The molecular chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a critical modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogenrelated receptors (ERR␣ and ERR␥). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor ␥ coactivator (PGC-1␣) stimulates the expression of PDK4. Here we report that ERR␣ and ERR␥ stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1␣ to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERR␣ and ERR␥. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1␣. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1␣ from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression. The pyruvate dehydrogenase complex (PDC)3 catalyzes the irreversible oxidative decarboxylation of pyruvate to acetylCoA (1). Long term changes in PDC activity entail changes in PDC phosphorylation, whereas short term inhibition is mediated by the reaction products acetyl-CoA and NADH (1, 2). The pyruvate dehydrogenase kinases (PDK) decrease PDC activity via phosphorylation, whereas the pyruvate dehydrogenase phosphatases activate the PDC activity by dephosphorylation (3, 4). There are three serine phosphorylation sites on the ␣-subunit of pyruvate dehydrogenase (E1) that are targeted by PDKs, and phosphorylation of the ␣-subunit of the E1 element completely inhibits the activity of PDC (4). There is increased phosphorylation of PDC in the heart and skeletal muscle in starvation and diabetes, allowing pyruvate to be conserved while fatty acid oxidation is increased (5-7). In diabetes the decrease in PDC activity is due primarily to the increased PDK activity (5).Four PDK isoenzymes (PDK1, -2, -3, -4) have been identified and characterized in mammalian tissues (1). The expression patterns of the PDK isoforms are tissue-specific (8). The PDK2 and PDK4 isoforms are highly expressed in liver, heart, and skeletal muscle (9). PDK2 and PDK4 gene expression is elevated with diabetes and starvation, with PDK4 being the most highly regulated isoform (2, 4). Insulin administration and refeeding inhibit the induction of PDK4 gene expression in the skeletal muscles and heart of diabetic and fasted animals, respectively (7, 10). In Morris hepatoma cells, long chain fatty acids, glucocorticoids, and peroxisome...

SUMMARY Resistance to chemotherapy represents a major obstacle for long-term remission and effective strategies to overcome drug resistance would have significant clinical impact. We report here that after paclitaxel/carboplatin treatment, ovarian carcinomas have upregulated spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.

The introduction of immune checkpoint inhibitors has revolutionized treatment of multiple cancers and has bolstered interest in this treatment approach. So far, emerging clinical data show limited clinical efficacy of these agents in ovarian cancer with objective response rates of 10–15% with some durable responses. In this review, we present emerging clinical data of completed trials of immune checkpoint inhibitors and review ongoing studies. In addition we examine the current knowledge of the tumor microenvironment of ovarian cancers with a focus on the significance of PD-L1 expression and tumor-infiltrating lymphocytes on predicting response to immune checkpoint blockade. We evaluate approaches to improve treatment outcomes through the use of predictive biomarkers and patient selection. Finally, we review management considerations including immune related adverse events and response criteria.

The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.

Estrogen-related receptor alpha (ERRα) is an orphan member of the nuclear receptor family of transcription factors. In addition to its function as a metabolic regulator, ERRα has been implicated in the growth and progression of several malignancies. In the setting of breast cancer, not only is ERRα a putative negative prognostic factor, but we have recently found that knockdown of its expression retards tumor growth in a xenograft model of this disease. The specific aspects of ERRα function that are responsible for its actions in breast cancer, however, remain unclear. Using the coactivator PGC-1α as a protein ligand to regulate ERRα activity, we analyzed the effects of this receptor on gene expression in the ERα-positive MCF-7 cell line. This analysis led to the identification of a large number of potential ERRα target genes, many of which were subsequently validated in other breast cancer cell lines. Importantly, we demonstrate in this study that activation of ERRα in several different breast cancer cell lines leads to a significant increase in VEGF mRNA expression, an activity that translates into an increase in VEGF protein secretion. The induction of VEGF results from the interaction of ERRα with specific ERR-responsive elements within the VEGF promoter. These findings suggest that ERRα-dependent induction of VEGF may contribute to the overall negative phenotype observed in tumors in which ERRα is expressed and provide validation for its use as a therapeutic target in cancer.

Aromatase inhibitors are widely used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. While the agents are associated with slightly improved survival outcomes when compared to tamoxifen alone, bone and musculoskeletal side effects are substantial and often lead to discontinuation of therapy. Ideally, the symptoms should be prevented or adequately treated. This review will focus on bone and musculoskeletal side effects of aromatase inhibitors, including osteoporosis, fractures, and arthralgias. Recent advances have been made in identifying potential mechanisms underlying these effects. Adequate management of symptoms may enhance patient adherence to therapy, thereby improving breast cancer-related outcomes.

2538 Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x109. Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.