RÉSUMÉ
Cancer immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD); however, a significant proportion of patients do not respond. Recent transcriptomic studies to understand determinants of immunotherapy response have pinpointed stromal-mediated resistance mechanisms. To gain a better understanding of stromal biology at the cellular and molecular level in LUAD, we performed single-cell RNA sequencing of 256,379 cells, including 13,857 mesenchymal cells, from 9 treatment-naïve patients. Among the mesenchymal cell subsets, FAP+PDPN+ cancer-associated fibroblasts (CAF) and ACTA2+MCAM+ pericytes were enriched in tumors and differentiated from lung-resident fibroblasts. Imaging mass cytometry revealed that both subsets were topographically adjacent to the perivascular niche and had close spatial interactions with endothelial cells (EC). Modeling of ligand and receptor interactomes between mesenchymal and ECs identified that NOTCH signaling drives these cell-to-cell interactions in tumors, with pericytes and CAFs as the signal receivers and arterial and PLVAPhigh immature neovascular ECs as the signal senders. Either pharmacologically blocking NOTCH signaling or genetically depleting NOTCH3 levels in mesenchymal cells significantly reduced collagen production and suppressed cell invasion. Bulk RNA sequencing data demonstrated that NOTCH3 expression correlated with poor survival in stroma-rich patients and that a T cell-inflamed gene signature only predicted survival in patients with low NOTCH3. Collectively, this study provides valuable insights into the role of NOTCH3 in regulating tumor stroma biology, warranting further studies to elucidate the clinical implications of targeting NOTCH3 signaling. SIGNIFICANCE: NOTCH3 signaling activates tumor-associated mesenchymal cells, increases collagen production, and augments cell invasion in lung adenocarcinoma, suggesting its critical role in remodeling tumor stroma.
Sujet(s)
Adénocarcinome pulmonaire , Fibroblastes associés au cancer , Tumeurs du poumon , Invasion tumorale , Récepteur Notch3 , Analyse sur cellule unique , Cellules stromales , Microenvironnement tumoral , Humains , Adénocarcinome pulmonaire/anatomopathologie , Adénocarcinome pulmonaire/métabolisme , Adénocarcinome pulmonaire/génétique , Fibroblastes associés au cancer/métabolisme , Fibroblastes associés au cancer/anatomopathologie , Communication cellulaire , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Tumeurs du poumon/génétique , Récepteur Notch3/métabolisme , Récepteur Notch3/génétique , Transduction du signal , Cellules stromales/métabolisme , Cellules stromales/anatomopathologieRÉSUMÉ
OBJECTIVE: This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment-associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study. METHODS: Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for TcellinfGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-TcellinfGEP signatures; all but TcellinfGEP and TMB were adjusted for multiplicity. RESULTS: No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and TcellinfGEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c+ and CD11c+/MHCII-/CD163-/CD68- in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively). CONCLUSIONS: This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c+ and CD11c+/MHCII-/CD163-/CD68- phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02674061.
Sujet(s)
Antinéoplasiques immunologiques , Tumeurs de l'ovaire , Humains , Femelle , Antinéoplasiques immunologiques/usage thérapeutique , Anticorps monoclonaux humanisés/usage thérapeutique , Survie sans progression , Carcinome épithélial de l'ovaire/traitement médicamenteux , Marqueurs biologiques tumoraux/génétique , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs de l'ovaire/génétique , Tumeurs de l'ovaire/induit chimiquement , Microenvironnement tumoralRÉSUMÉ
BACKGROUND: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. METHODS: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 non-TcellinfGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-ß, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for TcellinfGEP (prespecified α=0.05) and the 10 non-TcellinfGEP signatures (multiplicity-adjusted; prespecified α=0.10). RESULTS: RNA sequencing data were available for 137 patients in each treatment group. TcellinfGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellinfGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. CONCLUSIONS: This exploratory analysis of tumor TcellinfGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis. TRIAL REGISTRATION NUMBER: NCT02370498.
