22 results on '"Marilyne Labrie"'
Search Results
2. Systems approach to rational combination therapy: PARP inhibitors
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Gordon B. Mills, Chaoyang Sun, Xi Li, Yong Fang, and Marilyne Labrie
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G2 Phase ,MAPK/ERK pathway ,DNA Repair ,Combination therapy ,Poly ADP ribose polymerase ,Cell Cycle Proteins ,Poly(ADP-ribose) Polymerase Inhibitors ,Biochemistry ,Article ,S Phase ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Medicine ,Enzyme Inhibitors ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Clinical Trials as Topic ,0303 health sciences ,biology ,business.industry ,Protein-Tyrosine Kinases ,G2-M DNA damage checkpoint ,Wee1 ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,PARP inhibitor ,biology.protein ,Cancer research ,Poly(ADP-ribose) Polymerases ,business ,DNA Damage - Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated activity across a broad spectrum of molecular backgrounds and tumor types, with the greatest activity observed in patients with aberrations in the homologous recombination DNA damage repair pathway. Despite remarkable responses in a subset of patients, the response is usually modest and transient due to the almost inevitable emergence of resistance. Tumors develop resistance through rapid adaptation to the effects of PARPi as well as by generation or selection of genomic aberration. Although adaptive responses results in drug resistance, it also induces therapeutic vulnerabilities that could be exploited with rational combination therapies. To fulfill this role, we established the combinatorial adaptive response therapy (CART) platform by performing reverse-phase protein arrays to characterize adaptive responses, and develop rational combination therapies. Our series of studies strongly support the efficacy of this strategy, wherein targeting the emerging adaptive responses to PARPi with MEK/ERK inhibitors, WEE1/ATR inhibition (inhibitors of S-phase and G2 DNA damage checkpoint), and PI3K/AKT/mTOR inhibition, and showed promising anti-tumor activity in various preclinical models. Importantly, this approach has been proven highly efficient, and several combinational therapies developed from the CART platform are being evaluated in ongoing clinical trials (NCT03801369, NCT03586661, NCT03162627, NCT03544125, NCT02659241, NCT02208375, NCT02316834, and NCT03637491).
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- 2020
3. Adaptive responses in a PARP inhibitor window of opportunity trial illustrate limited functional interlesional heterogeneity and potential combination therapy options
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Yong Fang, Anil K. Sood, Robert L. Coleman, Tae-Beom Kim, Shannon N. Westin, Yiling Lu, Marilyne Labrie, Pedro T. Ramirez, Zhenlin Ju, Nicole D. Fleming, Ken Chen, Michael Frumovitz, Sanghoon Lee, Gordon B. Mills, Larissa A. Meyer, and Wei Zhao
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Combination therapy ,medicine.medical_treatment ,Knight Cancer Institute ,Gynecologic oncology ,Poly (ADP-Ribose) Polymerase Inhibitor ,combination therapy ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,adaptive response ,Internal medicine ,Medicine ,Talazoparib ,poly (ADP-ribose) polymerase inhibitor ,business.industry ,Cancer ,targeted therapy ,medicine.disease ,3. Good health ,ovarian cancer ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,PARP inhibitor ,business ,Research Paper - Abstract
// Marilyne Labrie 1 , Tae-Beom Kim 2 , Zhenlin Ju 2 , Sanghoon Lee 3 , Wei Zhao 3 , Yong Fang 1 , Yiling Lu 3 , Ken Chen 2 , Pedro Ramirez 4 , Michael Frumovitz 4 , Larissa Meyer 4 , Nicole D. Fleming 4 , Anil K. Sood 4 , Robert L. Coleman 4 , Gordon B. Mills 1 , 3 and Shannon N. Westin 4 1 Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA 2 Department of Bioinformatics and Computational Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 3 Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 4 Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Shannon N. Westin, email: swestin@mdanderson.org Keywords: poly (ADP-ribose) polymerase inhibitor; combination therapy; adaptive response; ovarian cancer; targeted therapy Received: March 12, 2019 Accepted: May 02, 2019 Published: May 28, 2019 ABSTRACT Poly (ADP-ribose) polymerase inhibitor (PARPi)-based combination therapies are demonstrating efficacy in patients, however, identifying the right combination for the right patient remains a critical challenge. Thus, it is urgent to develop approaches able to identify patients likely to benefit from specific combination therapies. Several groups, including ours, have demonstrated that targeting adaptive responses induced by PARPi increases depth and duration of response. In this study, we instituted a talazoparib (PARPi) monotherapy window of opportunity trial to identify informative adaptive responses in high grade serous ovarian cancer patients (HGSOC). Patients were treated for 7 to 14 days with PARPi monotherapy prior to surgery with tissue samples from multiple sites being collected pre- and post-treatment in each patient. Analysis of these samples demonstrated that individual patients displayed different adaptive responses with limited interlesional heterogeneity. Ability of combination therapies designed to interdict adaptive responses to decrease viability was validated using model systems. Thus, assessment of adaptive responses to PARPi provides an opportunity for patient-specific selection of combination therapies designed to interdict patient-specific adaptive responses to maximize patient benefit.
