Oncology
Abstract
Current treatment protocols for most types of cancers require chemotherapeutic agents that are associated with significant side effects, including chemotherapy-induced peripheral neuropathy (CIPN). Currently, there are no effective CIPN prevention strategies, and current treatment approaches remain limited. The enzyme purine nucleoside phosphorylase (PNPase) actively modulates both oxidative injury and cellular damage. Here, we tested the hypothesis that the signs and symptoms of CIPN are due to a chemotherapy-induced dysregulation of the purine metabolome. We assessed the effect of PNPase inhibition on paclitaxel-induced (PAC-induced) CIPN. Female adult Sprague-Dawley rats were treated with PAC and randomized to oral treatment with either the PNPase inhibitor 8-aminoguanine (8-AG) or its vehicle. Some rats were injected with shRNA against PNPase prior to PAC injections. PAC-treated rats exhibited multiple abnormalities: mechanical allodynia and changes in damaging purines, intraepidermal nerve fiber (IENF) density, and signaling cascades involved in mitochondrial disruption and axonal damage. Inhibition of PNPase improved behavioral function (mechanical allodynia), rescued the loss/damage of IENF, and normalized markers for mitochondrial dysfunction and nerve damage. These findings support the hypothesis that inhibition of PNPase prevented (and potentially reversed) CIPN through several mechanisms that included a reduction in neuronal damage and development of mechanical allodynia.
Authors
Lori A. Birder, Amanda Wolf-Johnston, Jonathan Franks, Mara L.G. Sullivan, Simon C. Watkins, Anthony J. Kanai, Vladimir B. Ritov, Edwin K. Jackson
Abstract
Cytotoxic chemotherapy primarily targets rapidly proliferating cancer cells but also depletes normal myeloid cells. The resulting cell loss triggers reactive myelopoiesis, a compensatory process in which hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) regenerate myeloid lineages. We previously showed that the alkylating agent cyclophosphamide (CTX) induces myelopoiesis leading to the expansion of immunosuppressive monocytes in mice. However, the molecular features and clinical relevance of these cells remain poorly understood. Here, we report the emergence of immunosuppressive monocytes in the peripheral blood of lymphoma patients receiving CTX-containing chemotherapy. To gain mechanistic insight into CTX-induced myelopoiesis, we performed single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on BM monocytes from CTX-treated mice. These analyses revealed a heterogeneous monocyte population and demonstrated that CTX skews myelopoiesis toward the generation of neutrophil-like monocytes (NeuMo). Moreover, CTX-induced NeuMo cells, enriched within the CXCR4⁺CX3CR1⁻ monocyte subset, exhibited potent T-cell suppressive activity. Using the NeuMo gene signature, reanalysis of public scRNA-seq datasets identified a transcriptionally similar monocyte subset in chemotherapy-treated cancer patients. Collectively, our findings suggest that the expansion of NeuMo-like cells following chemotherapy represents a conserved immunoregulatory feedback mechanism with potential impact on tumor response to chemoimmunotherapy.
Authors
Huidong Shi, Zhi-Chun Ding, Ogacheko D. Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C. Hedrick, Locke J. Bryan, Gang Zhou
Abstract
Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a new strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.
Authors
Young-Mi Kim, Prathibha Mohan, Urmila Sehrawat, Evan Seffar, Rafaela Muniz De Queiroz, Kalyani Chadalavada, Nikita Persaud, Tomoyo Okada, Anirudh Kulkarni, Jianan Lin, Nathalie Lailler, Shaleigh Smith, Bhumika Jadeja, Nicholas D. Socci, Zhengqing Ouyang, Hans-Guido Wendel, Samuel Singer
Abstract
Hypoxia critically restricts the effectiveness of immunotherapy in triple-negative breast cancer (TNBC). Comprehensive bioinformatics analyses demonstrated that highly hypoxic TNBC tumors exhibited elevated T cell exhaustion, increased immune checkpoint molecule expression, and diminished responsiveness to immune checkpoint blockade (ICB). Consequently, strategies aimed at alleviating tumor hypoxia may effectively augment ICB therapy. Although ultrasound-targeted microbubble cavitation (UTMC) has been shown to reduce tumor hypoxia, the precise molecular mechanisms remain unclear. Here, we provided evidence that UTMC activated endothelial nitric oxide synthase (eNOS) through G protein–coupled signaling, resembling pathways induced by fluid shear stress. UTMC-induced eNOS activation was largely Ca²⁺-dependent and resulted in increased nitric oxide production. Enhanced nitric oxide generation was associated with improved tumor perfusion and reduced hypoxia. Combining UTMC with anti–PD-L1 therapy markedly improved the tumor immune microenvironment, characterized by increased CD8+ T cell infiltration, reduced T cell exhaustion, diminished regulatory T cell infiltration, increased macrophage polarization from an M2 to M1 phenotype, and elevated production of pro-inflammatory cytokines. Collectively, our findings identified UTMC as a promising adjunctive therapeutic approach to mitigate hypoxia and enhance the efficacy of anti–PD-L1 immunotherapy in TNBC. These results support further translational evaluation of UTMC-based combination strategies in hypoxic TNBC.
