Citations

TPS276 Background: Metastatic castration-resistant prostate cancer (mCRPC) can evolve into a neuroendocrine-like subtype with aggressive behavior and poor outcomes (1). Nuclear Receptor-Binding SET Domain Protein 2 (NSD2) is overexpressed in prostate cancer and is a driver of both androgen-receptor (AR)-dependent signaling and of neuroendocrine differentiation, where cancer cells lose AR dependence and response to AR pathway inhibitors (ARPIs) (2,3,4). In studies of patient-derived neuroendocrine prostate cancer (NEPC) models, genetic depletion of NSD2 led to restoration of AR expression, reversal of adeno-to-neuroendocrine differentiation, and re-sensitization to ARPI (4). We hypothesize that NSD2 inhibition can reverse resistance to ARPIs in patients with progressive mCRPC, including with neuroendocrine differentiation. KTX-2001 is an oral, potent and selective small molecule inhibitor of NSD2. It is the sponsor’s second NSD2 inhibitor to enter the clinic. The sponsor’s first in class NSD2 inhibitor, KTX-1001, was shown to be tolerable and have preliminary efficacy in patients with relapsed/refractory multiple myeloma (5). Methods: STRIKE-001 (NCT07103018) is a multicenter, open-label phase 1 dose escalation trial of KTX-2001 monotherapy (Part A) and KTX-2001 + darolutamide (Part B). Key inclusion criteria are males age ≥18 years with mCRPC, progression after receiving ARPI, Eastern Cooperative Oncology Group performance score of 0-1, willingness to undergo biopsy if safe and feasible, and life expectancy of ≥6 months. Participants take KTX-2001 by mouth once daily alone (Part A) or with darolutamide 600 mg twice daily (Part B). Dose escalation of KTX-2001 in Parts A and B will follow a 3+3 design and occur in parallel at multiple planned dose levels. Primary objectives are to assess the safety and tolerability, determine MTD, and determine RP2D(s) for further study of KTX-2001 alone and in combination with darolutamide. Secondary objectives include characterization of efficacy and PK parameters for both KTX-2001 monotherapy and in combination with darolutamide. Exploratory objectives include study of pharmacodynamic effects, circulating tumor cells, and cell-free DNA. 1. Conteduca V, Eur J Cancer 2019. 2. Parolia A, Nat Genet 2024. 3. Aytes A, Nat Commun 2018 4. Li J, bioRxiv 2023.07.18.549585 5. Bories P, Blood Vol 144, Suppl 1,2024. Clinical trial information: NCT07103018 .

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Abstract Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1 , PLEKHM1 , LRP2 , P2RX1 , and HAP1. Subsequent analysis of these genes in Parkinson’s disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

An understanding of regions of endemicity and the spectrum of organ system involvement can improve recognition of the imaging features of coccidioidomycosis, which can overlap with those of other diseases.

Abstract Background Research on gender and ethnic differences in white matter tracts yields mixed results. Although men show larger global corpus callosum (CC) in absolute values, women have demonstrated larger splenium and isthmus. Additionally, men have shown greater white matter and fractional anisotropy (FA) in multiple regions than women. This study investigates sex and ethnic differences in the corpus callosum and transcallosal white matter tissue microstructure of older individuals with normal cognition and memory disorders. Method 191 participants (Female n = 120; Hispanics n = 115; Non‐Hispanics n = 76; Age mean = 71.07; SD = 7.75) were included in the sample from the 1Florida ADRC with cognitively normal ( n = 75), MCI ( n = 88), and dementia ( n = 28) diagnoses. Corpus callosum volumes were collected using a Siemens Skyra 3T MRI scanner and were divided into anterior, mid‐anterior, central, mid‐posterior, and posterior regions. Also, MRI‐based free water diffusion tensor imaging (FW‐DTI) measured FW‐corrected FA (fwcFA) to assess and compare the integrity of transcallosal tract templates (TCATT) across motor, temporal, parietal, and occipital regions across males and females and ethnic groups. Result Univariate ANCOVAs controlling for age and clinical diagnosis were performed; females had larger normalized CC volumes in the posterior, F (1, 184) = 8.92, p = .003, η p 2 = .046, mid‐anterior, F (1,184)= 5.68, p = .018, η p 2 = .030, and anterior, F (1,184)= 14.54, p < .001, η p 2 = .073, regions, which all survived FDR corrections, with no ethnic differences observed. For transcallosal tracts, females had higher fwcFA in the inferior temporal gyrus, η p 2 Hispanics had higher fwcFA in the premotor cortex, η p 2 η p 2 Conclusion Sex and ethnicity influence white matter changes during aging independently of age and cognitive diagnosis. However, the effect explained by these demographic variables was very small, suggesting the influence of additional factors.

Abstract Ferritin, consisting of ferritin heavy chain (FTH1) and light chain (FTL) subunits, is an essential intracellular iron storage protein fundamental for cellular function. However, the source and the biological role of extracellular ferritin (ex-ferritin) are less understood. Recent studies have linked elevated serum ex-ferritin with adverse outcomes in individuals with acute respiratory distress syndrome (ARDS). In this study, we demonstrate that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AMs) of individuals with ARDS, a phenomenon we successfully replicate in a murine hyperoxia-induced acute lung injury (HALI) model. We show that FTH1 is consistently upregulated in macrophages during lung injury development, and mice with a targeted deletion of FTH1 in myeloid (LysMcre) or resident lung macrophage (Cd11ccre) populations exhibit attenuated HALI. This reduced injury is linked to macrophage resistance to ferroptotic cell death, ferritinophagy, altered airway inflammatory responses, and lower lung extracellular iron and higher levels of FTL-ex-ferritin. Transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid to wild-type mice protected against HALI. The ratio of FTL-ex-ferritin to FTH1 in the serum of individuals with ARDS who died was higher than that of those that survived, suggesting that the balance between FTH1 and FTL may play a role in injury modulation. Our findings highlight macrophage ferritin as a key regulator of macrophage survival and the response of the lung to injury, presenting a potentially targetable pathway for ARDS treatment.

