Citations

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P < 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P < 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P < 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P < 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Background/Objectives: Lung cancer is a devastating disease with the highest mortality rate among cancer types. Over 60% of non-small cell lung cancer (NSCLC) patients, accounting for 87% of lung cancer diagnoses, require radiation therapy. Rapid treatment initiation significantly increases the patient’s survival rate and reduces the mortality rate. Accurate tumor segmentation is a critical step in diagnosing and treating NSCLC. Manual segmentation is time- and labor-consuming and causes delays in treatment initiation. Although many lung nodule detection methods, including deep learning-based models, have been proposed. Most of these methods still have a long-standing problem of high false positives (FPs). Methods: Here, we developed an electronic health record (EHR)-guided lung tumor auto-segmentation called EXACT-Net (EHR-enhanced eXACtitude in Tumor segmentation), where the extracted information from EHRs using a pre-trained large language model (LLM) was used to remove the FPs and keep the TP nodules only. Results: The auto-segmentation model was trained on NSCLC patients’ computed tomography (CT), and the pre-trained LLM was used with the zero-shot learning approach. Our approach resulted in a 250% boost in successful nodule detection using the data from ten NSCLC patients treated in our institution. Conclusions: We demonstrated that combining vision-language information in EXACT-Net multi-modal AI framework greatly enhances the performance of vision only models, paving the road to multimodal AI framework for medical image processing.

Abstract Systematic multiomic analysis has revealed ancestry-dependent molecular alterations, but their impact on the efficacy of anticancer treatment is yet largely unknown. In this study, we analyzed clinical trials from ClinicalTrials.gov and found that only 8,779/102,721 (8.5%) oncology clinical trials posted information on enrollment by race/ethnicity. The underrepresentation of non-White populations suggests that it remains challenging to determine differences in the efficacy of antitumor treatments among different racial groups. Through a comprehensive analysis of clinically actionable genes, imputed drug responses, and immune features, we identified potential differences in treatment responses to targeted therapy, chemotherapy, and immunotherapy between different ancestral populations. Further analysis of multiple independent cohorts confirmed some of our key findings. Such potential ancestral effects are also identified in response to emerging new treatments like chimeric antigen receptor T-cell therapy and proteolysis-targeting chimeras. These findings are made publicly available in a comprehensive web portal, Ancestral Differences of Efficacy in Cancers (https://hanlaboratory.com/ADEC), to facilitate their further investigation. Significance: Our study charts a global landscape of ancestry-associated differences in therapeutic efficacy, highlighting the importance of considering ancestry in anticancer therapies.

The hierarchical organization of the connective tissue, more specifically, the musculoskeletal soft tissue, has been extensively studied. With advancements in experimental methodology, investigation of the structure–function relationship has provided more insight into how the mechanical integrity of the tissue is created. Such information is essential in the linking the macroscopic loading environment of the tissue to the microscopic level of the tissue to be experienced by the cell. The flexibility and elastic modulus of gross connective tissue, the fascicle, the fiber and then the collagen molecule are compared based on the data available in the literature.

Abstract Lymphopenia following chemoradiation for high grade gliomas (HGG) is common and is associated with decreased survival. NT-I7 (efineptakin alfa) is a long-acting analog of the lymphocyte pro-survival cytokine, interleukin-7. Our Phase I dose-escalation study of 19 patients with HGG demonstrated early elevations in CD4+ and CD8+ T cells in the first 4 weeks after administration of NT-I7. In this study, we explored the diversity and potential functionality of the NT-I7-expanded T cell population. A subset of 4 subjects with glioblastoma multiforme (GBM) treated at 720 µg/kg of NT-I7 during adjuvant temozolomide in our study (NCT03687957) underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) of peripheral blood. CITE-seq with TCR clonotype sequencing (10x Genomics 5’) permitted simultaneous tracking of the T cell phenotype at the protein level, individual T cell clones, and gene expression dynamics between 4 timepoints: pre-treatment, and post-treatment weeks 1, 2, and 13. Here, we report the results of differential expression analyses between timepoints and patient-specific differences in T cell clonotype expansions. Both CD4+ and CD8+ T cells in our study patients had increased expression of T cell activation markers LTB, CISH, and CD74. CD8+ T cell subsets demonstrated additional elevations in genes important in cytotoxic function (granzymes (GZMA, GZMB) and perforin (PRF1)), MHC Class II expression (HLA-DRA, HLA-DRB1), and AP-1 transcription factor subunits (JUND, JUN, JUNB, FOS, FOSB). After excluding known viral antigen clonotypes, 2 of 4 patients demonstrated TCR clonotype expansion. Notably, nearly all the expanded TCR clonotypes were found within CD8+ T cells, but not CD4+ T cells. NT-I7 promotes activation, cytotoxic function, and selective clonotype expansion of CD8+ T cells in patients with HGG. This, combined with its role in increased CD4+ T cell counts, suggests NT-I7 may be a powerful tool to restore immune function after treatment-associated lymphopenia in HGG.

Abstract BACKGROUND Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG. METHODS We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS). RESULTS We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference. CONCLUSIONS rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.

Abstract INTRODUCTION Immunotherapy has not improved survival in recurrent GBM (rGBM). Indoleamine 2,3 dioxygenase 1 (IDO1), highly expressed in ~90% of patients with malignant glioma, is a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn) and enables immune escape. METHODS We hypothesized combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies would overcome tumor-related immunosuppression. This was an open-label Phase II study of two regimens: Arm A consisted of retifanlimab (anti-PD1, 500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B added the IDO inhibitor, epacadostat (400mg po BID), initiated prior to HFRT. Key inclusion criteria included dexamethasone ≤ 4 mg/day. The primary endpoint was overall survival (OS) at 9 months (OS-9). 24 evaluable patients were required to detect an OS-9 of 60% with 80% power, compared to 38% in historical controls (bevacizumab alone) by 1-sided 1-sample log rank test at alpha=0.1. RESULTS We previously reported Arm A. Here, we present results from Arm B. 25 of the 27 patients enrolled to regimen B were evaluable: median age 58years (23-71); 28% female; 23% MGMT promotor methylated; median KPS 90 (70 - 100); a median of 6 cycles of epacadostat as of May 2024 (1 - 13). 18 of 25 died with a median follow up 9.23 months. Median PFS was 7.52 months (95%CI: 5.52-9.43). Median OS was 9.5 months (95%CI 8.08-11.96). Regimen B met its primary endpoint with OS-9 of 61.07% (95%CI: 38.23-77.65%). There were 5 possible immune-related grade 3+ toxicities to date (2 ALT/AST increase; 3 rash). CONCLUSIONS Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders.

ABSTRACT Background The sterol regulatory element‐binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B‐cell lymphoma remains unclear. Methods We examined SREBP protein expression in human B‐cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B‐cell lymphoma cells. Results Our analysis revealed high levels of SREBP2 protein expression in human B‐cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG‐CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B‐cell lymphoma cell proliferation. However, B‐cell lymphoma cells responded to statin treatment by activating the mTORC1‐pS6 pathway, suggesting a compensatory mechanism to overcome statin‐induced cell cycle arrest. Combining low‐dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B‐cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B‐cell lymphoma.