Therapeutics
Abstract
Glioblastoma (GBM) is one of the most lethal adult brain tumors with limited effective therapeutic options. Immunotherapy targeting B7-H3 (CD276) has shown promising efficacy in the treatment of gliomas. However, the response to this treatment varies among glioma patients due to individual differences. It’s necessary to find an effective strategy to improve the efficacy of targeting B7-H3 immunotherapy for non-responders. In this study, we demonstrated a strong correlation between aurora kinase A (AURKA) and CD276 expression in glioma tissue samples. Additionally, both AURKA knockdown and overexpression resulted in parallel changes in B7-H3 expression levels in glioma cells. Mechanistically, AURKA elevated B7-H3 expression by promoting epidermal growth factor receptor (EGFR) phosphorylation, which was validated in glioma cell lines and primary GBM cells. What’s more, the combination of AURKA inhibitor (alisertib) and anti-B7-H3 antibody markedly reduced tumor size and promoted CD8+ T cell infiltration and activation in mouse orthotopic syngeneic glioma models. To our knowledge, this study is the first to demonstrate AURKA-mediated B7-H3 upregulation in glioma cells; moreover, it proposes a promising therapeutic strategy combining the AURKA inhibitor alisertib with B7-H3-specific blocking mAbs.
Authors
Jinqiu Liu, Yuxuan Deng, Zhuonan Pu, Yazhou Miao, Zhaonian Hao, Herui Wang, Shaodong Zhang, Hanjie Liu, Jiejun Wang, Yifan Lv, Boyi Hu, Hong Wan, Zhengping Zhuang, Tai Sun, Shuyu Hao, Nan Ji, Jie Feng
Abstract
Tacrolimus-induced chronic nephrotoxicity (TICN) hinders its long-term use, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate NFAT. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in various homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain- and loss-of-function rescued the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation both by phosphorylation sites mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-seq data. Growth arrest and DNA damage-inducible 45α (GADD45α) was identified as a transcriptional target of TFEB via chromatin immunoprecipitation and dual luciferase reporter assays. And then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro, and vise versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of TFEB-GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention of TICN.
Authors
Ping Gao, Xinwei Cheng, Maochang Liu, Hui Peng, Guodong Li, Tianze Shang, Jianqiao Wang, Qianyan Gao, Chenglong Zhu, Zhenpeng Qiu, Chengliang Zhang
Abstract
The proof-of-principle of the therapeutic potential of heat shock protein 47 (HSP47) for diseases characterized by defects in the collagen I synthesis is here proved in osteogenesis imperfecta (OI), a prototype of collagen disorders. Most of the OI mutations delay collagen I chains folding, increasing their exposure to post translational modifications that affect collagen secretion and impact extracellular matrix fibrils assembly. As model, we used primary fibroblasts from OI individuals with defect in the collagen prolyl-3-hydroxylation complex, since are characterized by the synthesis of homogeneously overmodified collagen molecules. We demonstrated that the exogenous recombinant HSP47 (rHSP47) is uptaken by the cells and localizes at the ER exit sites and ER Golgi intermediate compartment. rHSP47 treatment increased collagen secretion, reduced collagen post translational modifications and intracellular collagen retention and ameliorated the general ER proteostasis, leading to improved cellular homeostasis and vitality. These positive changes were also mirrored by an increased collagen content in the OI matrix. A mutation dependent effect was found in fibroblasts from three probands with collagen I mutations, for which rHSP47 was effective only in cells with the most N-term defect. A beneficial effect on bone mineralization was proved in vivo in the zebrafish p3h1-/- OI model.
