Lineage-specific biomarkers predict response to FGFR inhibition.
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ABSTRACT:
SUBMITTER: Loch DC
PROVIDER: S-EPMC4300517 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UnlabelledFGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.SignificanceRobust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
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Project description:Nivolumab is a fully human immunoglobulin (Ig) G4 antibody that selectively inhibits the programmed death 1 (PD-1) immune checkpoint molecule, and has recently been launched for the treatment of renal cell cancer (RCC) in Japan. Based on its promising anti-tumor efficacy and manageable safety profile demonstrated in the phase III Checkmate 025 trial, nivolumab therapy is rapidly being introduced in metastatic RCC clinical practice. The phase Ia study of atezolizumab, which is a humanized anti-PD-ligand 1 (PD-L1) monoclonal IgG1 antibody, also demonstrated excellent treatment results. The identification of biomarkers to predict the response and side-effects of checkpoint inhibitor therapy is thus urgently needed. In this review, we introduce the current candidate biomarkers of immune checkpoint inhibitor therapy. Based on the mechanism of efficacy, the number of neoantigens and expression of major histocompatibility complex molecules are strong candidate biomarkers. Despite the various interference factors, PD-L1 expression can be considered a potential biomarker. In terms of clinical factors, serum clinical factors and severity of adverse events are examined. Although further implementation in prospective studies is necessary, if validated, these biomarkers can be utilized to measure therapeutic response and design treatment strategies for metastatic RCC.
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Project description:Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.
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Project description:Cancer cells can leverage several cell-intrinsic and -extrinsic mechanisms to escape immune system recognition. The inherent complexity of the tumor microenvironment, with its multicellular and dynamic nature, poses great challenges for the extraction of biomarkers of immune response and immunotherapy efficacy. Here, we use RNA-sequencing (RNA-seq) data combined with different sources of prior knowledge to derive system-based signatures of the tumor microenvironment, quantifying immune-cell composition and intra- and intercellular communications. We applied multi-task learning to these signatures to predict different hallmarks of immune responses and derive cancer-type-specific models based on interpretable systems biomarkers. By applying our models to independent RNA-seq data from cancer patients treated with PD-1/PD-L1 inhibitors, we demonstrated that our method to Estimate Systems Immune Response (EaSIeR) accurately predicts therapeutic outcome. We anticipate that EaSIeR will be a valuable tool to provide a holistic description of immune responses in complex and dynamic systems such as tumors using available RNA-seq data.
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Project description:The effectiveness of immunotherapy as a treatment for metastatic breast cancer is limited due to low numbers of infiltrating lymphocytes in metastatic lesions. Herein, we demonstrated that adjuvant therapy using FIIN4, a covalent inhibitor of fibroblast growth factor receptor (FGFR), dramatically delayed the growth of pulmonary metastases in syngeneic models of metastatic breast cancer. In addition, we demonstrated in a syngeneic model of systemic tumor dormancy that targeting of FGFR enhanced the immunogenicity of the pulmonary tumor microenvironment through increased infiltration of CD8+ lymphocytes and reduced presence of myeloid suppressor cells. Similar impacts on immune cell infiltration were observed upon genetic depletion of FGFR1 in tumor cells, which suggested a direct influence of FGFR signaling on lymphocyte trafficking. Suppression of CD8+ lymphocyte infiltration was consistent with FGFR-mediated inhibition of the T-cell chemoattractant CXCL16. Initial attempts to concomitantly administer FIIN4 with immune checkpoint blockade failed due to inhibition of immune-mediated tumor cell killing via blockade of T-cell receptor signaling by FIIN4. However, this was overcome by using a sequential dosing protocol that consisted of FIIN4 treatment followed by anti-PD-L1. These data illustrate the complexities of combining kinase inhibitors with immunotherapy and provide support for further assessment of FGFR targeting as an approach to enhance antitumor immunity and improve immunotherapy response rates in patients with metastatic breast cancer.
