ATM Deficiency Confers Specific Therapeutic Vulnerabilities in Bladder Cancer

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer

Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a serious, progressive, and often fatal disease that is in urgent need of improved therapies that treat it. One of the remaining therapeutic challenges is the increasingly recognized skeletal muscle dysfunction that interferes with exercise tolerance. Here we report that in the adult rat Sugen/hypoxia (SU/Hx) model of severe pulmonary hypertension (PH), there is highly significant, almost 50%, decrease in exercise endurance, and this is associated with a 25% increase in the abundance of type II muscle fiber markers, thick sarcomeric aggregates and an increase in the levels of FoxO1 in the soleus (a predominantly type I fiber muscle), with additional alterations in the transcriptomic profiles of the diaphragm (a mixed fiber muscle) and the extensor digitorum longus (a predominantly Type II fiber muscle). In addition, soleus atrophy may contribute to impaired exercise endurance. Studies in L6 rat myoblasts have showed that myotube differentiation is associated with increased FoxO1 levels and type II fiber markers, while the inhibition of FoxO1 leads to increased type I fiber markers. We conclude that the formation of aggregates and a FoxO1-mediated shift in the skeletal muscle fiber-type specification may underlie skeletal muscle dysfunction in an experimental study of PH

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin

Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue. Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV. Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV. Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV. This retrospective study demonstrates poor outcomes of metastatic urothelial carcinoma patients following discontinuation of Enfortumab Vedotin (EV). Only 51% received therapy after discontinuation of EV. Benchmarks for the interpretation of activity of new agents following EV were identified. The duration of EV was identified as a potential prognostic factor following discontinuation of EV

Impact of FGFR2/3 activating genomic alterations on response to enfortumab vedotin in metastatic urothelial carcinoma (mUC)

472 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment

Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC

Importance: Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy. Objective: To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin-stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022. Exposures: All patients received anti-PD-(L)1 monotherapy. Main Outcomes and Measures: Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR. Results: Overall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (≥250 cells/mm 2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P =.006; OS: HR, 0.74; P =.03) and validation (PFS: HR = 0.80; P =.01; OS: HR = 0.75; P =.001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (<1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65). Conclusions and Relevance: In these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.

Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11 -Mutant Non-Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) with has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring comutations could have favorable outcomes to ICIs. NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for versus NSCLC. Overall, 12.6% of NSCLC tumors had a with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in NSCLC ( < .01). Compared with , tumors with had higher CD8+T cells and natural killer cells ( < .01), higher TMB ( < .001) and neoantigen load ( < .001), and increased expression of and ( < .01), along with higher expression ( < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with . In the DFCI cohort, compared with the cohort, the tumors had higher objective response rates (42.9% 16.7%; = .04) and also had longer TTF (14.5 4.5 months, adj = .054) with ICI. NSCLC with comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches

The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

UNLABELLED: African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men. SIGNIFICANCE: With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer