Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Immune cells and their inflammatory mediators modify ß cells and cause checkpoint inhibitor-induced diabetes.

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti-PD-L1. Changes in ß cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel ß cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human ß cells in vitro. Treatment with anti-IFN-γ and anti-TNF-α prevented CPI-DM in anti-PD-L1-treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in ß cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma.

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in MYCN-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of SLC3A2 (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is the cysteine-glutamate antiporter that exports glutamate and imports cystine. Cystine is converted to cysteine intracellularly. Here, we investigated other ways MYCN may increase cysteine levels. By performing metabolomics in a syngeneic NB cell line either expressing MYCN or GFP, we demonstrate that the transsulfuration pathway is activated by MYCN. Furthermore, we demonstrate that MYCN-amplified NB cell lines and tumors have higher levels of cystathionine beta-synthase (CBS), the rate-limiting enzyme in transsulfuration, which leads to higher levels of the thioether cystathionine (R-S-(2-amino-2-carboxyethyl)-l-homocysteine). In addition, MYCN-amplified NB tumors have high levels of methylthioadenosine phosphorylase (MTAP), an enzyme that helps salvage methionine following polyamine metabolism. MYCN directly binds to the promoter of MTAP. We propose that MYCN orchestrates both enhanced cystine uptake and enhanced activity of the transsulfuration pathway to counteract increased reactive oxygen species (ROS) from iron-induced Fenton reactions, ultimately contributing to a ferroptosis vulnerability in MYCN-amplified neuroblastoma.

Type 2 diabetes mellitus and cardiovascular disease: focus on the effect of antihyperglycemic treatments on cardiovascular outcomes.

Introduction: Type 2 diabetes mellitus and cardiovascular disease contribute to significant morbidity, mortality, and health-care resource expenditure. The pathophysiological and clinical associations between diabetes and cardiovascular disease have been the subject of multiple studies, most recently culminating in large trials of several new antiglycemic agents being found to confer additional cardiovascular risk reduction. Understanding the potential cardiovascular benefits of antiglycemic medications offers the unique opportunity to reduce the morbidity and mortality presented by both diseases at once.Areas covered: The literature search was comprised of a Pubmed search querying 'cardiovascular outcomes' and 'diabetes'. This article reviews the pathophysiology of cardiovascular complications in type 2 diabetes and the cardiovascular outcome trials related to newer antiglycemic medications.Expert opinion: The treatment of patients with type 2 diabetes mellitus and cardiovascular disease is rapidly advancing. In particular, the sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular benefit by reducing major adverse cardiovascular events and cardiovascular mortality. Future directions of the treatment of type 2 diabetes and cardiovascular disease will focus on targeting and preventing diabetic cardiomyopathy and further defining the role of SGLT2 inhibitors and of GLP-1 receptor agonists in additional patient populations.

Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors.

Checkpoint inhibitor immunotherapy has significantly advanced treatment of a growing number of advanced malignancies. A consequences of immune system activation that leads to tumor cell destruction by checkpoint inhibitor therapy is the development of immune-related adverse events, some of which can be life threatening. There are limited data on the use of checkpoint inhibitor therapy in patients with preexisting autoimmunity owing to concerns that underlying autoimmune disease may be exacerbated by checkpoint inhibitor treatment. Decisions to treat these patients are made after careful consideration of the risks and benefits of treatment. We describe a patient with active and severe ulcerative colitis with metastatic melanoma who underwent elective colectomy prior to initiation of anti-PD-1 and anti-CTLA-4. The patient had excellent tumor response without flare of his ulcerative colitis suggesting that in select patients with high-risk inflammatory bowel disease, elective colectomy may be an effective treatment option.

Hypothyroidism: Cardiovascular Endpoints of Thyroid Hormone Replacement.

Thyroid dysfunction, either thyrotoxicosis or hypothyroidism, represents an important cardiovascular risk factor. Heart disease is the leading cause of death for men and women in the United States. Cardiovascular disease is multifactorial and many efforts have been made to assess precipitants for optimal guideline-based, primary, and secondary prevention. Thyroid hormone receptors are present in the myocardium and endothelium, and small alterations in its levels could have significant effects in cardiac function. Specifically, overt hypothyroidism is associated with an increased risk for atherosclerotic cardiovascular disease due to metabolic and hemodynamic effects. Several concomitant factors like impaired lipid profile, low-grade chronic inflammatory state, increased oxidative stress and increased insulin resistance enforce this relationship. The last decade has seen a renewed interest on the impact of subclinical hypothyroidism on the cardiovascular system and whether or not it should be treated. The aim of this review is to provide current evidence of the effect of thyroid hormone replacement, either with levothyroxine mono-therapy or in combination with liothyronine, on specific cardiovascular parameters.

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy.

BACKGROUND: Bullous disorders associated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established. OBJECTIVE: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy. METHODS: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018. RESULTS: We identified 9 of 853 patients who developed bullous eruptions (∼1%) that were treated with an-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSIONS: Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents.

Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors.

Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti-PD-1 or anti-PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti-PD-1 or -PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.

Implications of the EMPA-REG Trial for Clinical Care and Research.

EMPA-REG OUTCOME was a multicenter, randomized placebo-controlled trial that examined the effect of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor in addition to standard of care in patients with type 2 diabetes and established cardiovascular (CV) disease. The primary goal was to assess CV safety, as mandated by the US Food and Drug Administration since 2008 for all new glucose-lowering agents. Secondary goals were to examine the effects of empagliflozin on microvascular outcomes and, in particular, kidney disease. This landmark study had several important findings, including striking reductions in the incidence of CV death and heart failure hospitalization and in the progression of renal dysfunction. In this review, we describe the trial's main findings, discuss the possible mechanisms that could explain its results, suggest ways in which clinical care may be influenced, and propose directions for future research.