ABSTRACT
PURPOSE: We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR). EXPERIMENTAL DESIGN: We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs between 2011 and 2022. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), next-generation sequencing (NGS), and whole-exome sequencing (WES) data were analyzed to identify characteristics enriched in patients achieving LTR compared with STR and non-LTR. RESULTS: Among 3,118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival (OS) of 81% and 18% among LTR and STR patients, respectively. High TMB (≥50th percentile) enriched for LTR compared with STR (P = 0.001) and non-LTR (P < 0.001). Whereas PD-L1 ≥ 50% enriched for LTR compared with non-LTR (P < 0.001), PD-L1 ≥ 50% did not enrich for LTR compared with STR (P = 0.181). Nonsquamous histology (P = 0.040) and increasing depth of response [median best overall response (BOR) -65% vs. -46%, P < 0.001] also associated with LTR compared with STR; no individual genomic alterations were uniquely enriched among LTR patients. CONCLUSIONS: Among patients with advanced NSCLC treated with ICIs, distinct features including high TMB, nonsquamous histology, and depth of radiographic improvement distinguish patients poised to achieve LTR compared with initial response followed by progression, whereas high PD-L1 does not.
Subject(s)
Antineoplastic Agents, Immunological , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen , Retrospective Studies , Antineoplastic Agents, Immunological/adverse effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/therapeutic useABSTRACT
PURPOSE: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued. EXPERIMENTAL DESIGN: Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. RESULTS: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM-wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. CONCLUSIONS: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.
Subject(s)
Ataxia Telangiectasia Mutated Proteins , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Female , Humans , Ataxia Telangiectasia Mutated Proteins/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Genomics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Mutation, MissenseABSTRACT
BACKGROUND: Dyskeratosis congenita (DC) is a telomere biology disorder associated with high rates of bone marrow failure (BMF) and other medical complications. Oral androgens are successfully used to treat BMF in DC but often have significant side effects, including elevation of serum lipids. This study sought to determine the extent to which oral androgen therapy altered lipid and lipoprotein levels. METHODS: Nuclear magnetic resonance (NMR) was used to evaluate serum lipid profiles, and lipoprotein particle number and size in nine androgen-treated individuals with DC, 45 untreated individuals with DC, 72 unaffected relatives of DC patients, and 19 untreated individuals with a different inherited BMF syndrome, Fanconi anaemia (FA). FINDINGS: Androgen-treated individuals with DC had significantly decreased serum HDL cholesterol, HDL particle number and HDL particle size (p < 0·001, p < 0·001 and p < 0·001, respectively); significantly increased serum LDL cholesterol and LDL particle number (p < 0·001, p < 0·001, respectively), decreased apoA-I and increased apoB (p < 0â 001, p < 0â 05 respectively) when compared with untreated individuals with DC. There were no significant lipid profile differences between untreated DC and untreated FA participants; or between untreated DC participants and their unaffected relatives. Branched chain amino acids and lipoprotein insulin resistance were not significantly different with androgen treatment. GlycA, an inflammatory acute phase reactant, was significantly increased with androgen treatment (p < 0â 001). INTERPRETATION: Androgen treatment in DC creates an atherogenic lipoprotein profile, raising concern for the potential of elevated cardiovascular disease risk. Clinical guidelines for individuals on androgens for DC-related BMF should include cardiovascular disease monitoring. These findings could be relevant in individuals treated with androgen for other indications. FUNDING: Intramural research programs of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Heart, Lung, and Blood Institute.
Subject(s)
Androgens , Dyskeratosis Congenita , Androgens/adverse effects , Apolipoproteins B , Dyskeratosis Congenita/drug therapy , Dyskeratosis Congenita/genetics , Dyskeratosis Congenita/metabolism , Humans , Lipoproteins , Telomere/metabolismABSTRACT
Recessive dystrophic epidermolysis bullosa (RDEB) is a complex inherited skin disorder caused by loss-of-function mutations in the COL7A1 gene. For an effective treatment of this disorder to be realized, both a thorough understanding of the regulation of COL7A1 and an understanding of the underlying nature of the complications of RDEB are needed. Currently, both posttranscriptional regulation of COL7A1 and the underlying causes of fibrosis in RDEB patients are poorly understood. Here, we describe a mechanism of regulation, to our knowledge previously unknown, by which micro RNA-29 (miR-29) regulates COL7A1 in a complex network: both directly through targeting its 3' untranslated region at two distinct seed regions and indirectly through targeting an essential transcription factor required for basal COL7A1 expression, SP1. In turn, miR-29 itself is regulated by SP1 activity and transforming growth factor-ß signaling. RDEB mice express high levels of transforming growth factor-ß and significantly lower miR-29 compared with wild-type cohorts. The sustained decrease in miR-29 in RDEB skin leads to an increase of miR-29 target genes expressed in the skin, including profibrotic extracellular matrix collagens. Collectively, we identify miR-29 as an important factor in both regulating COL7A1 and inhibiting transforming growth factor-ß-mediated fibrosis.