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- 2019
4. PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness
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Lulu Wang, Marilyne Labrie, Jianfeng Shen, Timothy A. Yap, Gordon B. Mills, Guang Peng, Wei Zhao, Zhenlin Ju, and Yang Peng
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0301 basic medicine ,Cancer Research ,Poly ADP ribose polymerase ,Genes, BRCA2 ,Mutant ,Genes, BRCA1 ,Mice, Nude ,Poly(ADP-ribose) Polymerase Inhibitors ,Article ,Antibodies ,B7-H1 Antigen ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Polymerase ,Mice, Knockout ,Ovarian Neoplasms ,Mice, Inbred BALB C ,biology ,business.industry ,Membrane Proteins ,Drug Synergism ,DNA ,Immune checkpoint ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Female ,Colorectal Neoplasms ,business ,Signal Transduction - Abstract
PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS–STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. Significance: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.
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- 2019
5. ME-VAE: Multi-Encoder Variational AutoEncoder for Controlling Multiple Transformational Features in Single Cell Image Analysis
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Luke Ternes, Mark Dane, Sean Gross, Marilyne Labrie, Gordon Mills, Joe Gray, Laura Heiser, and Young Hwan Chang
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Computer science ,business.industry ,Pattern recognition ,Artificial intelligence ,business ,Autoencoder ,Encoder ,Image (mathematics) - Abstract
Image-based cell phenotyping relies on quantitative measurements as encoded representations of cells; however, defining suitable representations that capture complex imaging features is challenged by the lack of robust methods to segment cells, identify subcellular compartments, and extract relevant features. Variational autoencoder (VAE) approaches produce encouraging results by mapping an image to a representative descriptor, and outperform classical hand-crafted features for morphology, intensity, and texture at differentiating data. Although VAEs show promising results for capturing morphological and organizational features in tissue, single cell image analyses based on VAEs often fail to identify biologically informative features due to uninformative technical variation. Herein, we propose a multi-encoder VAE (ME-VAE) in single cell image analysis using transformed images as a self-supervised signal to extract transform-invariant biologically meaningful features, including emergent features not obvious from prior knowledge. We show that the proposed architecture improves analysis by making distinct cell populations more separable compared to traditional VAEs and intensity measurements by enhancing phenotypic differences between cells and by improving correlations to other analytic modalities.
