Clinical Research
Abstract
Background: Despite therapeutic advances in the early-stage triple negative breast cancer (TNBC) setting, residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and is a major obstacle to improving patient outcomes. Methods: To better characterize RD and identify survival associated features, we performed comprehensive transcriptomic profiling of 340 pre-treatment stage II/III TNBCs and 70 matched post-treatment RD samples from the randomized CALGB 40603 (Alliance) Phase 2 clinical trial. Preclinical treatment strategies mimicking RD patients were explored using Antibody Drug Conjugate (ADC) treatment in patient derived xenograft (PDX) mouse models. Results: Our study shows that prognostic genomic features measured prior to treatment may differ from prognostic features measured after treatment from RD specimens. Specifically, we identified that patients with a genomic PAM50 subtype of Basal-like in RD specimens have a poor survival outcome and their matching pre-treatment tumors are characterized by elevated chromosomal amplifications of oncogenic drivers (i.e., MYC, CDK6, and CCND1) as well as significantly reduced B- and T-cell expression features. Paired analyses of Basal-like RD and matched pre-treatment tumors reveal further lymphocyte depletion in the RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a Basal-like and conventional chemotherapy-resistant PDX model, resembling Basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response. Conclusion: RD biology differs from pre-treatment tumors, with Basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Pre-clinical modeling suggests that this high-risk group may benefit from adjuvant ADC therapy. Trial registration: ClinicalTrials.gov NCT00861705 Funding: National Cancer Institute (NCI) U10CA180821 (Alliance for Clinical Trials in Oncology) NCI U24CA176171 (Alliance for Clinical Trials in Oncology) NCI UG1CA233373 (Alliance for Clinical Trials in Oncology) NCI Breast SPORE program P50-CA058223 (CMP) Susan G. Komen SAC-160074 (CMP, PDR) Breast Cancer Research Foundation BCRF-23-127 (CMP) NCI R01-CA229409 (CMP) UNC LCCC Triple Negative Breast Cancer Center (CMP)
Authors
Patrick D. Rädler, Brooke M. Felsheim, Aranzazu Fernandez-Martinez, Adam D. Pfefferle, Michele C. Hayward, Baljit Singh, William Sikov, Lisa A. Carey, Charles M. Perou
Abstract
Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease. The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]; P<0.01). Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO had more inducible AF via a transesophageal pacing study compared to chow controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice (P<0.01). Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline→TMA(O) metabolic transformation, reduced circulating TMAO levels (P<0.0001) and choline induced AF onset (P<0.01). Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF. In summary, the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction, and is a therapeutic target for prevention of AF.
Authors
Selvam Arjunan, Isaiah Pemberton, Xinmin S. Li, Naseer Sangwan, Lydia Akino, Emmanuel Opoku, Dmitriy Verbovetskiy, Ina Nemet, Hyun Su Kim, Haruko Masumiya, Zeneng Wang, Joseph A. Lupica, Melissa Y. Tian, Karis Mao, Deepthi P. Mallela, Maradumane Mohan, Sarah Schumacher, Julie H. Rennison, Sathyamangla Prasad, Kenneth R. Laurita, Vamsi Chodisetty, Mina K. Chung, David R. Van Wagoner, John Barnard, Jonathan D. Smith, Oussama Wazni, Stanley L. Hazen, Robert A. Koeth
Abstract
BACKGROUND Obesity and weight loss in adults have been associated with distinct metabolome and gut microbiome features, but the extent to which those associations apply to adolescent stages remain unclear.METHODS The Pediatric Obesity Microbiome and Metabolism Study (POMMS) enrolled 220 adolescents aged 10–18 with severe obesity (OB) and 67 individuals who were healthy weight controls (HWCs). Blood, stool, and clinical measures were collected at baseline and after a 6-month obesity intervention for the OB group. Metabolomic profiling in serum using targeted quantitative mass spectrometry and microbiome profiling in stool were performed, and those features were assessed for associations with BMI, insulin resistance, and inflammation. Fecal microbiome transplants (FMT) were performed on germ-free mice using samples from both groups to assess effects on weight gain and metabolic pathways.RESULTS Adolescents with OB exhibited higher serum branched-chain amino acid (BCAA) but lower branched-chain ketoacid (BCKA) levels compared with HWC. This pattern was sex- and age-dependent and differed from adults with obesity who show elevated levels of both BCAA and BCKA. Longitudinal analysis identified metabolic and microbial features correlated with changes in health measures during the intervention. The fecal microbiomes of adolescents with OB and HWC had similar diversity but differed in membership and functional potential. FMT from both OB and HWC donors had similar effects on mouse body weight, but specific taxa were linked to weight gain in recipients of FMT.CONCLUSION Adolescents with OB have unique metabolomic adaptations and microbiome signatures compared with their HWC counterparts and adults with OB.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03139877 (Observational Study) and NCT02959034 (Repository).FUNDING SUPPORT American Heart Association Grants: 17SFRN33670990, 20PRE35180195; National Institute of Diabetes and Digestive and Kidney Diseases Grant: R24-DK110492.
Authors
Jessica R. McCann, Chengxin Yang, Nathan A. Bihlmeyer, Runshi Tang, Tracy Truong, Wei Zhou, Jie An, Jayanth Jawahar, Olga Ilkayeva, Michael J. Muehlbauer, Zhengzheng Hu, Holly Kloos Dressman, Lisa Poppe, Joshua A. Granek, Jason W. Arnold, Lawrence A. David, Julia Oh, Pixu Shi, Pinar Gumus Balikcioglu, Svati H. Shah, Sarah C. Armstrong, Christopher B. Newgard, Patrick C. Seed, John F. Rawls
Abstract
ATR inhibition is under evaluation for treatment of high-grade serous ovarian cancer (HGSOC) to reverse acquired resistance to poly (ADP-ribose) polymerase (PARP) inhibition and to exacerbate chemotherapy-induced replicative stress. Here, we define PTEN deficiency as a predictive biomarker for response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared to PTEN-proficient cells, PTEN-deficient cells are prone to (1) uncoupling of DNA polymerase and helicase activities, leading to excessive single-stranded DNA and replication stress; (2) cytoplasmic sequestration of CHK1, compromising cell cycle checkpoint control with reduced compensatory effects by ATM and DNA-PK, leading to mitotic catastrophe; and (3) reduced RAD51 recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses demonstrate that patients with HGSOC expressing low PTEN levels experience greater clinical benefit on ATR inhibitor-based trials than those with high levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.
Authors
Jie Hao, Bose Kochupurakkal, Timothy B. Branigan, Ozge Sezin Somuncu, Renyan Liu, Heta Jadhav, Alexandre Andre B.A. da Costa, Yuqing Jiao, Jenny Z. Yu, David B. Martignetti, Golbahar Sadatrezaei, Sirisha Mukkavalli, Prafulla C. Gokhale, Su-Chun Cheng, Steven J. Skates, Dimitrios Nasioudis, Panagiotis A. Konstantinopoulos, Joyce F. Liu, Stephanie L. Gaillard, Robert L. Giuntoli II, Lainie P. Martin, Janos L. Tanyi, Nawar Latif, Ian S. Heller, Fiona Simpkins, Kalindi Parmar, Alan D. D'Andrea, Geoffrey I. Shapiro
Abstract
Background. CIS43LS is a long-acting mAb that targets the Plasmodium falciparum circumsporozoite protein. A phase 2 trial showed that a single dose of CIS43LS conferred >85% sterile protection against infection in Malian adults over 6 months. Understanding the pharmacokinetics and pharmacodynamics (PK/PD) of CIS43LS is critical for the further development of CIS43LS and other anti-malaria mAbs. Methods. Using 3,777 serum samples collected from 348 trial participants over the 6-month study period, we performed a PK/PD analysis of CIS43LS that included assessments for anti-drug antibodies and target-mediated drug disposition. A two-compartment, non-linear mixed effects population PK model that evaluated demographic, anthropometric, hematologic, baseline parasitemia, and endogenous IgG and IgG1 as potential covariates was used to estimate PK parameters and serum concentrations required to achieve 80% efficacy. Results. The median CIS43LS t1/2 was 63.2 days (95%CI 59.4–67.2 days). Serum concentrations ≥64 μg/mL (95%CI 49–93 μg/mL) corresponded to ≥80% efficacy against infection over 6 months. A simulated dose of 30 mg/kg maintained serum concentrations >64 µg/mL in >97.5% of individuals for 4 months, the timeframe for the World Health Organization preferred product characteristics for anti-malaria mAbs. There was no evidence of anti-drug antibodies. Among infected individuals who received CIS43LS, no marked evidence of target-mediated drug disposition was observed. Conclusion. This study indicates that protective CIS43LS levels can be maintained over the course of a single malaria season and provides guidance for PK/PD analyses of anti-malaria mAbs in malaria-endemic populations. Trial registration. NCT04329104. Funding. National Institutes of Health and Gates Foundation.
