Oncology
Abstract
Nearly 50% of patients with KRAS-mutant colorectal cancer (CRC) currently lack effective targeted therapy. The accumulation of KRAS-mutant proteins can trigger a sustained high level of endoplasmic reticulum (ER) stress, and the UPR-based long-term protective regulatory pathway inhibits the aggregation of unfolded proteins, thereby maintaining the stability of the ER and enabling the continued survival of KRAS-mutant tumors. However, the critical factors that affect the regulation of ER homeostasis in KRAS-mutant CRC are still unclear. Mono-ADP ribosylation (MARylation) catalyzed by ART1 is the most important modification of GRP78/BiP and stabilizes the internal environment of the ER. In this study, KRAS mutation increased the levels of ART1, ER stress, and MARylated GRP78/BiP in CRC cells. Inhibiting MARylated GRP78/BiP can impede the downstream IRE1α/XBP1/TFAF2/JNK and PERK/eIF2α/ATF4 cascades by affecting the binding and dissociation of GRP78/BiP with receptors to hinder the growth of KRAS-mutant CRC cells and accelerate their apoptosis. We propose that KRAS-mutant CRC cells are more sensitive to intervention with MARylated GRP78/BiP because more modifications are needed to maintain ER stability. We also conducted a preliminary study on the specific site of function. Clarifying this molecular mechanism can provide a experimental basis for identifying effective targets for the intervention of KRAS-mutant CRC.
Authors
Shuxian Zhang, Xiaodan Chen, Qian Gong, Jing Huang, Yi Tang, Ming Xiao, Ming Li, Qingshu Li, Yalan Wang
Abstract
Anoikis resistance or evasion of cell death triggered by matrix detachment is a hallmark of cancer cell survival and metastasis. We show that repeated exposure to suspension stress followed by recovery under attached conditions leads to development of anoikis resistance. The acquisition of anoikis resistance is associated with enhanced invasion, chemoresistance, and immune evasion in vitro and distant metastasis in vivo. This acquired anoikis resistance is not genetic, persisting for a finite duration without detachment stress, but is sensitive to CDK8/19 Mediator kinase inhibition that can also reverse anoikis resistance. Transcriptomic analysis reveals that CDK8/19 kinase inhibition induces bidirectional transcriptional changes in both sensitive and resistant cells, disrupting the balanced reprogramming required for anoikis adaptation and resistance by reversing some resistance associated pathways and enhancing others. Both anoikis resistance and in vivo metastatic growth of ovarian cancers are sensitive to CDK8/19 inhibition, thereby providing a therapeutic opportunity to both prevent and suppress ovarian cancer metastasis.
Authors
Mehri Monavarian, Resha Rajkarnikar, Emily Faith Page, Asha Kumari, Liz Quintero Macias, Felipe Massicano, Nam Y. Lee, Sarthak Sahoo, Nadine Hempel, Mohit Kumar Jolly, Lara Ianov, Elizabeth Worthey, Abhyudai Singh, Igor B. Roninson, Eugenia V. Broude, Mengqian Chen, Karthikeyan Mythreye
Abstract
Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.
Authors
Matthew A. Loberg, George J. Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Heather A. Hartmann, Jean-Nicolas Gallant, Courtney J. Phifer, Andres A. Ocampo, Dayle K. Wang, Reilly G. Fankhauser, Kirti A. Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M. Shaddy, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Barbara A. Murphy, Jennifer H. Choe, Jennifer R. Wang, Eric C. Huang, Quanhu Sheng, Luciane T. Kagohara, Elizabeth M. Jaffee, Ryan H. Belcher, Ken S. Lau, Fei Ye, Ethan Lee, Vivian L. Weiss
Abstract
Radiotherapy is a critical modality in cancer treatment, not only to eradicate cancer cells but also to trigger anti-tumor immunity. Interleukin-21 (IL-21), an immunomodulatory cytokine with potential in cancer therapy, has unexplored synergy with radiotherapy. Our study, leveraging human cancer databases and tissue microarrays, identified a positive correlation between IL-21 and radiotherapy outcomes, particularly in tumor microenvironment (TME) activation. In mouse tumor models, IL-21 combined with radiation significantly enhances TME, boosting CD8+ T cell activation and function, reducing tumor burden, and extending survival. Single-cell transcriptome sequencing revealed that the combination of IL-21 and radiation increased the cytotoxicity of effector and memory CD8+ T cells and prevented their exhaustion. These effects were further validated in humanized mice, where IL-21 combined with radiation reduced A549 tumor growth and enhanced CD8+ T cell function. Post-neoadjuvant radiotherapy samples from patients with esophageal cancer showed a positive correlation between IL-21 levels and CD8+ T cell infiltration. Our findings suggest that IL-21 is a promising adjuvant to radiotherapy, potentially improving the treatment efficacy through TME enhancement. This study provides a foundation for future clinical exploration of IL-21 for enhancing radiotherapy.
Authors
Xinyang Li, Xueqi Xie, Baochao Wei, Xiaozheng Sun, Minxin Chen, Rufei Liu, Qingxu Tao, Yiheng Huang, Qian Wang, Shuangshuang Ma, Ling Wei, Rong Xiao, Zhaoyun Liu, Jinming Yu, Meng Wu, Dawei Chen
Abstract
The tumor microenvironment plays a key role in cancer progression and therapy resistance, with cancer-associated fibroblasts (CAFs) contributing to desmoplasia, extracellular matrix (ECM) remodeling, and elevated interstitial fluid pressure, all of which hinder drug delivery. We investigated fibroblast activation protein–targeted (FAP-targeted) near-infrared photoimmunotherapy (NIR-PIT) as a strategy to improve drug penetration in CAF-rich tumors. In clinical esophageal cancer samples, FAP expression strongly correlated with increased collagen I, hyaluronic acid, and microvascular collapse. CAF-rich 3D spheroids demonstrated elevated ECM deposition and significantly impaired drug uptake compared with CAF-poor models. FAP-targeted NIR-PIT selectively reduced CAFs, reduced ECM components, and restored drug permeability. In vivo, FAP-targeted NIR-PIT enhanced the accumulation of panitumumab and Abraxane in CAF-rich tumors and improved antitumor efficacy when combined with chemotherapy. These findings highlight FAP-targeted NIR-PIT as a promising therapeutic approach to remodel the tumor stroma and overcome drug resistance in desmoplastic solid tumors.
Authors
Seitaro Nishimura, Kazuhiro Noma, Tasuku Matsumoto, Yasushige Takeda, Tatsuya Takahashi, Hijiri Matsumoto, Kento Kawasaki, Hotaka Kawai, Tomoyoshi Kunitomo, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Shunsuke Tanabe, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Peter L. Choyke, Hisataka Kobayashi, Toshiyoshi Fujiwara
Abstract
BACKGROUND. Chimeric antigen receptor (CAR) T-cells are a leading immunotherapy for refractory B-cell malignancies; however, their impact is limited by toxicity and incomplete efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success; however, their clinical relevance to CAR T-cell therapy remains unknown. METHODS. We retrospectively analyzed CAR T-cell survival and complications based on infusion time at two geographically distinct hospitals in St. Louis, Missouri (n=384), and Portland, Oregon (n=331) between 1/2018 and 3/2025. The primary outcome was 90-day overall survival (OS). Secondary outcomes included event-free survival (EFS), cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), ICU admission, shock, respiratory failure, and infection. We quantified the independent relationship between infusion time and outcomes using multivariable mixed-effects logistic regression and time-to-event models, adjusting for patient, oncologic, and treatment characteristics. RESULTS. The therapeutic index of CAR-T cells inversely correlated with administration time, with later infusions associated with lower effectiveness and more adverse outcomes. For each hour that CAR T-cell treatment was delayed, the adjusted odds of 90-day mortality increased by 24% (aOR 0.64-0.88, p=<0.001), severe neurotoxicity by 17% (p=0.023), and mechanical ventilation by 27% (p=0.026). These temporal patterns were most pronounced in patients receiving CD19-targeting CAR T-cell products. In contrast, we did not find an association between infusion time and severe CRS (aOR 0.99, 95% CI 0.75–1.27, p=0.92). CONCLUSION. Time of day is a potent and easily modifiable factor that could optimize CAR T-cell clinical performance. FUNDING. National Institutes of Health.
Authors
Patrick G. Lyons, Emily Gill, Prisha Kumar, Melissa Beasley, Brenna Park-Egan, Zulfiqar A. Lokhandwala, Katie M. Lebold, Brandon Hayes-Lattin, Catherine L. Hough, Nathan Singh, Guy Hazan, Huram Mok, Janice M. Huss, Colleen A. McEvoy, Jeffrey A. Haspel
Abstract
Fusion-positive rhabdomyosarcoma (FP-RMS), driven by PAX-FOXO1, represents the subtype of RMS with the poorest prognosis. However, the oncogenic mechanisms and therapeutic strategies of PAX-FOXO1 remain incompletely understood. Here, we discovered that N-Myc, in addition to being a classic downstream target of PAX-FOXO1, can also activate its expression and form a transcriptional complex with PAX-FOXO1, thereby markedly amplifying oncogenic signaling. The reciprocal transcriptional activation of PAX3-FOXO1 and N-Myc is critical for FP-RMS malignancy. We further identified YOD1 as a deubiquitinating enzyme (DUB) that stabilizes both PAX-FOXO1 and N-Myc. Knocking down YOD1 or inhibiting it by G5 could suppress FP-RMS growth both in vitro and in vivo, through promoting the degradation of both PAX-FOXO1 and N-Myc. Collectively, our results identify that YOD1 promotes RMS progression by regulating the PAX3-FOXO1-N-Myc positive feedback loop, and highlight YOD1 inhibition as a promising therapeutic strategy that concurrently reduces the levels of both oncogenic proteins.