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- 2021
6. Phase 1b dose expansion and translational analyses of olaparib in combination with the oral AKT inhibitor capivasertib in recurrent endometrial, triple negative breast, and ovarian, primary peritoneal, or fallopian tube cancer
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Marszalek, Christopher P. Vellano, Robert L. Coleman, Marilyne Labrie, Ningping Feng, Gordon B. Mills, Nashwa Kabil, Aurora Blucher, Amir A. Jazaeri, Anil K. Sood, Allison L. Creason, Bryan Fellman, Shannon N. Westin, Tae-Beom Kim, Kathleen M. Schmeler, Anca Chelariu-Raicu, Yong Fang, Michael Frumovitz, Pamela T. Soliman, Tsun Hsuan Chen, Ravi Murthy, Jinsong Liu, Charlotte C. Sun, Xiao Yan Ma, Larissa A. Meyer, Sun Joo Lee, Karen H. Lu, Ying Yuan, and Jennifer K. Litton
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Oncology ,medicine.medical_specialty ,Leukopenia ,business.industry ,Endometrial cancer ,Cancer ,medicine.disease ,Olaparib ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Fallopian tube cancer ,Internal medicine ,PARP inhibitor ,medicine ,medicine.symptom ,Adverse effect ,business ,Fallopian tube - Abstract
BackgroundCombining poly (ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and determine a recommended phase 2 dose (RP2D) for PARP inhibitor olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance.MethodsAs part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a four day on three day off schedule was evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days.Findings38 patients were enrolled. 7 (18%) patients had known germlineBRCA1/2mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting in absence of maximum supportive care. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (n=6) with no DLTs, confirming this as RP2D. Most common treatment-related grade 3 or 4 adverse events were anemia (23.7%) and leukopenia (10.5%).Of 32 subjects evaluable for response, 6 (19%) had partial response (PR) with a PR rate of 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlation between response and immune activity, as well as alterations in cell cycle and DNA damage response genes. Therapy resistance was associated with receptor tyrosine kinase (RTK) and RAS-MAPK pathway activity, as well as metabolism and epigenetics.InterpretationThe combination of olaparib and capivasertib is well tolerated and demonstrates evidence of durable activity in women’s cancers, with particularly promising response in endometrial cancer. Importantly, tumor samples acquired pre and on-therapy can help predict patient benefit.FundingAstraZeneca, MDACC Moonshots Program, MDACC Support Grant CA016672 NCI SPOREs in Ovarian (CA217685) and Uterine (CA098258) Cancer and a kind gift from the Miriam and Sheldon Medical Research Foundation. AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).
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- 2021
7. Characterizing advanced breast cancer heterogeneity and treatment resistance through serial biopsies and comprehensive analytics
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Zahi Mitri, Marilyne Labrie, Laura M. Heiser, Carol Beadling, Brett Johnson, Allen G. Li, Joe W. Gray, Annette Kolodzie, Janice Patterson, George Thomas, Christopher L. Corless, Gordon B. Mills, Alexander R. Guimaraes, Jamie M. Keck, Molly Downey, Allison L. Creason, Swapnil Parmar, and Raymond C. Bergan
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Tumour heterogeneity ,Advanced breast ,medicine.medical_treatment ,Disease ,Article ,Targeted therapy ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Internal medicine ,Cancer genomics ,medicine ,Clinical significance ,RC254-282 ,Molecular medicine ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,medicine.disease ,Metastatic breast cancer ,030104 developmental biology ,Analytics ,030220 oncology & carcinogenesis ,business - Abstract
Molecular heterogeneity in metastatic breast cancer presents multiple clinical challenges in accurately characterizing and treating the disease. Current diagnostic approaches offer limited ability to assess heterogeneity that exists among multiple metastatic lesions throughout the treatment course. We developed a precision oncology platform that combines serial biopsies, multi-omic analysis, longitudinal patient monitoring, and molecular tumor boards, with the goal of improving cancer management through enhanced understanding of the entire cancer ecosystem within each patient. We describe this integrative approach using comprehensive analytics generated from serial-biopsied lesions in a metastatic breast cancer patient. The serial biopsies identified remarkable heterogeneity among metastatic lesions that presented clinically as discordance in receptor status and genomic alterations with mixed treatment response. Based on our study, we highlight clinical scenarios, such as rapid progression or mixed response, that indicate consideration for repeat biopsies to evaluate intermetastatic heterogeneity (IMH), with the objective of refining targeted therapy. We present a framework for understanding the clinical significance of heterogeneity in breast cancer between metastatic lesions utilizing multi-omic analyses of serial biopsies and its implication for effective personalized treatment.
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- 2021
8. Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies
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Marilyne Labrie, Zahi Mitri, Koei Chin, Annette Kolodzie, Aurora Blucher, Gordon B. Mills, Allison L. Creason, Alexander R. Guimaraes, Lina Gao, Jeremy Goecks, Jamie M. Keck, Young Hwan Chang, Swapnil Parmar, Courtney Betts, Molly Downey, Jeong Youn Lim, Brett Johnson, Christopher Boniface, Kiara Siex, Allen G. Li, Joe W. Gray, Hongli Ma, Lisa M. Coussens, Christopher L. Corless, Paul T. Spellman, Shamilene Sivagnanam, Raymond C. Bergan, and Jacqueline Vuky
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Cancer Research ,business.industry ,medicine.medical_treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Exceptional Responder ,Article ,Basal (phylogenetics) ,Cancer therapeutic resistance ,Breast cancer ,Immune system ,Targeted therapies ,Oncology ,PARP inhibitor ,medicine ,Cancer research ,business ,RC254-282 ,Triple-negative breast cancer ,CD8 - Abstract
In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.