Authors
Tuan M. Tran, Zonghui Hu, Kassoum Kayentao, Aissata Ongoiba, Sam Jones, Nada Abla, Sara A. Healy, Hamidou Cisse, Bickey H. Chang, Jeff Skinner, Leonid Serebryannyy, Sandeep R. Narpala, Robin Schlesinger, Kwang Huei Low, Rachel Kazmierski, Bob C. Lin, Joana Dias, Safiatou Doumbo, Didier Doumtabe, Anne C. Preston, Shanping Li, Mary E. Peterson, Amit Oberai, Adam D. Shandling, Joseph J. Campo, Sean C Murphy, Shinyi Telscher, Emily E. Coates, Edmund V. Capparelli, Amagana Dolo, Boubacar Traore, Robert A. Seder, Peter D. Crompton
Abstract
BACKGROUND. B cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma (MM), yet its whole-body in vivo distribution and role in disease assessment remain incompletely defined. We aimed to evaluate the safety, diagnostic performance, and clinical utility of a novel BCMA-targeted PET tracer, 68Ga-PFBC01, in patients with plasma cell disorders. METHODS. We conducted a single-center, prospective, single-arm phase I trial (ClinicalTrials.gov NCT06717113). Fifty patients underwent 68Ga-PFBC01 PET/CT, including 40 with paired 18F-FDG PET/CT for head-to-head comparison. Primary outcomes included diagnostic performance (sensitivity, specificity, PPV, NPV, and inter-reader agreement). Secondary outcomes included correlations with clinical biomarkers, treatment response assessment, impact on clinical decision-making, and safety. RESULTS.68Ga-PFBC01 PET/CT demonstrated superior diagnostic performance compared with 18F-FDG PET/CT (sensitivity 96.9% vs 84.6%; specificity 71.4% vs 60.0%). Quantitative PET-derived tumor burden correlated with M protein (R = 0.325, P = 0.026), free light chains (R = 0.340–0.437, P ≤ 0.015), soluble BCMA (R = 0.433, P = 0.050), and bone marrow plasma cells (R = 0.682, P < 0.001). Imaging findings altered clinical management in multiple cases, enabling both therapy escalation and de-escalation. Blood-pool uptake strongly correlated with soluble BCMA (R = 0.899, P < 0.001) and overall disease burden (R = 0.736, P < 0.001). No serious tracer-related adverse events were observed; two patients (4%) experienced mild events. CONCLUSION.68Ga-PFBC01 PET/CT provides biologically specific, whole-body assessment of MM, outperforming 18F-FDG and enabling integrated evaluation of tumor burden and systemic disease activity, with direct implications for clinical decision-making. TRIAL REGISTRATION. ClinicalTrials.gov NCT06717113. FUNDING. National Natural Science Foundation of China (82472018, 82402320) to Prof. Lei Kang, 82402320 to Dr. Tianyao Wang); Beijing Nova Program (20240484725) to Prof. Lei Kang; National High Level Hospital Clinical Research Funding (Interdisciplinary Research Project of Peking University First Hospital, 2024IR07, Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2025CX38, 2024CX18) to Prof. Lei Kang.