| S-EPMC7710538 | biostudies-literature
Project description:Vascular risk factors, including inflammation, may contribute to dementia development. We investigated the associations between peripheral inflammatory biomarkers and cognitive decline in five domains (memory, construction, language, psychomotor speed, and executive function).Community-dwelling older adults from the Ginkgo Evaluation of Memory Study (n = 1,159, aged 75 or older) free of dementia at baseline were included and followed for up to 7 years. Ten biomarkers were measured at baseline representing different sources of inflammation: vascular inflammation (pentraxin 3 and serum amyloid P), endothelial function (endothelin-1), metabolic function (adiponectin, resistin, and plasminogen activating inhibitor-1), oxidative stress (receptor for advanced glycation end products), and general inflammation (interleukin-6, interleukin-2, and interleukin-10). A combined z-score was created from these biomarkers to represent total inflammation across these sources. We utilized generalized estimating equations that included an interaction term between z-scores and time to assess effect of inflammation on cognitive decline, adjusting for demographics (such as age, race/ethnicity, and sex), cardiovascular risk factors, and apolipoprotein E ?4 carrier status. A Bonferroni-adjusted significance level of .01 was used. We explored associations between individual biomarkers and cognitive decline without adjustment for multiplicity.The combined inflammation z-score was significantly associated with memory and psychomotor speed (p < .01). Pentraxin 3, serum amyloid P, endothelin-1, and interleukin-2 were associated with change in at least one cognitive domain (p < .05).Our results suggest that total inflammation is associated with memory and psychomotor speed. In particular, systemic inflammation, vascular inflammation, and altered endothelial function may play roles in domain-specific cognitive decline of nondemented individuals.
| S-EPMC5861845 | biostudies-literature
Project description:SHP2 mediates RAS activation downstream of multiple receptor tyrosine kinases (RTKs) and cancer cell lines dependent on RTKs are in general dependent on SHP2. Profiling of the allosteric SHP2 inhibitor SHP099 across cancer cell lines harboring various RTK dependencies reveals that FGFR-dependent cells are often insensitive to SHP099 when compared to EGFR-dependent cells. We find that FGFR-driven cells depend on SHP2 but exhibit resistance to SHP2 inhibitors in vitro and in vivo. Treatment of such models with SHP2 inhibitors results in an initial decrease in phosphorylated ERK1/2 (p-ERK) levels, however p-ERK levels rapidly rebound within two hours. This p-ERK rebound is blocked by FGFR inhibitors or high doses of SHP2 inhibitors. Mechanistically, compared with EGFR-driven cells, FGFR-driven cells tend to express high levels of RTK negative regulators such as the SPRY family proteins, which are rapidly downregulated upon ERK inhibition. Moreover, over-expression of SPRY4 in FGFR-driven cells prevents MAPK pathway reactivation and sensitizes them to SHP2 inhibitors. We also identified two novel combination approaches to enhance the efficacy of SHP2 inhibitors, either with a distinct site 2 allosteric SHP2 inhibitor or with a RAS-SOS1 interaction inhibitor. Our findings suggest the rapid FGFR feedback activation following initial pathway inhibition by SHP2 inhibitors may promote the open conformation of SHP2 and lead to resistance to SHP2 inhibitors. These findings may assist to refine patient selection and predict resistance mechanisms in the clinical development of SHP2 inhibitors and to suggest strategies for discovering SHP2 inhibitors that are more effective against upstream feedback activation.
| S-EPMC6980623 | biostudies-literature
Project description:The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors.
2021-11-07 | GSE188318 | GEO
Project description:BackgroundClinical trials based on FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue.MethodsExpression profiles of FGFs and FGFRs in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained and followed by integrative bioinformatics analysis.ResultsFGFs and FGFRs were frequently dysregulated in pancancer. Most of the expression of FGFs and FGFRs were significantly associated with overall survival in at least two cancer types. Moreover, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast, liver, lung and ovarian cancer. The predicted positive ratios of FGFR1-4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratios were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), and ovarian cancer (34%).ConclusionsFGFR expression was a promising predictive biomarker for FGFR inhibition response in clinical trials, and different combinations of FGFR genes should be used in screening for patients in certain tumor types.
| S-EPMC7293733 | biostudies-literature
Project description:Immune checkpoint inhibitor (ICI) treatment could bring long-lasting clinical benefits to patients with metastatic cancer. However, only a small proportion of patients respond to PD-1/PD-L1 blockade, so predictive biomarkers are needed. Here, based on DNA methylation profiles and the objective response rates (ORRs) of PD-1/PD-L1 inhibition therapy, we identified 269 CpG sites and developed an initial CpG-based model by Lasso to predict ORRs. Notably, as measured by the area under the receiver operating characteristic curve (AUC), our model can produce better performance (AUC = 0.92) than both a model based on tumor mutational burden (TMB) (AUC = 0.77) and a previously reported TMB model (AUC = 0.71). In addition, most CpGs also have additional synergies with TMB, which can achieve a higher prediction accuracy when joined with TMB. Furthermore, we identified CpGs that are associated with TMB at the individual level. DNA methylation modules defined by protein networks, Kyoto Encylopedia of Genes and Genomes (KEGG) pathways, and ligand-receptor gene pairs are also associated with ORRs. This method suggested novel immuno-oncology targets that might be beneficial when combined with PD-1/PD-L1 blockade. Thus, DNA methylation studies might hold great potential for individualized PD1/PD-L1 blockade or combinatory therapy.
| S-EPMC6707807 | biostudies-literature