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- 2020
9. Multi-omics analysis of serial samples from metastatic TNBC patients on PARP inhibitor monotherapy provide insight into rational PARP inhibitor therapy combinations
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Brett Johnson, Annette Kolodzie, Raymond C. Bergan, Koei Chin, Jacqueline Vuky, Kiara Siex, Joe W. Gray, Paul T. Spellman, Alexander R. Guimaraes, Lina Gao, Marilyne Labrie, Shamilene Sivagnanam, Jamie M. Keck, Courtney Betts, Molly Downey, Aurora Blucher, Christopher Boniface, Christopher L. Corless, Lisa M. Coussens, Allison L. Creason, Swapnil Parmar, Hongli Ma, Zahi Mitri, Gordon B. Mills, Allen G. Li, Jeong Youn Lim, Young Hwan Chang, and Jeremy Goecks
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business.industry ,medicine.medical_treatment ,Immunotherapy ,G2-M DNA damage checkpoint ,medicine.disease ,Immune system ,Breast cancer ,PARP inhibitor ,medicine ,Cancer research ,Signal transduction ,business ,CD8 ,Triple-negative breast cancer - Abstract
Due to complexity of advanced epithelial cancers, it is necessary to implement patient specific combination therapies if we are to markedly improve patient outcomes. However, our ability to select and implement patient specific combination therapies based on dynamic molecular changes in the tumor and tumor ecosystem in response to therapy remains extremely limited. In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). Although PARP inhibition was consistently observed in all patients, deep molecular analysis of the tumor and its ecosystem revealed insights into potentially effective therapeutic PARPi combinations. In a BRCA-mutant basal breast cancer exceptional long-term survivor, we noted striking PARPi-induced tumor destruction accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor (LAR) rapid progressor in response to PARPi likely due to indifference to the effects of PARP inhibition. In this rapid progressor, there was minimal evidence of immune activation or protein network rewiring in response to PARPi, despite PARP being inhibited, and no clinical benefit was noted for this participant. Together, deep real-time analysis of longitudinal biopsies identified a suite of PARPi-induced emergent changes including immune activation, DNA damage checkpoint activation, apoptosis and signaling pathways including RTK, PI3K-AKT and RAS-MAPK, that could be used to select patient specific combination therapies, based on tumor and immune state changes that are likely to benefit specific patients.HighlightsLongitudinal analysis of serial tumor samples in real-time identifies adaptive mechanisms of resistance to PARPi therapies.Deep molecular analysis of the tumor reveals insights into potentially effective therapeutic PARPi combinations.Extensive protein network rewiring, microenvironment and immune state changes are assessable factors for patient specific combination therapies.
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- 2020
10. Using Reverse Phase Protein Array (RPPA) to Identify and Target Adaptive Resistance
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Zahi Mitri, Nicholas D. Kendsersky, Shannon N. Westin, Han Liang, Gordon B. Mills, Marilyne Labrie, Yong Fang, and Jun Li
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Tumor microenvironment ,Combination therapy ,business.industry ,medicine.medical_treatment ,Protein Array Analysis ,Reverse phase protein lysate microarray ,Immunotherapy ,Drug resistance ,Computational biology ,Biological Evolution ,Article ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Drug Resistance, Neoplasm ,Neoplasms ,medicine ,Tumor Microenvironment ,Humans ,030212 general & internal medicine ,business ,Adaptive resistance ,Protein network - Abstract
Tumor cells and the tumor ecosystem rapidly evolve in response to therapy. This tumor evolution results in the rapid emergence of drug resistance that limits the magnitude and duration of response to therapy including chemotherapy, targeted therapy, and immunotherapy. Thus, there is an urgent need to understand and interdict tumor evolution to improve patient benefit to therapy. Reverse phase protein array (RPPA) provides a powerful tool to evaluate and develop approaches to target the processes underlying one form of tumor evolution: adaptive evolution. Tumor cells and the tumor microenvironment rapidly evolve through rewiring of protein networks to bypass the effects of therapy. In this review, we present the concepts underlying adaptive resistance and use of RPPA in understanding resistance mechanisms and identification of effective drug combinations. We further demonstrate that this novel information is resulting in biomarker-driven trials aimed at targeting adaptive resistance and improving patient outcomes.