Authors
Tingfei Gu, Zhao Chen, Bo Tang, Tianyao Wang, Qi Yang, Huihui Liu, Zeyin Liang, Qian Wang, Yang Zhang, Yuhua Sun, Mingyi Di, Tingting Yuan, Yongkang Qiu, Yimeng Du, Lele Song, Shengnan Wu, Wei Wang, Xiaojie Xu, Yujun Dong, Lei Kang
Abstract
De novo heterozygous variants in CELF2 have recently been associated with a rare neurodevelopmental disorder, yet the mechanisms linking specific variants to distinct clinical phenotypes remain poorly understood. Here, we reported a cohort of 18 individuals and provided evidence that variants causing CELF2 mislocalization, but not protein-null variants, were associated with seizures. Using proband-derived human cortical neurons and transgenic mouse models, we demonstrated that CELF2 underwent activity-dependent nucleocytoplasmic shuttling in excitatory neurons and that its cytoplasmic retention caused neuronal hyperactivity, elevated seizure susceptibility, and learning and memory deficits. We further found that cytoplasmic CELF2 regulated mRNAs critical for synaptic function and neuronal excitability and implicated in epileptic seizures and intellectual disability. Drug screening further identified AKT signaling as a key regulator of CELF2 nucleocytoplasmic shuttling and a candidate target for reversing neuronal hyperactivity. Together, our findings expand the clinical and genetic spectrum of CELF2-related neurodevelopmental disorders and establish a variant-specific mechanism that links CELF2 mislocalization to neuronal hyperactivity, seizures, and cognitive impairment.
Authors
Michelle Hua, Mohamad-Reza Aghanoori, Melissa J. MacPherson, Yi Ren, Shehani V. Siripala, Yifan Yang, Yvonne Yan Yan Or, Malea Nguyen, Robert Duba-Kiss, Daniel Feng, Laura Williams, Christopher J. Gafuik, GengYi Wang, Chloe Quelin, Boris Keren, Sarah Schuhmann, Georgia Vasileiou, Alexia Bourgois, Antonio Vitobello, Christophe Philippe, Zornitza Stark, Richard J. Leventer, George McGillivray, Frederic Tran Mau-Them, Marine Tessarech, Clément Prouteau, Phillis Lakeman, Mahdi M. Motazacker, Donald R. Latner, Raymond C. Caylor, Yvette van Ierland, Eloise Prijoles, Angie Lichty, Evangelos Theodorou, David A. Sweetser, Edward Steel, Jan Cobben, Majed J. Dasouki, Daniel G. Calame, Bertrand Isidor, Benjamin Cogné, Mitchell Kesler, Brooke Rackel, Isabel Clark, Deborah M. Kurrasch, G. Campbell Teskey, James Ellis, Guiqiong He, Scott D. Ryan, Douglas J. Mahoney, A. Micheil Innes, Jonathan R. Epp, Guang Yang
Abstract
BACKGROUND. Sepsis is a leading cause of morbidity and mortality in critically ill children, yet heterogeneous immune responses complicate the development of targeted therapies and the host immune factors driving sepsis pathobiology remain unclear. METHODS. We integrated deep immune phenotyping, plasma proteomics, single-cell transcriptomics, and phosphoflow cytometry in a prospective cohort of 88 critically ill children to elucidate the mechanisms underlying immune heterogeneity. RESULTS. Unsupervised clustering of plasma cytokines identified three immunologic subgroups, including a high-severity group (“Group C”) characterized by hypercytokinemia driven by IL-6 and IFN-γ. Group C exhibited distinct alterations in immune cell frequency and activation, with a strong association between hyperinflammatory cytokine signaling and lymphocyte dysfunction. Single-cell RNA sequencing revealed transcriptional signatures of T cell activation and metabolic stress, with suppression of a lymphoid protective gene program across CD8⁺ T cell subsets. Despite increased expression of activation markers, T cell