 Eg5, a kinesin essential for bipolar spindle assembly. Unfortunately, Eg5 inhibitors (K5Is) have been largely ineffective in the clinic, possibly due to the activity of a second kinesin, KIF15, that can suppress the cytotoxic effect of K5Is by driving spindle assembly through an Eg5-independent pathway. We hypothesized that pairing of K5Is with small molecule inhibitors of KIF15 will be more cytotoxic than either inhibitor alone. Here we present the results of a high-throughput screen from which we identified two inhibitors that inhibit the motor activity of KIF15 both in vitro and in cells. These inhibitors selectively inhibit KIF15 over other molecular motors and differentially affect the ability of KIF15 to bind microtubules. Finally, we find that chemical inhibition of KIF15 reduces the ability of cells to acquire resistance to K5Is, highlighting the centrality of KIF15 to K5I resistance and the value of these inhibitors as tools with which to study KIF15 in a physiological context.

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers.

Ovarian cancer ranks fifth in cancer related deaths for women in USA. The high mortality rate associated with ovarian cancer is due to diagnosis at later stages of disease and the high recurrence rate of 60-80%. Recurrent ovarian cancers are more likely to present as multidrug resistance (MDR) leading to unfavorable response from 2nd and 3rd line chemotherapy. Nanoemulsions (NEs) are emerging as an attractive drug delivery system to overcome MDR challenges. NEs can also minimize exposure of therapeutic cargo to normal tissues potentially reducing side effects. In >80% of ovarian cancers, Folate Receptor-α (FR-α) is expressed at 10- to 100-fold higher levels than on non-pathological tissues. Therefore, folate (FA) is being evaluated as an active targeting moiety for FR-α+ ovarian cancer. To improve therapeutic outcome with reduced toxicity, we developed NMI-500, a FA targeted gadolinium (Gd) annotated NE loaded with docetaxel (DTX). NMI-500 has been developed as theranostic agents as Gd will enable physician to acquire real time pharmacodynamics data on NE + DTX accumulation in target lesions. In present study, characterization for key translational metrics of NMI-500 showed size distribution in range of 120 to 150 nm and zeta potential around -45 mV. Active targeting of FA was evaluated against FR-α+ KB cells and results demonstrated significant improvement in cell association which was surface ligand density dependent. We found that NMI-500 was able to inhibit tumor growth in a spontaneous transgenic ovarian cancer model with improved safety profile and this growth inhibition could be longitudinally followed by MRI. These results indicate NMI-500 warrants advancement to clinical trials.