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- 2019
11. Tissue and plasma levels of galectins in patients with high grade serous ovarian carcinoma as new predictive biomarkers
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Yves St-Pierre, Laudine Communal, Marilyne Labrie, Anne Marie Mes-Masson, and Lorenna Oliveira Fernandes de Araujo
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Stromal cell ,Galectins ,lcsh:Medicine ,Kaplan-Meier Estimate ,Article ,03 medical and health sciences ,0302 clinical medicine ,Ovarian carcinoma ,Internal medicine ,Biomarkers, Tumor ,Medicine ,Humans ,Neoplasms, Glandular and Epithelial ,Stage (cooking) ,Cystadenocarcinoma ,lcsh:Science ,Galectin ,Aged ,Ovarian Neoplasms ,Multidisciplinary ,business.industry ,lcsh:R ,Middle Aged ,medicine.disease ,3. Good health ,Cystadenocarcinoma, Serous ,Serous fluid ,030104 developmental biology ,030220 oncology & carcinogenesis ,CA-125 Antigen ,Cancer cell ,Female ,lcsh:Q ,business ,Ovarian cancer - Abstract
Galectins are moving closer to center stage in detecting glycosylation aberration in cancer cells. Here, we have investigated the expression of galectins in ovarian cancer (OC) and examined their potential as biomarkers in tissues and blood plasma samples of high grade serous ovarian carcinoma (HGSC) patients. In tissues, we found that increased protein expression of stromal gal-1 and epithelial gal-8/9 was associated with a poor response to treatment of HGSC patients. Gal-8/9 were both independent predictors of chemoresistance and overall survival (OS), respectively. This galectin signature increased the predictive value of the cancer antigen 125 (CA125) on 5-year disease-free survival (DFS), post-chemotherapy treatment and 5-year OS. In CA125LOW patients, epithelial gal-9 was associated with a lower 5-year OS while stromal gal-1 and epithelial gal-8 were both associated with a lower 5-year DFS. Such negative predictive value of gal-8 and gal-9 was also found using plasma samples. In both cases, high plasma levels of gal-8 and gal-9 was associated with a lower OS and DFS. Overall, these data suggest that galectins may be promising biomarkers to identify subgroups of HGSC patients with poorer prognosis. Our study also contributes to better define the heterogeneity of the disease.
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- 2017
12. Proteomics advances for precision therapy in ovarian cancer
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Marilyne Labrie, Jennifer Eng, Hongli Ma, Koei Chin, Nicholas D. Kendsersky, Lydia G. Campbell, and Gordon B. Mills
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0301 basic medicine ,Proteomics ,DNA Copy Number Variations ,Proteome ,Serous carcinoma ,Computational biology ,Biochemistry ,Article ,03 medical and health sciences ,Mutation Rate ,medicine ,Humans ,Copy-number variation ,Molecular Biology ,Epigenomics ,Ovarian Neoplasms ,030102 biochemistry & molecular biology ,business.industry ,Adaptive response ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Mutation ,Protein microarray ,Female ,Ovarian cancer ,Robust analysis ,business - Abstract
Introduction: Due to the relatively low mutation rate and high frequency of copy number variation, finding actionable genetic drivers of high-grade serous carcinoma (HGSC) is a challenging task. Furthermore, emerging studies show that genetic alterations are frequently poorly represented at the protein level adding a layer of complexity. With improvements in large-scale proteomic technologies, proteomics studies have the potential to provide robust analysis of the pathways driving high HGSC behavior. Areas covered: This review summarizes recent large-scale proteomics findings across adequately sized ovarian cancer sample sets. Key words combined with 'ovarian cancer' including 'proteomics', 'proteogenomic', 'reverse-phase protein array', 'mass spectrometry', and 'adaptive response', were used to search PubMed. Expert opinion: Proteomics analysis of HGSC as well as their adaptive responses to therapy can uncover new therapeutic liabilities, which can reduce the emergence of drug resistance and potentially improve patient outcomes. There is a pressing need to better understand how the genomic and epigenomic heterogeneity intrinsic to ovarian cancer is reflected at the protein level and how this information could be used to improve patient outcomes.