Sujet(s)
Paclitaxel , Tumeurs de l'estomac , Humains , Paclitaxel/pharmacologie , Paclitaxel/usage thérapeutique , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/anatomopathologie , Transcriptome , Anticorps monoclonaux humanisés/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Over half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s). METHODS: We classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring MEK pathway activation, MEKi "bypass" resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154). RESULTS: Here we report a central role of SRC in mediating "bypass"-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P < 10-320), which is similarly associated with EMT (epithelial to mesenchymal transition), regional metastasis and disease recurrence with poor prognosis. Deeper analysis shows that both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype. This association is validated in additional independent CRC tumor and cell lines datasets. The CMS classification analysis demonstrates the strikingly-distinct associations of CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS mutant, mesenchymal CSC-like CMS4 CRCs. CONCLUSIONS: Large human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations. We identified SRC as a common targetable node--an Achilles' heel--in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC.
Sujet(s)
Antinéoplasiques/pharmacologie , Tumeurs colorectales/traitement médicamenteux , Résistance aux médicaments antinéoplasiques/génétique , Mitogen-Activated Protein Kinase Kinases/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/pharmacologie , src-Family kinases/antagonistes et inhibiteurs , Tumeurs colorectales/génétique , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Humains , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Protéines proto-oncogènes p21(ras)/génétique , Transcriptome/effets des médicaments et des substances chimiquesRÉSUMÉ
Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell-inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFß biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.
Sujet(s)
Antigène CD274 , Immunothérapie , Tumeurs , Récepteur-1 de mort cellulaire programmée , Animaux , Antigène CD274/antagonistes et inhibiteurs , Marqueurs biologiques tumoraux/génétique , Lignée cellulaire tumorale , Modèles animaux de maladie humaine , Humains , Inhibiteurs de points de contrôle immunitaires , Souris , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Microenvironnement tumoralRÉSUMÉ
PURPOSE: To explore relationships between biological gene expression signatures and pembrolizumab response. EXPERIMENTAL DESIGN: RNA-sequencing data on baseline tumor tissue from 1,188 patients across seven tumor types treated with pembrolizumab monotherapy in nine clinical trials were used. A total of 11 prespecified gene expression signatures [18-gene T-cell-inflamed gene expression profile (TcellinfGEP), angiogenesis, hypoxia, glycolysis, proliferation, MYC, RAS, granulocytic myeloid-derived suppressor cell (gMDSC), monocytic myeloid-derived suppressor cell (mMDSC), stroma/epithelial-to-mesenchymal transition (EMT)/TGFß, and WNT] were evaluated for their relationship to objective response rate (per RECIST, version 1.1). Logistic regression analysis of response for consensus signatures was adjusted for tumor type, Eastern Cooperative Oncology Group performance status, and TcellinfGEP, an approach equivalent to evaluating the association between response and the residuals of consensus signatures after detrending them for their relationship with the TcellinfGEP (previously identified as a determinant of pembrolizumab response) and tumor type. Testing of the 10 prespecified non-TcellinfGEP consensus signatures for negative association [except proliferation (hypothesized positive association)] with response was adjusted for multiplicity. RESULTS: Covariance patterns of the 11 signatures (including TcellinfGEP) identified in Merck-Moffitt and The Cancer Genome Atlas datasets showed highly concordant coexpression patterns in the RNA-sequencing data from pembrolizumab trials. TcellinfGEP was positively associated with response; signatures for angiogenesis, mMDSC, and stroma/EMT/TGFß were negatively associated with response to pembrolizumab monotherapy. CONCLUSIONS: These findings suggest that features beyond IFNγ-related T-cell inflammation may be relevant to anti-programmed death 1 monotherapy response and may define other axes of tumor biology as candidates for pembrolizumab combinations. See related commentary by Cho et al., p. 1479.