SUMMARY Artificial intelligence (AI)-based methods are increasingly critical in peptide drug discovery, but their applications are limited in a narrow scope such as antimicrobial peptides. For indications where peptide therapy inherently excels, such as metabolism, endocrinology, and tissue regeneration, AI-based pipeline for therapeutic peptide discovery is long awaited but still unmet. Here, we propose a deep learning-based pipeline, Deepeptide, capable of identifying therapeutic oligopeptides for various metabolism-related indications. Leveraging the intrinsical relationship of ‘disease indication — biological processes — molecular functions’, Deepeptide discovers oligopeptides with indication-ameliorating-related molecular functions as lead candidates for indication of interest. Deepeptide was applied in five representative indications of metabolism, endocrinology, and tissue regeneration: angiogenesis, lipid metabolism, osteogenesis, glucose metabolism, and anti-angiogenesis. Overall, 62% of the identified oligopeptide candidates demonstrated significant bioactivity in vitro, with most of them showing comparable potency to the first-line drugs. Notably, the heptapeptide AP7 exhibited angiogenic potency comparable to VEGF in excisional wound splinting mouse model by promoting cell migration rather than proliferation, and hexapeptide TP6 showed significant dual-efficacy against hyperlipidemia and obesity in high-fat diet mice by inhibiting lipid synthesis and regulating gut microbiota. These findings highlight the potential and generalizability of Deepeptide in therapeutic oligopeptide discovery for metabolic diseases.

Localized cutaneous squamous cell carcinoma (cSCC) has a favorable prognosis, unlike advanced disease, especially with clinical perineural invasion (PNI), which poses substantial management challenges due to aggressivity and higher recurrence, metastasis, and mortality risks. PNI, a high-risk staging feature, has worse outcomes, particularly when clinically evident rather than incidental. Clinical PNI (cPNI) is evident by clinical symptoms (such as pain, paresthesia, or motor deficits) or radiologic findings, whereas incidental PNI (iPNI) is identified only histologically without associated symptoms or radiologic evidence. PNI remains a novel area with varying practice patterns across institutions. Improving risk stratification and tailoring multidisciplinary approaches are critical for optimizing outcomes. Our review outlines clinical practice patterns at our institution, providing insights into managing cSCC with PNI, focusing on diagnosis, imaging, staging, and emerging immunotherapies. A structured search was conducted using the terms “perineural invasion,” “cutaneous squamous cell carcinoma,” and “immunotherapy.” cPNI has a poor prognosis and requires nuanced clinical decision-making. Surgery and radiation remain central to management. Adjuvant therapy offers substantial survival benefit in cSCC with PNI, with improved disease-free and overall survival compared with surgery alone, supporting its use in appropriately selected high-risk patients. Traditional systemic therapies, including cisplatin and cetuximab, remain foundational but have shown only moderate response rates and limited durability in advanced or neurotropic cSCC. In contrast, immunotherapy—now preferred for advanced or unresectable cases—has transformed management, with programmed cell death protein-1 (PD-1) inhibitors showing promising results (up to 69% response rate) and disease stabilization. Neoadjuvant immunotherapy may enable tumor downstaging, improve radiation planning, and reduce surgical morbidity. Imaging for squamous cell carcinoma (SCC) with PNI aids staging and surveillance, but symptoms remain key for detecting recurrence. Our multidisciplinary approach emphasizes personalized care. Larger trials are needed to define the optimal role and sequencing of immunotherapy in this high-risk patient population.

Abstract While immunotherapy has transformed treatment in multiple solid tumors, its efficacy in high-grade glioma (HGG) remains limited. Understanding the molecular and clinical factors that influence HGG’s response to immunotherapy is essential to improving outcomes. We identified patients with grade 4 gliomas who had been treated with checkpoint inhibitor (CPI), virus therapy, or CMV-specific T- cell therapy and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes. We identified 66 patients, 57 glioblastoma and 9 astrocytoma, IDH-mutant grade 4; 38 were treated with CPI, 22 with virus therapy, and 6 with CMV-specific T- cell therapy. PIK3CA mutation was associated with shorter PFS and OS (p=0.022, 0.073, respectively) among all patients and a shorter OS among CPI-treated patients (p=0.004). PIK3CA wild-type tumors had less PD-1 expression in CD3+/CD8+ T cells. In CPI-treated patients, IDH1/2 mutation was associated with a shorter OS (p=0.002), and mutations in RB1 and TERT promoter were associated with a shorter PFS (p-value=0.00056, 0.022, respectively). Length of CPI therapy of more than 6 months was associated with increased PFS and OS (p=0.048, 0.062, respectively), while steroid use at baseline was associated with a shorter OS (p=0.00023). Multifocal disease was associated with shorter PFS and OS durations (p=0.0017, 0.0013, respectively) among all patients. In HGG, PIK3CA, IDH1/2, RB1, and TERT promoter mutations may be associated with a poor response to immunotherapy. These results need to be validated in larger studies. Our results may provide the rationale for clinical trials combining PI3K and IDH inhibitors with CPI in HGG.