Authors
Zhiyu Zhao, Li Ba, Siwei Li, Jianxin Wang, Yuzhou Luo, Sihan Wang, Yan Jin, Changjun Wu
Abstract
Pancreatic ductal adenocarcinoma (PDAC) shows profound resistance to immunotherapy due to its immunosuppressive tumor microenvironment. Here, we studied the relationship between T cell infiltration and innate immune signaling in PDAC, identifying Toll-like receptor 2 (TLR2) as a key regulator of T cell exclusion. TLR2 expression correlated with T cell infiltration in both human and mouse PDAC tumors. Using genetic knockout models and adoptive T cell transfer experiments, we found that TLR2 expression in both T cells and non-T cells contributes to T cell exclusion in PDAC. Notably, successful infiltration of adoptively transferred tumor-specific T cells required TLR2 deletion in both the transferred cells and the recipient host. The therapeutic implications of these findings are demonstrated through both genetic deletion and pharmacological inhibition of TLR2 using AAV-mediated and antibody-based approaches in murine models, resulting in decreased tumor growth and extended survival. Collectively, these findings identify TLR2 as a key modulator of T cell trafficking and immune suppression within the PDAC microenvironment, suggesting its potential as a therapeutic target for improving treatment outcomes.
Authors
Jacqueline Plesset, Meredith L. Stone, John C. McVey, Heather Coho, Kelly Markowitz, Kayjana Coho, Jesse Lee, Anna S. Thickens, Devora Delman, Gregory L. Beatty
Abstract
VIC-1911 (formerly TAS-119) is a next-generation, ATP-competitive Aurora kinase A (AURKA) inhibitor with a favorable biosafety profile. However, it has not been evaluated in prostate cancer (PC), wherein AURKA is highly expressed in advanced stages and represents a critical therapeutic target. Here, we demonstrate that VIC-1911 potently inhibits AURKA activity with high selectivity over AURKB/C across diverse PC cell lines. Treatment with VIC-1911, even at nanomolar concentrations, substantially inhibits the growth of both androgen receptor (AR)-positive and AR-negative PC cells. VIC-1911 triggers mitotic failure, induces DNA double-strand breaks (DSBs), and activates the p53 pathway, halting cell division and inducing cell death. Notably, VIC-1911 showed synergistic effects in inhibiting PC cell growth in vitro and xenograft tumor growth in vivo with poly (ADP-ribose) polymerase inhibitors (PARPi), which have proven effective in PC with a deficiency in Homologous Recombination (HR) repair. Mechanistically, VIC-1911 disabled HR-mediated repair of DSBs in otherwise HR-proficient PC cells, leading to a “BRCAness” phenotype and pronounced accumulation of DNA damage and mitotic catastrophe. In summary, our study uncovers what we believe a novel mechanism to functional “BRCAness” by inducing mitotic arrest and highlights VIC-1911 as a promising therapeutic agent for advanced PC, either as a single agent or in combination, sensitizing HR-proficient tumors to PARP inhibitors.
Authors
Galina Gritsina, Sandip Kumar Rath, Hongshun Shi, Qi Chu, Wanqing Xie, Que Thanh Thanh Nguyen, Sambhavi Senthil, Thomas J. Myers, Mehmet A. Bilen, Sarah E. Fenton, Maha Hussain, David S. Yu, Jonathan C. Zhao, Jindan Yu
Abstract
Glioblastoma (GBM) is the most malignant primary brain tumor. The presence of glioma stem/initiating cells (GICs) is known to cause strong treatment resistance; therefore, GICs are a major target for GBM therapy, although there are no therapies targeting GICs clinically. To identify novel treatments for GBMs, we performed drug repositioning screening using GICs and identified T-type calcium channel blocker lomerizine—a migraine prophylactic drug. Lomerizine inhibited proliferation, migration, invasion, and cell cycle progression and induced apoptosis in GICs and differentiated glioma cells. Lomerizine had antitumor effects by inactivating STAT3 in all cell lines. Furthermore, lomerizine also dephosphorylated AKT and ERK only in GICs and strong tumor suppressive ability. Lomerizine also reduced tumor volume and prolonged overall survival in vivo. Based on our data from in vitro and in vivo experiments, lomerizine has potential as a novel GBM therapeutic agent targeting against both GICs and differentiated glioma cells and could benefit for GBM patients.
Authors
Toshiya Ichinose, Sho Tamai, Nozomi Hirai, Takashi Maejima, Kosuke Nambu, Hemragul Sabit, Shingo Tanaka, Masashi Kinoshita, Masahiko Kobayashi, Michihiro Mieda, Atsushi Hirao, Mitsutoshi Nakada
Abstract
Glycosylation changes are pivotal in colorectal cancer (CRC) development. The role of bisecting GlcNAc, a specific N-glycosylation type catalyzed by glycosyltransferase MGAT3, in CRC progression remains elusive. Previous studies indicated that dietary interventions can be beneficial for patients with certain congenital disorders of glycosylation. However, the impact of dietary fatty acids, such as palmitic acid (PA), on glycosylation regulation remains largely unclear. Here, we observed markedly decreased levels of bisecting GlcNAc and MGAT3 in colonic tissues of CRC patients. Downregulation of bisecting GlcNAc in CRC cells increased cell proliferation, migration, and invasion, while decreasing apoptosis. Moreover, a PA-rich diet inhibited CRC carcinogenesis in azoxymethane/dextran sodium sulfate–induced CRC mice by elevating bisecting GlcNAc levels. However, in Mgat3fl/fl Villin-Cre mice the inhibitory effects of the PA-rich diet were abolished. Intact glycopeptide analysis revealed that PA enhanced the bisecting GlcNAc modification on desmoglein 2 (DSG2). Additionally, DSG2 was identified to inhibit CRC carcinogenesis through the EGFR/AKT signaling pathway. In conclusion, dietary PA suppresses CRC carcinogenesis by regulating bisecting GlcNAc modification on DSG2, providing a direct mechanistic link between dietary fatty acids and CRC.
Authors
Lei Lei, Juan Tang, Yuejiao Lv, Bingyi Jia, Wenqing Cai, Shuangshuang Sheng, Keying Li, Zhiwen Shi, Ning Fan, Zengqi Tan, Xiang Li, Feng Guan
Abstract
Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of several cancer types. However, their effectiveness remains limited to a subset of patients, in part due to insufficient preexisting antitumor immunity. In this study, we hypothesized that intracellular delivery of noncoding dsDNA encapsulated in lipid nanoparticles (DNA-LNPs), which have recently been demonstrated to activate both STING and absent in melanoma 2 (AIM2) pathways, could enhance antitumor immune responses and potentiate ICI therapy. Using multiple animal models of cancer, including hepatocellular carcinoma, acute myeloid leukemia, melanoma, and melanoma lung metastasis, we show that DNA-LNP treatment triggered strong cytokine induction and robust CD8+ T cell recruitment to the tumor microenvironment. This immune activation mediated potent CD8+ T cell–dependent antitumor effects and prolonged animal survival across multiple models. Notably, empty LNPs did not elicit potent cytokine elevation or antitumor effects, suggesting that these responses are triggered by the activation of cytosolic DNA-sensing pathways. Moreover, DNA-LNPs synergized with anti–PD-L1, substantially extending animal survival in both ICI-responsive and ICI-resistant tumor models. These findings position DNA-LNPs as a promising immunotherapy strategy, either alone or in combination with ICI therapies, to enhance antitumor immunity across diverse cancer types.
Authors
Seoyun Yum, Alba Rodríguez-Garcia, Joan Castellsagué, Marta Giménez-Alejandre, Guillem Colell, Salut Colell, Teresa Lobo-Jarne, Mark A. LaRue, Michael A. Minnier, Mustafa N. Yazicioglu, Rui Zhang, Xavier M. Anguela, Ali Nahvi, Matthew C. Walsh, Sean M. Armour, Sonia Guedan, Pedro J. Cejas
Abstract
Background: The molecular landscape of lung adenocarcinoma (LUAD) is often illustrated as a driver-oncogene “pie chart,” but identical mutations exhibit heterogeneous signaling shaped by co-mutations, transcriptional programs, and lineage context. We propose a lineage-integrated signaling framework using an EGFR mutation signature (mSig). Methods: We defined EGFR mSig using differentially expressed genes in EGFR-mutant (mt) LUADs. Semi-supervised clustering and machine learning models were used to test reproducibility in different combinations of datasets. We analyzed molecular subtypes, lineage markers, co-occurring mutations and EGFR copy number alterations in EGFR mSig-defined subtypes of LUAD. Results: EGFR mSig showed robust classification performance (AUROC = 0.83-0.95; mean NPV = 96.3%). Validated gene expression subtypes and lung lineage markers were closely aligned with EGFR mSig status. Most EGFR mSig(+) tumors, including many without EGFR mutations belonged to Bronchioid subtype. A subset of canonical RAS mutations were mSig(+) and mirrored the EGFR mutation pattern. EGFR wild-type (WT)/mSig(-) tumors were enriched for non-Bronchioid subtypes and had co-mutations in TP53 or RAS/RAF/RTKs. We highlighted a parsimonious collection of coordinated mutations identified including RAS, KEAP1, STK11, TP53, and CDKN2A, supportive of prior reports. Conclusions: A novel EGFR mSig that captures the transcriptional footprint of EGFR activation revealed a subset of EGFR WT LUADs with “mt-like” features. mSig refines LUAD taxonomy beyond mutation-only pie-chart models by incorporating lineage and co-mutation context. Lineage-directed stratification with co-alteration identifies clinically relevant groups across EGFR and RAS states and highlights new treatment opportunities for patients currently considered “oncogene-negative.” Funding: NCI U01CA272541, R01CA262296, U24CA264021, UG1CA233333, R01CA211939.
Authors
Minjeong Kim, Wisut Lamlertthon, Heejoon Jo, Yan Cui, Miyeon Yeon, Hyo Young Choi, Katherine A. Hoadley, Matthew P. Smeltzer, Michele C. Hayward, Matthew D. Wilkerson, Liza Makowski, D. Neil Hayes
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