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Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients.

ABSTRACT: Clinical, epidemiological and experimental data identified the insulin-like growth factor-1 receptor (IGF1R) as a candidate therapeutic target in oncology. While this paradigm is based on well-established biological facts, including the potent anti-apoptotic and cell survival capabilities of the receptor, most Phase III clinical trials designed to target the IGF1R led to disappointing results. The present study was aimed at evaluating the hypothesis that combined treatment composed of selective IGF1R inhibitor along with classical chemotherapy might be more effective than individual monotherapies in breast cancer treatment. Analyses included comprehensive measurements of the synergism achieved by various combination regimens using the CompuSyn software. In addition, proteomic analyses were conducted to identify the proteins involved in the synergistic killing effect at a global level. Data presented here demonstrates that co-treatment of IGF1R inhibitor along with chemotherapeutic drugs markedly improves the therapeutic efficiency in breast cancer cells. Of clinical relevance, our analyses indicate that high IGF1R baseline expression may serve as a predictive biomarker for IGF1R targeted therapy. In addition, we identified a ten-genes signature with potential predictive value. In conclusion, the use of a series of bioinformatics tools shed light on some of the biological pathways that might be responsible for synergysm in cancer therapy.

SUBMITTER: Sinai-Livne T

PROVIDER: S-EPMC7197451 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients.

Sinai-Livne Tali T Pasmanik-Chor Metsada M Cohen Zoya Z Tsarfaty Ilan I Werner Haim H Berger Raanan R

Oncotarget 20200428 17

Clinical, epidemiological and experimental data identified the insulin-like growth factor-1 receptor (IGF1R) as a candidate therapeutic target in oncology. While this paradigm is based on well-established biological facts, including the potent anti-apoptotic and cell survival capabilities of the receptor, most Phase III clinical trials designed to target the IGF1R led to disappointing results. The present study was aimed at evaluating the hypothesis that combined treatment composed of selective ...[more]

PMID: 32391121

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Project description:BackgroundNeoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity.MethodsWe performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments.ResultsThe most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients.ConclusionsOur study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1P409L, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that is characterized by its poor prognosis, rapid progression and development of drug resistance. Chemotherapy is a vital treatment option for most of PDAC patients. Stratification of PDAC patients, who would have a higher likelihood of responding to chemotherapy, could facilitate treatment selection and patient management.MethodsA quantitative proteomic study was performed to characterize the protein profiles in the plasma of PDAC patients undergoing chemotherapy to determine if specific biomarkers could be used to predict likelihood of therapeutic response.ResultsBy comparing the plasma proteome of the PDAC patients with positive therapeutic response and longer overall survival (Good-responders) to those who did not respond as well with shorter survival time (Limited-responders), we identified differential proteins and protein variants that could effectively segregate Good-responders from Limited-responders. Functional clustering and pathway analysis further suggested that many of these differential proteins were involved in pancreatic tumorigenesis. Four proteins, including vitamin-K dependent protein Z (PZ), sex hormone-binding globulin (SHBG), von Willebrand factor (VWF) and zinc-alpha-2-glycoprotein (AZGP1), were further evaluated as single or composite predictive biomarker with/without inclusion of CA 19-9. A composite biomarker panel that consists of PZ, SHBG, VWF and CA 19-9 demonstrated the best performance in distinguishing Good-responders from Limited-responders.ConclusionBased on the cohort investigated, our data suggested that systemic proteome alterations involved in pathways associated with inflammation, immunoresponse, coagulation and complement cascades may be reporters of chemo-treatment outcome in PDAC patients. For the majority of the patients involved, the panel consisting of PZ, SHBG, VWF and CA 19-9 was able to segregate Good-responders from Limited-responders effectively. Our data also showed that dramatic fluctuations of biomarker concentration in the circulating system of a PDAC patient, which might result from biological heterogeneity or confounding complications, could diminish the performance of a biomarker. Categorization of PDAC patients in terms of their tumor stages and histological types could potentially facilitate patient stratification for treatment.

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Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients.

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Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients.

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