Authors
Roberta Besio, Nadia Garibaldi, Alessandra Sala, Francesca Tonelli, Carla Aresi, Elisa Maffioli, Claudio Casali, Camilla Torriani, Marco Biggiogera, Simona Villani, Antonio Rossi, Gabriella Tedeschi, Antonella Forlino
Abstract
Pediatric high-grade gliomas (pHGGs) are the most aggressive brain tumors in children, necessitating innovative therapies to improve outcomes. Unlike adult gliomas, recent research reveals that childhood gliomas have distinct biological features, requiring specific treatment strategies. Here, we focused on deciphering unique genetic dependencies specific to childhood gliomas. Using a pooled CRISPR/Cas9 knockout screening approach on 65 pediatric and 10 adult high-grade glioma (HGG) cell lines, myeloid cell leukemia 1 (MCL1) emerged as a key antiapoptotic gene essential in pediatric but not adult gliomas. We demonstrated that MCL1 is targetable using current small molecule inhibitors, and its inhibition leads to potent anticancer activity across pediatric HGG cell lines irrespective of genotype. Employing predictive modeling approaches on a large set of childhood cancer cell lines with multiomics data features, we identified a potentially previously unreported cluster of CpG sites in the antiapoptotic BCL-xL/BCL2L1 gene, which predicted MCL1 inhibitor response. We extended these data across multiple pediatric tumor types, showing that BCL2L1 methylation is a broad predictor of MCL1 dependency in vitro and in vivo. Overall, our multidimensional, integrated genomic approach identified MCL1 as a promising therapeutic target in several BCL2L1-methylated pediatric cancers, offering a translational strategy to identify patients most likely to benefit from MCL1 inhibitor therapy.
Authors
Shazia Adjumain, Paul Daniel, Claire Xin Sun, Gabrielle Bradshaw, Nicole J. Chew, Vanessa Tsui, Hanbyeol Lee, Melissa Loi, Nataliya Zhukova, Dilru Habarakada, Abigail Yoel, Vijesh G. Vaghjiani, Shaye Game, Louise E. Ludlow, Naama Neeman, E. Alejandro Sweet-Cordero, David D. Eisenstat, Jason E. Cain, Ron Firestein
Abstract
Chronic wounds have emerged as a tough clinical challenge. An improved understanding of wound healing mechanisms is paramount. Collagen XVII (COL17), a pivotal constituent of hemidesmosomes, holds considerable promise for regulating epidermal cell adhesion to the basement membrane, as well as for epidermal cell motility and self-renewal of epidermal stem cells. However, the precise role of COL17 in wound repair remains elusive, and the upstream regulatory mechanisms involved have not been fully elucidated. In this study, we delineated the temporal and spatial expression patterns of COL17 at the epidermal wound edge. Subsequently, we investigated the indispensable role of COL17 in keratinocyte activation and re-epithelialization during wound healing, demonstrating the restoration of the normal repair process by COL17 overexpression in diabetic wounds. Notably, we identified a key transcriptional signaling pathway for COL17, wherein PKM2 (Pyruvate kinase isozyme M2) promotes phosphorylation of STAT3, leading to its activation and subsequent induction of COL17 expression upon injury. Ultimately, by manipulating this pathway using the PKM2 nuclear translocator SAICAR, we revealed a promising therapeutic strategy for enhancing the healing of chronic wounds.
Authors
Yangdan Liu, Chia-kang Ho, Dongsheng Wen, Jiaming Sun, Yuxin Liu, Qing-Feng Li, Yifan Zhang, Ya Gao
Abstract
The impact of remdesivir on SARS-CoV-2 diversity and evolution in vivo has remained unclear. In this single-center, retrospective cohort study, we assessed SARS-CoV-2 diversification and diversity over time in a cohort of hospitalized patients who did or did not receive remdesivir. Whole genome sequencing was performed on 98 paired specimens collected from 49 patients before and after remdesivir administration. Genetic divergence between paired specimens was not significantly different from what was observed in paired specimens from patients who did not receive the drug. However, when comparing minority variants, several positions showed preferential diversification after remdesivir treatment, several of which were associated with different variants of concern. Most notably, remdesivir administration resulted in strong selection for a nonsynonymous mutation in nsp12, G671S, previously associated with enhanced viral fitness. This same mutation was found enriched in a second cohort of 143 inpatients with specimens collected after remdesivir administration compared to controls. Only one other mutation previously implicated in remdesivir resistance (nsp12:V792I) was found to be preferentially selected for after remdesivir administration. These data suggest that SARS-CoV-2 variants with enhanced replicative fitness may be selected for in the presence of antiviral therapy as an indirect means to overcome this selective pressure.
