Androgen receptor (AR) signaling is a target in prostate cancer therapy and can be treated with non-steroidal anti-androgens (NSAA) including enzalutamide, and apalutamide for patients with advanced disease. Metastatic castration-resistant prostate cancer (mCPRC) develop resistance becomes refractory to therapy limiting patient overall survival. Darolutamide is a novel next-generation androgen receptor-signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC). Imipridone ONC201/TIC10 is first-in-class small molecule imipridone that activates the integrated stress response (ISR), upregulates TNF-related apoptosis-inducing ligand (TRAIL) and has activity against CRPC alone or in combination with enzalutamide in preclinical models. We hypothesized that combination of imipridones with androgen receptor signaling blockers such as darolutamide may synergize in anti-tumor efficacy against mCRPC cells. mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with imipridones ONC201, ONC206, apalutamide, darolutamide, or enzalutamide as single agents or in combinations. Combinations of ONC201 or ONC206 and androgen receptor signaling blockers demonstrated synergistic effects in mCRPC cells. Combinations of ONC201 and darolutamide or enzalutamide reduced PSA levels in LNCaP cells and induced of ATF4 in both LNCaP and 22RV1 cell lines. Darolutamide synergized with ONC201 regardless of AR status or castration sensitivity in vitro. Flow cytometric analysis showed increased intra-tumoral NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. ONC201 and darolutamide demonstrated anti-tumor effects in vivo in the 22RV1 CRPC model. Our results prompt further translational and clinical studies with imipridones ONC201 or ONC206 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer.
AJCR Copyright © 2024.

Immune checkpoint therapy for prostate cancer (PCa) has failed in clinical trials; however, the precise underlying mechanisms involved remain elusive. PCa, a classic "immune-cold” tumor, is characterized by an immunosuppressive tumor microenvironment. Within this milieu, macrophages, the predominant immune cell population, have a propensity to infiltrate the hypoxic zones of tumors. In a previous study, we showed that Yin Yang 1 (YY1) is highly expressed in macrophages in PCa tissues. Here, through multiplexed imaging mass cytometry (IMC) of a PCa tissue microarray, we further demonstrate that YY1 + macrophages aggregate in hypoxic areas of tumors and that hypoxia promotes the phase separation of YY1 in the nucleus by increasing YY1 tyrosine phosphorylation in macrophages. Furthermore, YY1 binds to NUSAP1 and promotes the SUMOylation of HIF-1α, which promotes phase separation and stabilization of the HIF-1α protein. We also demonstrated that either treatment with a small molecule inhibitor (tenapanor) to decrease the YY1–NUSAP1–HIF-1α interaction or myeloid-specific YY1 gene knockout impairs subcutaneous PCa tumor formation. Furthermore, we present a first-generation tetrahedral DNA nanostructure (TDN) based on the proteolysis targeting chimera (PROTAC) technique, named YY1-DcTAC, which targets and degrades YY1 in tumor-associated macrophages. In a PCa mouse model, YY1-DcTAC exhibited prolonged drug efficacy, robust macrophage-specific responsiveness, potent antitumor effects, and increased CD8 + T cell tumor infiltration. In summary, our findings underscore the pivotal role of YY1 within the hypoxia/HIF-1α pathway in tumor-associated macrophages and affirm the therapeutic potential of targeting YY1 for treating PCa.

Androgen receptor (AR) signaling plays a primary role in prostate cancer progression. Non-steroidal anti- androgens (NSAA) including enzalutamide, and apalutamide have been used to treat patients with advanced disease. However, patients with metastatic castration-resistant prostate cancer (mCPRC) develop resistance, resulting in limited overall survival benefit. Darolutamide is a novel next-generation androgen receptor- signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC). Imipridone ONC201/TIC10 is first-in-class small molecule that activates the integrated stress response (ISR) and upregulates TNF-related apoptosis-inducing ligand (TRAIL). Our study investigates ISR and AR signaling in anti-tumor efficacy with ONC201 and enzalutamide or darolutamide against mCRPC cells. mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with ONC201, darolutamide, and enzalutamide as single agents or in combinations. Combinations of ONC201 and darolutamide or enzalutamide demonstrated synergistic effects in mCRPC cells. Combinations of ONC201 and darolutamide or enzalutamide reduced PSA levels in LNCaP cells and induced of ATF4 in both LNCaP and 22RV1 cell lines. Darolutamide synergized with ONC201 regardless of AR status or castration sensitivity in vitro. Flow cytometric analysis showed increased intra-tumoral NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. ONC201 and darolutamide demonstrated anti-tumor effects in vivo in the 22RV1 CRPC model. Our results prompt further translational and clinical studies with imipridones ONC201 or ONC201 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer.

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients.
Copyright © 2024 Lima, Ferrari, Pradella, Carvalho, Rivero, Quintiliano, Souza, Brunetti, Marques, Santos, Farias, Oliveira and Santos.