Sujet(s)
Antinéoplasiques immunologiques , Tumeurs , Anticorps monoclonaux humanisés , Antinéoplasiques immunologiques/effets indésirables , Humains , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Tumeurs/anatomopathologie , ARN , Transcriptome , Facteur de croissance transformant bêta/génétiqueRÉSUMÉ
BACKGROUND: EGFR is a major therapeutic target for colorectal cancer. Currently, extended RAS/RAF testing identifies only nonresponders to EGFR inhibitors (EGFRi). We aimed to develop a mutation signature that further refines drug-sensitive subpopulations to improve EGFRi outcomes. METHODS: A prespecified, 203-gene expression signature score measuring cetuximab sensitivity (CTX-S) was validated with two independent clinical trial datasets of cetuximab-treated patients with colorectal cancer (n = 44 and n = 80) as well as an in vitro dataset of 147 cell lines. The CTX-S score was then used to decipher mutated genes that predict EGFRi sensitivity. The predictive value of the identified mutation signature was further validated by additional independent datasets. RESULTS: Here, we report the discovery of a 2-gene (APC+TP53) mutation signature that was useful in identifying EGFRi-sensitive colorectal cancer subpopulations. Mutant APC+TP53 tumors were more predominant in left- versus right-sided colorectal cancers (52% vs. 21%, P = 0.0004), in microsatellite stable (MSS) versus microsatellite instable (MSI) cases (47% vs. 2%, P < 0.0001), and in the consensus molecular subtype 2 versus others (75% vs. 37%, P < 0.0001). Moreover, mutant APC+TP53 tumors had favorable outcomes in two cetuximab-treated patient-derived tumor xenograft (PDX) datasets (P = 0.0277, n = 52; P = 0.0008, n = 98). CONCLUSIONS: Our findings suggest that the APC and TP53 combination mutation may account for the laterality of EGFRi sensitivity and provide a rationale for refining treated populations. The results also suggest addition of APC+TP53 sequencing to extended RAS/RAF testing that may directly increase the response rates of EGFRi therapy in selected patients. IMPACT: These findings, if further validated through clinical trials, could also expand the utility of EGFRi therapies that are currently underutilized.
Sujet(s)
Tumeurs colorectales/génétique , Gènes APC/physiologie , Protéine p53 suppresseur de tumeur/génétique , Femelle , Humains , Mâle , Mutation , PronosticRÉSUMÉ
PURPOSE: Molecular profiling of large databases of human tumor gene expression profiles offers novel opportunities for informing decisions in clinical development programs. EXPERIMENTAL DESIGN: Gene expression profile of programmed death ligand 1 (PD-L1) was explored in a dataset of 16,000 samples, including approximately 4,000 metastatic tumors, across >25 tumor types prevalent in the United States, looking for new indications for the programmed death 1 (PD-1) inhibitor pembrolizumab. PD-L1 expression was highly concordant with several genomic signatures indicative of immune-inflamed tumor microenvironment. Prevalence of activated immune-inflamed tumors across all tumor types was explored and used to rank tumor types for potential response to pembrolizumab monotherapy. RESULTS: The analysis yielded 3 tiers of indications in which high levels of PD-L1 and immune-inflamed signatures were found in up to 40% to 60%, 20% to 40%, and 0% to 20% of tumors. Tier 1 contained novel indications known at the time of analysis to be responsive to PD-1 checkpoint blockade in the clinic (such as melanoma and non-small cell lung cancer), as well as indications not studied in the clinic previously, including microsatellite instability-high colorectal, head and neck, bladder, and triple-negative breast cancers. Complementary analysis of an Asian/Pacific cancer dataset (gastric cancer) revealed high prevalence of immune-inflamed tumors in gastric cancer. These data contributed to prioritization of these indications for clinical development of pembrolizumab as monotherapy. CONCLUSIONS: Data highlight the value of molecular profiling in identifying populations with high unmet needs with potentially favorable response characteristics and accelerating development of novel therapies for these patients.See related commentary by Mansfield and Jen, p. 1443.