receptor repertoire analysis revealed no dominant clonotypes, consistent with bystander activation. Phosphoflow cytometry demonstrated baseline STAT1/STAT3 hyperactivation in Group C CD8⁺ T cells, which failed to respond to αCD3/αCD28/αCD49d stimulation. CONCLUSIONS. These findings define an IL‑6/IFN‑γ–driven endotype of T cell dysfunction in pediatric sepsis and highlight the JAK/STAT axis as a rational target for immunomodulatory therapy. FUNDING. K12HD047349, K23GM159013, K08AI135091, R01HD095976, Thrasher Research Foundation, Burroughs Wellcome Fund CAMS, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute
Authors
Robert B. Lindell, Samir U. Sayed, Jose S. Campos Duran, Sydney A. Sheetz, Apoorva Babu, Montana S. Knight, Andrea A. Mauracher, Ceire A. Hay, Peyton E. Conrey, Julie C. Fitzgerald, Nadir Yehya, Stephen T. Famularo III, Teresa Arroyo, Richard Tustin III, Hossein Fazelinia, Edward M. Behrens, David T. Teachey, Lisa R. Forbes Satter, Alexandra F. Freeman, Jenna R.E. Bergerson, Steven M. Holland, Jennifer W. Leiding, Scott L. Weiss, Mark W. Hall, Deanne M. Taylor, Rui Feng, E. John Wherry, Nuala J. Meyer, Sarah E. Henrickson
Abstract
Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of breast cancer patients and showed that cytotoxic treatments led to strong therapeutic bottlenecks, resulting in significant reductions in hematopoietic allelic populations and differential clonal selection. Positively selected CH that expanded through dose-dependent therapeutic bottlenecks harbored mutations in TP53, PPM1D, SRCAP, DNMT3A, and YLPM1. Patients with positively selected CH during treatment had the shortest progression-free and overall survival compared to patients with unchanging or negatively selected CH across all therapies. These findings, validated in independent breast cancer and pan-cancer cohorts, provide strong evidence for clinical relevance of monitoring CH during cancer treatment.
Authors
Mona Arabzadeh, Yi-Han Tang, Christelle Colin-Leitzinger, Sadegh Marzban, Daniel Walgenbach, Stefania Morganti, Vaidhyanathan Mahaganapathy, Erika Harper, Mingxiang Teng, Jacob K. Kresovich, Iman Washington, Heather A. Parsons, Judy E. Garber, Jeffrey West, Shridar Ganesan, Hossein Khiabanian, Nancy Gillis
Abstract
BACKGROUND The relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood.METHODS We analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC patients in the IMmotion150 phase II clinical trial, where patients were randomized to atezolizumab, atezolizumab/bevacizumab, or sunitinib.RESULTS Angiogenic tumors (clusters 1 and 2) had a higher rate of pancreatic (21% vs. 6.9%; P = 0.002) and lower absolute number of lymph node (2.5 vs. 4.2; P = 0.006) metastases. In contrast, proliferative tumors (clusters 4 and 5) exhibited a higher absolute number of lymph node metastases (5.5 vs. 3.5; P = 0.019). Patients with pancreatic metastases receiving sunitinib had higher odds of overall response (OR, 7.13; 95% CI, 1.81–28.07; P = 0.0049) and longer progression-free survival than those without pancreatic metastases (P = 0.02).CONCLUSION ccRCC metastatic tropism relates to molecular clusters that predict response to therapy for tumors that metastasize to the pancreas.TRIAL REGISTRATION ClinicalTrials.gov NCT01984242FUNDING NIH grants R01CA154475 and P50CA196516.
Authors
Gaelle Haddad, Junyu Guo, Yin Xi, Emin Albayrak, Mahrukh Huseni, Habib Hamidi, Romain Banchereau, Edward Kadel, Sarita Dubey, Corey Carter, Payal Kapur, James Brugarolas, Ivan Pedrosa
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)