Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.

BACKGROUND: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. METHODS: We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s). RESULTS: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition. CONCLUSIONS: Our findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX , defining molecular alterations in IDH -mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX knockout glioma models in the presence and absence of the IDH1 R 132 H mutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo . However, the presence of IDH1 R 132 H dampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1 R132H inhibition. IDH1 R132H co-expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1 R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.

Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.

Inactivating mutations in ATRX characterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo . Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer. One Sentence Summary: Our study demonstrates that SIRT2 inhibition promotes senescence in ATRX-deficient glioma model systems through global epigenomic remodeling, impacting key downstream transcriptional profiles.

The epigenetic dysfunction underlying malignant glioma pathogenesis.

Comprehensive molecular profiling has dramatically transformed the diagnostic neuropathology of brain tumors. Diffuse gliomas, the most common and deadly brain tumor variants, are now classified by highly recurrent biomarkers instead of histomorphological characteristics. Several of the key molecular alterations driving glioma classification involve epigenetic dysregulation at a fundamental level, implicating fields of biology not previously thought to play major roles glioma pathogenesis. This article will review the major epigenetic alterations underlying malignant gliomas, their likely mechanisms of action, and potential strategies for their therapeutic targeting.

Clinical and dosimetric evaluation of recurrent breast cancer patients treated with hyperthermia and radiation.

Background: Treatment for locally recurrent breast cancer poses a significant challenge because the benefits in local control must be weighed against the increased risk of side effects of the treatment. Frequently, patients have been heavily pre-treated with radiation and several types of chemotherapy. Moreover, they often present with large volumes of bulky disease, further complicating management. Hyperthermia can be used to improve the efficacy of radiation, particularly in the setting of recurrent disease. Methods: We reviewed our clinical and dosimetric experience of breast cancer patients who received hyperthermia and radiation for recurrent breast cancer from 2011 to 2017. Thirty-six patients were treated with hyperthermia and radiation. Median follow-up was 11 months. Thirty patients (83.3%) received prior radiotherapy. The most commonly used radiation fraction scheme was 32 Gy in 8 fractions. The median radiation dose at the time of recurrence was 35.5 Gy (range 20-64 Gy). Mild temperature hyperthermia was delivered two times per week. Results: The median repeat radiation volume was 574 cc (range 11-3620 cc). Electrons, conventional photons, and IMRT radiation techniques were used. IMRT was used for large and complex treatment volumes and showed acceptable doses to organs at risk. The overall response rate was 61.1%. Complete response was observed in 17 patients (47.2%), partial response in 5 patients (13.9%), stable disease in 11 patients (30.6%), and progressive disease in 3 patients (8.3%). Twenty-six patients experienced acute grade 1 and 2 toxicities, primarily pain and erythema; and 26 experienced long-term grade 1 and 2 toxicities, mainly hyperpigmentation and lymphedema. Three patients developed new ulcerations that healed with conservative management. One patient developed pulmonary fibrosis resulting in mild dyspnea on exertion. Conclusion: Hyperthermia and radiation provide good local control with a favorable side effect profile. Thermoradiotherapy may be offered to patients with recurrent breast cancer, including those with extensive volumes of disease.

Biofilms and beyond: expanding echinocandin utility.

Echinocandins have been in use for over 15 years, starting with the first approval in 2001. Current trends, such as increasing resistance to fluconazole and shifts toward non-albicans spp. of Candida, suggest a growing role for echinocandins, as reflected by recent (2016) updates to guidelines that recommend echinocandins as first-line treatment for candidaemia. The efficacy, tolerability, and safety of echinocandins and their target site of action (1,3-ß-d-glucan synthesis) have prompted research into potential new uses, such as for treatment of biofilm infections, MDR Candida auris and dermatophytes. Moreover, new mycobiome discoveries linking inflammatory bowel disease (IBD; for instance Crohn's disease) to fungi have led to preliminary but encouraging data regarding echinocandin therapy and treatment of IBD. In this article, we will review the available evidence and potential utility of echinocandins and 1,3-ß-d-glucan synthesis inhibition in these areas of emerging interest.