Sujet(s)
Anticorps monoclonaux humanisés/usage thérapeutique , Antinéoplasiques immunologiques/usage thérapeutique , Marqueurs biologiques tumoraux , Analyse de profil d'expression de gènes , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Anticorps monoclonaux humanisés/administration et posologie , Anticorps monoclonaux humanisés/effets indésirables , Antinéoplasiques immunologiques/administration et posologie , Antinéoplasiques immunologiques/effets indésirables , Antigène CD274/génétique , Antigène CD274/métabolisme , Prise de décision clinique , Bases de données génétiques , Prise en charge de la maladie , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Humains , Mutation , Tumeurs/anatomopathologie , Plan de recherche , Transcriptome , Résultat thérapeutique , États-UnisRÉSUMÉ
Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
Sujet(s)
Anticorps monoclonaux humanisés/usage thérapeutique , Antinéoplasiques immunologiques/usage thérapeutique , Marqueurs biologiques tumoraux/génétique , Thérapie moléculaire ciblée/méthodes , Tumeurs/génétique , Tumeurs/thérapie , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Points de contrôle du cycle cellulaire , Marqueurs génétiques , Humains , Immunothérapie , Inflammation/génétique , Mutation , Lymphocytes T/immunologie , Transcriptome , Charge tumorale/génétiqueRÉSUMÉ
BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Carcinome du canal pancréatique/traitement médicamenteux , Tumeurs du pancréas/traitement médicamenteux , Adulte , Sujet âgé , Amyloid precursor protein secretases/antagonistes et inhibiteurs , Protocoles de polychimiothérapie antinéoplasique/pharmacocinétique , Théorème de Bayes , Dérivés du benzène/administration et posologie , Dérivés du benzène/effets indésirables , Dérivés du benzène/pharmacocinétique , Carcinome du canal pancréatique/métabolisme , Désoxycytidine/administration et posologie , Désoxycytidine/effets indésirables , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacocinétique , Calendrier d'administration des médicaments , Femelle , Humains , Perfusions veineuses , Mâle , Adulte d'âge moyen , Tumeurs du pancréas/métabolisme , Propionates/administration et posologie , Propionates/effets indésirables , Propionates/pharmacocinétique , Récepteurs Notch/antagonistes et inhibiteurs , Récepteurs Notch/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Sulfones/administration et posologie , Sulfones/effets indésirables , Sulfones/pharmacocinétique ,RÉSUMÉ
Background: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods: Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs du cerveau/thérapie , Chimioradiothérapie , Glioblastome/thérapie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs du cerveau/anatomopathologie , Études de cohortes , Femelle , Études de suivi , Glioblastome/anatomopathologie , Humains , Mâle , Dose maximale tolérée , Adulte d'âge moyen , Pronostic , Taux de survie , Témozolomide/administration et posologie , Vorinostat/administration et posologie , Jeune adulteRÉSUMÉ
Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.
Sujet(s)
Anticorps monoclonaux humanisés/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Analyse de profil d'expression de gènes , Interféron gamma/métabolisme , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Tumeurs de l'estomac/immunologie , Antigène CD274/métabolisme , Biopsie , Carcinomes/traitement médicamenteux , Carcinomes/immunologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/immunologie , Régulation de l'expression des gènes tumoraux , Humains , Système immunitaire , Immunohistochimie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/immunologie , Mélanome/traitement médicamenteux , Mélanome/immunologie , Projets pilotes , Récepteur-1 de mort cellulaire programmée/métabolisme , Courbe ROC , Analyse de séquence d'ARN , Transduction du signal , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/immunologie , Tumeurs de l'estomac/traitement médicamenteux , Résultat thérapeutique , Microenvironnement tumoralRÉSUMÉ
Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.
Sujet(s)
Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Mutation/génétique , Protéines proto-oncogènes p21(ras)/génétique , Adulte , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Camptothécine/administration et posologie , Camptothécine/analogues et dérivés , Cétuximab/administration et posologie , Tumeurs colorectales/génétique , Survie sans rechute , Méthode en double aveugle , Exons/génétique , Femelle , Humains , Facteur de croissance IGF-I/génétique , Facteur de croissance IGF-II/génétique , Irinotécan , Mâle , Adulte d'âge moyen , Récepteur IGF de type 1/génétiqueRÉSUMÉ
BACKGROUND: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). PROCEDURE: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. RESULTS: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). CONCLUSIONS: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).