Subject(s)
Collagen Type VII/genetics , Epidermolysis Bullosa Dystrophica/genetics , MicroRNAs/genetics , Transforming Growth Factor beta/metabolism , Animals , Cell Line , Cells, Cultured , Fibrosis , Humans , Mice , Sp1 Transcription Factor/metabolismABSTRACT
BACKGROUND: Targeting drug delivery to invasive glioma cells is a particularly difficult challenge because these cells lie behind an intact blood-brain barrier (BBB) that can be observed using multimodality imaging. BBB-associated efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) influence drug distribution to these cells and may negatively impact efficacy. To test the hypothesis that efflux transporters influence brain pharmacokinetics/pharmacodynamics of molecularly targeted agents in glioma treatment, we assessed region-specific penetrance and molecular-targeting capacity for a PI3K/mTOR kinase inhibitor that has high substrate affinity for efflux transporters (GDC-0980) and an analog (GNE-317) that was purposely designed to have reduced efflux. METHODS: Brain tumor penetrance of GDC-0980 and GNE-317 was compared between FVB/n wild-type mice and Mdr1a/b(-/-)Bcrp(-/-) triple-knockout mice lacking P-gp and BCRP. C57B6/J mice bearing intracranial GL261 tumors were treated with GDC-0980, GNE-317, or vehicle to assess the targeted pharmacokinetic/pharmacodynamic effects in a glioblastoma model. RESULTS: Animals treated with GNE-317 demonstrated 3-fold greater penetrance in tumor core, rim, and normal brain compared with animals dosed with GDC-0980. Increased brain penetrance correlated with decreased staining of activated p-Akt, p-S6, and p-4EBP1 effector proteins downstream of PI3K and mTOR. CONCLUSIONS: GDC-0980 is subject to active efflux by P-gp and BCRP at the BBB, while brain penetrance of GNE-317 is independent of efflux, which translates into enhanced inhibition of PI3K/mTOR signaling. These data show that BBB efflux by P-gp and BCRP is therefore an important determinant in both brain penetrance and molecular targeting efficacy in the treatment of invasive glioma cells.
Subject(s)
ATP-Binding Cassette Transporters/antagonists & inhibitors , Antineoplastic Agents/pharmacokinetics , Brain Neoplasms/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Glioblastoma/metabolism , Phosphoinositide-3 Kinase Inhibitors , Pyrimidines/pharmacokinetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , Thiophenes/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Animals , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain Neoplasms/prevention & control , Drug Delivery Systems , Glioblastoma/prevention & control , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Hypoxia inducible factor (HIF) prolyl-4-hydroxylase domain-containing proteins (PHDs) promote the degradation of HIF-1alpha. Because HIF-1alpha is highly expressed in the renal medulla and HIF-1alpha-targeted genes such as nitric oxide synthase, cyclooxygenase, and heme oxygenase are important in the regulation of renal medullary function, we hypothesized that PHD regulates HIF-1alpha levels in the renal medulla and, thereby, participates in the control of renal Na(+) excretion. Using real-time RT-PCR, Western blot, and immunohistochemical analyses, we have demonstrated that all three isoforms of PHD, PHD1, PHD2, and PHD3, are expressed in the kidneys and that PHD2 is the most abundant isoform. Regionally, all PHDs exhibited much higher levels in renal medulla than cortex. A furosemide-induced increase in renal medullary tissue Po(2) significantly decreased PHD levels in renal medulla, whereas hypoxia significantly increased mRNA levels of PHDs in cultured renal medullary interstitial cells, indicating that O(2) regulates PHDs. Functionally, the PHD inhibitor l-mimosine (l-Mim, 50 mg x kg(-1) x day(-1) i.p. for 2 wk) substantially upregulated HIF-1alpha expression in the kidneys, especially in the renal medulla, and remarkably enhanced (by >80%) the natriuretic response to renal perfusion pressure in Sprague-Dawley rats. Inhibition of HIF transcriptional activity by renal medullary transfection of HIF-1alpha decoy oligodeoxynucleotides attenuated l-Mim-induced enhancement of pressure natriuresis, which confirmed that HIF-1alpha mediated the effect of l-Mim. These results indicate that highly expressed PHDs in the renal medulla make an important contribution to the control of renal Na(+) excretion through regulation of HIF-1alpha and its targeted genes.