Oncology
Abstract
Ubiquitin-Specific Protease 18 (USP18) is a deISGylation enzyme and antineoplastic target. To develop USP18 inhibitors, an enzymatically active human recombinant USP18 protein was engineered suitable for high-throughput screening of ~80,000 chemical compounds. Three of them substantially inhibited USP18 enzymatic activity with β-lapachone having prominent antineoplastic activity. Independent β-lapachone treatments of murine and human lung cancer cell lines statistically-significantly reduced proliferation and increased apoptosis. Gain of USP18 expression antagonized these effects. β-lapachone treatments statistically-significantly repressed lung cancer xenograft growth. β-lapachone increased reactive oxygen species (ROS), but antineoplastic effects occurred at dosages with negligible ROS production. ROS scavenger treatments did not rescue β-lapachone effects at these concentrations, consistent with an ROS-independent mechanism. Interferon-Stimulated Response Element (ISRE) reporter assays following β-lapachone treatment activated this reporter. USP18 co-transfection antagonized this activity. β-lapachone treatments increased global ISGylation. RNA sequencing of lung cancer cells engineered with or without enhanced USP18 expression showed specific pathways affected by β-lapachone treatment. Proteomic analysis of these treated cells revealed known and new ISGylated proteins. In silico modeling identified a unique USP18 pocket where these USP18 inhibitors bind. Engineered mutation of this pocket disrupted β-lapachone activity. Taken together, β-lapachone is an antineoplastic tool compound useful for USP18 inhibitor development.
Authors
Blessing O. Ogunlade, Kevin N. Dalby, Samuel C. Okpechi, Eun Jeong Cho, Liliya Tyutyunyk-Massey, Zibo Chen, Xiuxia Liu, Joseph Ivanic, Brian Luke, Shyamal D. Desai, Yair Alfaro, Ashwini K. Devkota, Rae M. Sammons, Gilbert G. Privé, Xi Liu, Ethan Dmitrovsky
Abstract
Antibody production by B cells has emerged as an important factor in regulating anti-tumor immunity with both suppressive and promotive roles in cancer. However, the specific impact of antibody deficiency during development of pancreatic ductal adenocarcinoma (PDAC) has not been explored. To address this question, we crossed the well-established KPC mouse model to mice lacking all circulating immunoglobulin (Ig) due to genetic ablation of both Ig secretion and Ig class switching (KPC-μSAID mice). KPC-μSAID mice exhibited a two-fold acceleration in tumor formation, a two-fold reduction in median survival, and increased liver metastases versus KPC-WT control mice. Immunofluorescence analysis of pancreatic tissues from antibody-sufficient KC- and KPC-WT mice showed that IgG was predominantly localized within extracellular matrix (ECM). Furthermore, in both KC- and KPC-μSAID mice, ECM density and podoplanin+ cancer-associated fibroblasts (CAFs) were significantly reduced. In the KPC-μSAID tumor microenvironment (TME), intratumoral myeloid-derived suppressor cells (MDSC) were also increased, while CD4+ and CD8+ T cells decreased, relative to tumor-bearing KPC-WT mice, with macrophage exhibiting a mixed polarization phenotype. These findings were recapitulated in antibody-subclass-deficient, KPC-AID mice, suggesting a potentially novel function of IgG in suppressing PDAC progression, by directly or indirectly regulating pancreatic fibrosis and the density of the ECM.
Authors
Jeremy B. Foote, Sujith Sarvesh, Sameer Al Diffalha, David K. Crossman, Changde Cheng, Myng-Hee Kim, Cherlene Hardy, Julienne L. Carstens, Kyoko Kojima, Bart J. Rose, Christopher A. Klug
Abstract
Authors
Tiziana Parisi, Blanca Santibanez Ocampo, Jacob Adelman, Yuyan Cai, Marie McConkey, Christopher J. Gibson, Benjamin L. Ebert, Peter Miller, Tyler Jacks
Abstract
T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T cell trafficking displayed an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce an approach for studying T cell migration and interactions within the TME, offering valuable insights into tumor-immune dynamics.
Authors
Lin Zhong, Bo Li, Zhikai Chi, Siyuan Zhang, Qiwei Li, Guanghua Xiao
Abstract
Cancer-induced bone pain (CIBP) is among the most common and debilitating symptoms in patients with bone metastasis. Current treatments are somewhat effective but have severe side effects. For the future development of safer CIBP treatment, in this study, we sought to investigate the mechanisms whereby the cancer/nerve interaction controls CIBP. We found that c-Kit, a receptor tyrosine kinase, was activated in the dorsal root ganglia (DRG) sensory neurons of mice with CIBP and that c-Kit’s sole ligand, stem cell factor (SCF), was enhanced in the bone marrow with bone metastasis. When DRGs were treated SCF or conditioned medium from high SCF-expressing cancer cells, in vitro nerve sprouting was enhanced, and this effect was abolished with c-Kit inhibitors. Mice, intrafemorally inoculated with cancer cells that had varying SCF-expression developed CIBP and enhanced peripheral nerve sprouting in an SCF-dependent manner. Downstream proteomic analysis revealed that SCF upregulated and activated fibroblast growth factor 1 (FGF1) in DRGs. When FGF1 was knocked down in DRGs, SCF-mediated nerve sprouting was prevented. Taken together, our studies demonstrate the importance of the SCF/c-Kit axis in CIBP and nerve sprouting, and identify the SCF/c-Kit/FGF1 pathway as a potential therapeutic target for CIBP.
Authors
Kelly F. Contino, Jenna Ollodart, Yang Yu, Sun H. Park, Shunsuke Tsuzuki, Kara Rollins, Tyler M. Heethouse, Joshua Chu, Laiton R. Steele, Takahiro Kimura, Jingyun Lee, Cristina M. Furdui, Lance D. Miller, Fang-Chi Hsu, Yusuke Shiozawa
Abstract
Authors
Natalie E. Andresen, Heehwa G. Son, Joongho J. Joh, Shadmehr Demehri
Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma
Abstract
Glioblastoma (GBM) cancer stem cells (CSCs) contribute to tumor recurrence, treatment resistance, and dismal clinical outcomes. Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a novel series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our novel WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify novel combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.
Authors
Jesse A. Coker, Steven R. Martinez, Sang Hoon Han, Anthony R. Sloan, Amit Kumar Gupta, George Bukenya, Paul Polzer, James H. Ramos, Emma G. Rico, Annabella Rico, A. Abigail Lindsey, Tanvi Navadgi, Natalie Reitz, Todd Romigh, Jonathan Macdonald, Dhiraj Sonawane, Christopher M. Goins, Christopher G. Hubert, Nancy S. Wang, Feixiong Cheng, Joseph Alvarado, Samuel A. Sprowls, Justin D. Lathia, Shaun R Stauffer
Abstract
BACKGROUND. Chimeric antigen receptor T-cell (CAR-T) therapies have revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, cytokine release syndrome (CRS), a common and potentially severe complication, requires inpatient monitoring, limiting access and increasing costs. Wearable devices could support outpatient CAR-T delivery, but feasibility for CRS detection versus standard care remains unproven. METHOD. We conducted a prospective, single-center observational pilot study to assess the feasibility of using wearable devices for monitoring vital signs and detecting CRS. Thirty patients receiving idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) were enrolled; 25 with sufficient monitoring data were evaluable. Sensors collected skin and axillary temperature, oxygen saturation, respiratory and heart rate, and motion. Peripheral blood cytokines were analyzed pre- and post-infusion using a multiplex proteomic platform. The primary outcome was feasibility, assessed by CRS detection sensitivity and specificity; secondary outcomes included adherence, lead time, and performance of models integrating wearable and cytokine data. RESULTS. CRS occurred in 20 of 25 patients. The best-performing wearable model detected 18 or 20 CRS episodes with a sensitivity of 0.72 (mean 0.75; 95% CI 0.60–0.91) and a specificity of 0.80 (mean 0.76; 95% CI 0.68–0.84), and a median lead time of 7:00 hours before nursing recognition. Median adherence during high-risk periods was 71%. Cytokine changes paralleled temperature elevations, and IFN-γ emerged as a consistent biomarker. CONCLUSION. Wearable devices are feasible for early CRS detection and may support outpatient CAR-T care. Larger outpatient studies are warranted. TRIAL REGISTRATION. This study did not meet the criteria for ClinicalTrials.gov registration.
Authors
Sridevi Rajeeve, Matt Wilkes, Nicole Zahradka, Lewis Tomalin, Mujahid Quidwai, Darren Pan, Nicholas J. Calafat, Martin Cusack, Adolfo Aleman, Kseniya Serebryakova, Katerina Kappes, Hayley Jackson, Sarita Agte, Santiago Thibaud, Larysa Sanchez, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Hearn Jay Cho, Ajai Chari, Sundar Jagannath, Alessandro Laganà, Adriana C. Rossi, Samir Parekh
Abstract
BACKGROUND. Asparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP. METHODS. We performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses, and integrated lipid–cytokine associations using proteomics. RESULTS. Across cohorts, we identified a reproducible lysophosphatidylcholine (LPC)–centered signature characterized by attenuated induction therapy-associated LPC responses and disruption of LPC co-regulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid–cytokine coupling, including a flip in association direction for LPC species and interleukin-18 (IL-18) between cases and controls. Although IL-18/LPC ratios do not differ globally, elevated post-induction IL-18/LPC ratios identify AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81). CONCLUSION. These findings support a systems-level model in which failure of coordinated lipid–immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies. TRIAL REGISTRATION. NCT00400946; NCT01574274; NCT03020030 (parent trials). FUNDING. Servier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec – Santé; Fondation Charles-Bruneau; The Leukemia & Lymphoma Society of Canada.
Authors
Cheng-Yu Tsai, Na Bo, Thai Hoa Tran, Maisam Abu-El-Haija, Gayathri Swaminathan, Bomi Lee, Sudhir Ghandikota, Li Wen, Yves Théorêt, Steven D. Mittelman, Elena J. Ladas, Anil G. Jegga, Lewis B. Silverman, Ying Ding, Sohail Z. Husain
Abstract
Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR’877), a novel PD-1-targeted immunocytokine that fuses a high-affinity anti-PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1+ T cells, enhancing proliferation and activation of antigen-experienced CD8+ and CD4+ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR’877 activates STAT5 signaling in PD-1+ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR’877 accelerated viral clearance and induced robust anti-tumor immunity by expanding cytotoxic CD8+ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed anti-PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR’877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.
Authors
Isaraphorn Pratumchai, Marie Bernardo, Julien Tessier, Jaroslav Zak, Kristi L. Marquardt, Joon Sang Lee, Maheeka Bimal, AHyun Choi, Anthony M. Byers, Mikielia G. Devonish, Roberto Carrio, Dan Lu, Stella A. Martomo, Jeegar Patel, Yu-an Zhang, Ingeborg M. Langohr, Virna Cortez-Retamozo, Dinesh S. Bangari, Angela Hadjipanayis, Xiangming Li, Valeria R. Fantin, Donald R. Shaffer, John R. Teijaro
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