Sujet(s)
Anticorps monoclonaux/usage thérapeutique , Tumeurs osseuses/traitement médicamenteux , Ostéosarcome/traitement médicamenteux , Récepteur IGF de type 1/antagonistes et inhibiteurs , Sarcome d'Ewing/traitement médicamenteux , Adolescent , Adulte , Sujet âgé , Anticorps monoclonaux/effets indésirables , Anticorps monoclonaux humanisés , Tumeurs osseuses/mortalité , Enfant , Femelle , Humains , Antigène KI-67/analyse , Mâle , Adulte d'âge moyen , Ostéosarcome/mortalité , Sarcome d'Ewing/mortalitéRÉSUMÉ
Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared with DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, vintafolide has achieved favorable responses in phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR, as in vintafolide, fails to overcome P-gp-mediated efflux of DAVLBH in both in vitro and in vivo preclinical models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Mol Cancer Ther; 15(8); 1998-2008. ©2016 AACR.
Sujet(s)
Sous-famille B de transporteurs à cassette liant l'ATP/génétique , Antinéoplasiques/pharmacologie , Résistance aux médicaments antinéoplasiques/génétique , Acide folique/analogues et dérivés , Expression des gènes , Alcaloïdes de Vinca/pharmacologie , Animaux , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/génétique , Analyse de regroupements , Biologie informatique/méthodes , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Femelle , Récepteurs des folates à ancre GPI/antagonistes et inhibiteurs , Acide folique/pharmacologie , Analyse de profil d'expression de gènes , Humains , Souris , Platine/pharmacologie , ARN messager/génétique , ARN messager/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinicopathologic staging for decades. There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies. Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens, which identified a subset of 17 genes that best classify CRC, with APC playing a central role in predicting overall survival. APC may assume 0, 1 or 2 truncating mutations, each with a striking differential impact on survival. Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours; however, two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined. Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.
Sujet(s)
Protéine de la polypose adénomateuse colique/génétique , Tumeurs colorectales/génétique , Mutation/génétique , Protéine de la polypose adénomateuse colique/métabolisme , Noyau de la cellule/métabolisme , Tumeurs colorectales/anatomopathologie , Gènes tumoraux , Humains , Estimation de Kaplan-Meier , Instabilité des microsatellites , Taux de mutation , Métastase tumorale , Pronostic , Modèles des risques proportionnels , Coloration et marquage , Statistique non paramétrique , Protéines de type Wingless/métabolisme , Voie de signalisation Wnt/génétique , bêta-Caténine/métabolismeRÉSUMÉ
PURPOSE: We previously found that an epithelial-to-mesenchymal transition (EMT)-based gene expression signature was highly correlated with the first principal component (PC1) of 326 colorectal cancer tumors and was prognostic. This study was designed to improve these signatures for better prediction of metastasis and outcome. EXPERIMENTAL DESIGN: A total of 468 colorectal cancer tumors including all stages (I-IV) and metastatic lesions were used to develop a new prognostic score (ΔPC1.EMT) by subtracting the EMT signature score from its correlated PC1 signature score. The score was validated on six other independent datasets with a total of 3,697 tumors. RESULTS: ΔPC1.EMT was found to be far more predictive of metastasis and outcome than its parent scores. It performed well in stages I to III, among microsatellite instability subtypes, and across multiple mutation-based subclasses, demonstrating a refined capacity to predict distant metastatic potential even in tumors with a "good" prognosis. For example, in the PETACC-3 clinical trial dataset, it predicted worse overall survival in an adjusted multivariable model for stage III patients (HR standardized by interquartile range [IQR] = 1.50; 95% confidence interval, 1.25-1.81; P = 0.000016, N = 644). The improved performance of ΔPC1.EMT was related to its propensity to identify epithelial-like subpopulations as well as mesenchymal-like subpopulations. Biologically, the signature was correlated positively with RAS signaling but negatively with mitochondrial metabolism. ΔPC1.EMT was a "best of assessed" prognostic score when compared with 10 other known prognostic signatures. CONCLUSIONS: The study developed a prognostic signature score with a propensity to detect non-EMT features, including epithelial cancer stem cell-related properties, thereby improving its potential to predict metastasis and poorer outcome in stage I-III patients.