Authors
Ted Ling-Hu, Lacy M. Simons, Estefany Rios-Guzman, Alexandre M. Carvalho, Maria Francesca R. Agnes, Arghavan Alisoltanidehkordi, Egon A. Ozer, Ramon Lorenzo-Redondo, Judd F. Hultquist
Abstract
The role played by anionic channels in diabetic kidney disease (DKD) is not known. Chloride channel accessory 1 (CLCA1) facilitates the activity of TMEM16A (Anoctamin-1), a Ca2+-dependent Cl– channel. We examined if CLCA1/TMEM16A had a role in DKD. In mice with type 2 diabetes, renal cortical CLCA1 and TMEM16A content was increased. CLCA1 and TMEM16A content was associated with hydrogen sulfide (H2S) deficiency, mTOR complex 1 (mTORC1) activation, albuminuria, and matrix increase. Administering sodium hydrosulfide (NaHS), a source of H2S, mitigated these changes. In proximal tubular epithelial (MCT) cells, high glucose rapidly increased CLCA1 by recruiting the IL-6/STAT3 axis and augmented TMEM16A expression by stimulating its mRNA translation; these changes were abolished by NaHS. Patch clamp experiments showed that high glucose increased Cl– current in MCT cells that was ameliorated by NaHS and a TMEM16A chemical inhibitor. siRNA against CLCA1 or TMEM16A and TMEM16A inhibitor abolished high glucose–induced mTORC1 activation and matrix protein increase. Tubular expression of TMEM16A correlated with albuminuria in kidney biopsies from people with type 2 diabetes. We report a pathway for DKD in which H2S deficiency results in kidney injury by the recruitment of the CLCA1/TMEM16A/Cl– current system.
Authors
Hak Joo Lee, Yuyang Sun, Falguni Das, Wenjun Ju, Viji Nair, Christopher G. Kevil, Shankara Varadarajan, Guanshi Zhang, Goutam Ghosh Choudhury, Brij B. Singh, Matthias Kretzler, Robert G. Nelson, Kumar Sharma, Balakuntalam S. Kasinath
Abstract
Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR’336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR’336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells’ proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR’336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR’336 promoted the differentiation of IL-33–responsive (ST2+), IL-10–producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR’336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.
Authors
Fernando Alvarez, Nicole V. Acuff, Glenn M. La Muraglia II, Nazila Sabri, Marcos E. Milla, Jill M. Mooney, Matthew F. Mackey, Mark Peakman, Ciriaco A. Piccirillo
Abstract
KRAS mutations are frequent in various human cancers. The development of selective inhibitors targeting KRAS mutations has opened a new era for targeted therapy. However, intrinsic and acquired resistance to these inhibitors remains a major challenge. Here, we found that cancer cells resistant to KRAS G12C inhibitors also display cross-resistance to other targeted therapies, such as inhibitors of RTKs or SHP2. Transcriptomic analyses revealed that the Hippo-YAP/TAZ pathway is activated in intrinsically resistant and acquired-resistance cells. Constitutive activation of YAP/TAZ conferred resistance to KRAS G12C inhibitors, while knockdown of YAP/TAZ or TEADs sensitized resistant cells to these inhibitors. This scenario was also observed in KRAS G12D–mutant cancer cells. Mechanistically, YAP/TAZ protects cells from KRAS inhibitor–induced apoptosis by downregulating the expression of proapoptotic genes such as BMF, BCL2L11, and PUMA, and YAP/TAZ reverses KRAS inhibitor–induced proliferation retardation by activating the SLC7A5/mTORC1 axis. We further demonstrated that dasatinib and MYF-03-176 notably enhance the efficacy of KRAS inhibitors by reducing SRC kinase activity and TEAD activity. Overall, targeting the Hippo-YAP/TAZ pathway has the potential to overcome resistance to KRAS inhibitors.
Authors
Wang Yang, Ming Zhang, Tian-Xing Zhang, Jia-Hui Liu, Man-Wei Hao, Xu Yan, Haicheng Gao, Qun-Ying Lei, Jiuwei Cui, Xin Zhou
Abstract
Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA-seq revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved the lacuno-canalicular network and reduced sclerostin production and the receptor activator of NF-κB/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechanostimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteum-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.
Authors
Nagahiro Ochiai, Yuki Etani, Takaaki Noguchi, Taihei Miura, Takuya Kurihara, Yuji Fukuda, Hidetoshi Hamada, Keisuke Uemura, Kazuma Takashima, Masashi Tamaki, Teruya Ishibashi, Shohei Ito, Satoshi Yamakawa, Takashi Kanamoto, Seiji Okada, Ken Nakata, Kosuke Ebina
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