Authors
Wenwen Ying, Jiayi Yu, Xiaomin Wang, Jiayi Liu, Boyu Deng, Xuejing Shao, Jinhu Wang, Ting Tao, Ji Cao, Qiaojun He, Bo Yang, Yifan Chen, Meidan Ying
Abstract
HDAC8, an evolutionarily distinct, X-linked, zinc-dependent class I histone/protein deacetylase, is implicated in developmental disorders, parasitic infections, myopathy, and cancers. Our study demonstrates the important role of HDAC8 in immune cells by conditional targeting of HDAC8 in murine T cells and application of selective HDAC8 inhibitors. Using flow cytometry, RNA-seq and ChIP-seq analyses, we demonstrate that knocking down or inhibiting HDAC8 impaired murine Treg suppressive function in vitro and in vivo, but promoted conventional host T cell responses, thereby limiting syngeneic tumor growth. Mechanistically, HDAC8 knockout downregulated Foxp3 expression, enhanced H3K27 acetylation levels and promoted IL-2, IL-6, Fas, and FasL expression in both Treg and conventional T-effector cells. Thus, our combined genetic and pharmacologic studies establish the central importance of HDAC8 in T cell responses and suggest that selective HDAC8 inhibitors represent a potential therapeutic approach in immuno-oncology.
Authors
Fanhua Kong, Yan Xiong, Liqing Wang, Rongxiang Han, Hossein Fazelinia, Jennifer Roof, Lynn A. Spruce, Aaron B. Beeler, Wayne W. Hancock
Abstract
BACKGROUND. WP1066 is an orally bioavailable, small molecule inhibitor of activated p-STAT3 that has demonstrated preclinical efficacy in pediatric brain tumor models. METHODS. In a first-in-child, single-center, single-arm 3+3 design Phase I clinical trial, ten patients were treated with WP1066 twice daily, Monday-Wednesday-Friday, for 14 days of each 28-day cycle to determine the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066. Compassionate use treatment with WP1066 in three pediatric patients with H3.3 G34R/V-mutant high-grade glioma (HGG) is also described. RESULTS. There was no significant toxicity and the MFD was determined to be 8 mg/kg. Treatment-related adverse events were Grade 1-2 (diarrhea and nausea most common); there were no dose-limiting toxicities. Median progression-free and overall survival were 1.8 months and 4.9 months, respectively. One partial response was observed in a patient with pontine glioma. Among the H3.3 G34R/V-mutant HGG patients not on study, WP1066 was administered after upfront radiation to one patient for 17 months. At all dose levels tested, WP1066 suppressed p-STAT3 expression by peripheral blood mononuclear cells (PBMCs). Single cell RNA-seq analysis of PBMCs demonstrated increased CD4+ and CD8+ T cells, pro-inflammatory TNFA signaling, differentiation activity in myeloid cells, and downregulation of Tregs after WP1066 treatment, consistent with systemically inhibited STAT3 activity. CONCLUSIONS. WP1066 is safe, has minimal toxicity, and induces anti-tumor immune responses in pediatric brain tumor patients. Phase II investigation of WP1066 at the MFD in this patient population is warranted. TRIAL REGISTRATION. ClinicalTrials.gov NCT04334863. FUNDING. CURE Childhood Cancer (TJM) and Peach Bowl, Inc. (TJM)
Authors
Robert C. Castellino, Hope L. Mumme, Andrea T. Franson, Bing Yu, M. Hope Robinson, Kavita Dhodapkar, Dolly Aguilera, Matthew J. Schniederjan, Rohali Keesari, Zhulin He, Manoj Bhasin, Waldemar Priebe, Amy B. Heimberger, Tobey J. MacDonald
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and current therapies show limited efficacy. Ligands and receptors of the TIGIT axis were analyzed using multicolor flow cytometry of tumor and blood samples, immunohistochemistry from primary tumors, and single-cell RNA sequencing from primary tumors and liver metastasis from patients with various stages of PDAC. The effect of soluble and plate-bound Nectin-4 on T cell function was tested in vitro. Further, patient-derived PDAC organoids were treated with the standard of care therapies FOLFIRINOX, gemcitabine plus paclitaxel, or the antibody-drug conjugate enfortumab vedotin. TIGIT expression was increased on tumor-infiltrating conventional and regulatory T cells compared with T cells from matched blood. Nectin-4, but not CD155 expression was associated with poor outcome. Nectin-4 was exclusively expressed by tumor cells and correlated with low immune infiltration. Notably, Nectin-4 inhibited T cell effector cytokine production in vitro. Targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in multiple patient-derived PDAC organoids. Collectively, our data underscores Nectin-4 as a novel therapeutic target and provides the rationale to test this agent in PDAC patients.
Authors
Max Heiduk, Carolin Beer, Sarah Cronjaeger, Emily A. Kawaler, Ulrich Sommer, Franziska Baenke, David Digomann, Loreen Natusch Bufe, Charlotte Reiche, Jessica Glück, Franziska Hoffmann, Sungsik Kim, Daniel E. Stange, Diane M. Simeone, Jürgen Weitz, Lena Seifert, Adrian M. Seifert
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