Sujet(s)
Tumeurs colorectales/diagnostic , Tumeurs colorectales/génétique , Analyse de profil d'expression de gènes , Transcriptome , Analyse de regroupements , Tumeurs colorectales/mortalité , Transition épithélio-mésenchymateuse/génétique , Femelle , Régulation de l'expression des gènes tumoraux , Humains , Estimation de Kaplan-Meier , Mâle , Instabilité des microsatellites , Métastase tumorale , Stadification tumorale , Évaluation des résultats des patients , Pronostic , Modèles des risques proportionnels , Reproductibilité des résultatsRÉSUMÉ
BACKGROUND: Insulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer. METHODS: Eligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided. RESULTS: The trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01). CONCLUSIONS: Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Récepteurs ErbB/antagonistes et inhibiteurs , Protéines proto-oncogènes/génétique , Récepteur IGF de type 1/métabolisme , Protéines G ras/génétique , Adulte , Sujet âgé , Anticorps monoclonaux/administration et posologie , Anticorps monoclonaux/effets indésirables , Anticorps monoclonaux humanisés , Asthénie/induit chimiquement , Camptothécine/administration et posologie , Camptothécine/effets indésirables , Camptothécine/analogues et dérivés , Cétuximab/administration et posologie , Cétuximab/effets indésirables , Tumeurs colorectales/génétique , Tumeurs colorectales/anatomopathologie , Survie sans rechute , Méthode en double aveugle , Calendrier d'administration des médicaments , Études de faisabilité , Femelle , Régulation de l'expression des gènes tumoraux , Humains , Hyperglycémie/induit chimiquement , Irinotécan , Estimation de Kaplan-Meier , Mâle , Adulte d'âge moyen , Protéines proto-oncogènes p21(ras) , Régulation positive/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Many disparate biomarkers have been proposed as predictors of response to histone deacetylase inhibitors (HDI); however, all have failed when applied clinically. Rather than this being entirely an issue of reproducibility, response to the HDI vorinostat may be determined by the additive effect of multiple molecular factors, many of which have previously been demonstrated. METHODS: We conducted a large-scale gene expression analysis using the Cancer Genome Project for discovery and generated another large independent cancer cell line dataset across different cancers for validation. We compared different approaches in terms of how accurately vorinostat response can be predicted on an independent out-of-batch set of samples and applied the polygenic marker prediction principles in a clinical trial. RESULTS: Using machine learning, the small effects that aggregate, resulting in sensitivity or resistance, can be recovered from gene expression data in a large panel of cancer cell lines.This approach can predict vorinostat response accurately, whereas single gene or pathway markers cannot. Our analyses recapitulated and contextualized many previous findings and suggest an important role for processes such as chromatin remodeling, autophagy, and apoptosis. As a proof of concept, we also discovered a novel causative role for CHD4, a helicase involved in the histone deacetylase complex that is associated with poor clinical outcome. As a clinical validation, we demonstrated that a common dose-limiting toxicity of vorinostat, thrombocytopenia, can be predicted (r = 0.55, P = .004) several days before it is detected clinically. CONCLUSION: Our work suggests a paradigm shift from single-gene/pathway evaluation to simultaneously evaluating multiple independent high-throughput gene expression datasets, which can be easily extended to other investigational compounds where similar issues are hampering clinical adoption.
Sujet(s)
Antinéoplasiques/pharmacologie , Autoantigènes/effets indésirables , Inhibiteurs de désacétylase d'histone/pharmacologie , Acides hydroxamiques/pharmacologie , Complexe Mi-2/NuRD/effets indésirables , Thrombopénie/diagnostic , Antinéoplasiques/effets indésirables , Lignée cellulaire tumorale , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes tumoraux , Inhibiteurs de désacétylase d'histone/effets indésirables , Humains , Acides hydroxamiques/effets indésirables , Valeur prédictive des tests , Thrombopénie/induit chimiquement , VorinostatRÉSUMÉ
Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.