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- 2019
13. Abstract PR03: Single-cell proteomic analysis of the tumoral heterogeneity in response to PARP inhibitor
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Yong Fang, Lydia G. Campbell, Gordon B. Mills, Marilyne Labrie, Nicholas D. Kendsersky, Koei Chin, Sanghoon Lee, Jenny Eng, Shannon N. Westin, and Hongli Ma
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Cancer Research ,medicine.diagnostic_test ,biology ,business.industry ,Poly ADP ribose polymerase ,Cell ,Cancer ,medicine.disease ,Immunofluorescence ,medicine.anatomical_structure ,Oncology ,Cancer cell ,PARP inhibitor ,Cancer research ,medicine ,biology.protein ,Antibody ,Ovarian cancer ,business - Abstract
Although poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in the treatment and maintenance of ovarian cancer patients, development of PARP inhibitor resistance is frequent. Our group and others have demonstrated that the cancer cells’ adaptive responses to PARP inhibitor can be detected at the protein level and targeting these adaptive responses increases the depth and duration of treatment and might prevent the development of drug resistance. However, it is still unclear if these adaptive responses are conserved across cancer cells from the same tumor and across cells from different lesions. Having a better understanding of the heterogeneity of adaptive responses might help develop better approaches of PARP-based combination therapies. The objective of this study was to develop a single-cell proteomic approach to investigate the heterogeneity of adaptive responses in ovarian cancer tumors. We developed a cyclic-immunofluorescence antibody panel and measured the expression of more than 40 proteins at the single-cell level in several ovarian cancer tumors that have been treated with PARP inhibitors. We also performed reverse-phased protein array (RPPA) analysis on protein extracted from the tumors and measured the activity of several pathways know to be altered in response to PARP inhibitors. Overall, our results demonstrated that adaptive responses can be detected at the single-cell level through cyclic immunofluorescence. Furthermore, although RPPA assays capture the main pathway alterations in response to PARP inhibitors, cyclic immunofluorescence adds complementary information by allowing a spatial-oriented analysis of the different cell populations as well as their frequency. Overall, this approach might lead to a better understanding of how cancer cells try to survive therapeutic stress and improve the decision-making process in the treatment of ovarian cancer patients. This abstract is also being presented as Poster A19. Citation Format: Nicholas D. Kendsersky, Hongli Ma, Yong Fang, Lydia G. Campbell, Jenny Eng, Sanghoon Lee, Koei Chin, Shannon N. Westin, Gordon B. Mills, Marilyne Labrie. Single-cell proteomic analysis of the tumoral heterogeneity in response to PARP inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR03.
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- 2020
14. Feasibility of real-time serial comprehensive tumor analytics: Pilot study of olaparib and durvalumab in metastatic triple negative breast cancer (mTNBC)
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Allen G. Li, Lisa M. Coussens, Jeong Youn Lim, Sam Sivagnanam, Gordon B. Mills, Brett Johnson, Courtney Betts, Marilyne Labrie, Christopher L. Corless, Zahi Mitri, Raymond C. Bergan, Joe W. Gray, and Jacqueline Vuky
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Oncology ,Cancer Research ,medicine.medical_specialty ,Durvalumab ,business.industry ,Olaparib ,chemistry.chemical_compound ,chemistry ,Analytics ,Internal medicine ,Medicine ,business ,Triple-negative breast cancer - Abstract
e13092 Background: Longitudinal analysis of serial tumor biopsies is an under-utilized approach to studying adaptive mechanisms of resistance. We have established a comprehensive analytic platform to evaluate real-time trial sample analysis to inform precision oncology combinations in mTNBC. The primary endpoint of the study is feasibility of completing all CLIA assays within 28 days of biopsy. Methods: Following a pre-treatment biopsy and 4 weeks of olaparib monotherapy mTNBC patients underwent an on-treatment (tx) biopsy and durvalumab was added to their therapy. Pre- and on-tx biopsies underwent comparative analysis using CLIA assays (immunohistochemistry-IHC, whole exome seq, RNAseq and phospho-proteomics) as well as research assays (multiplex IHC-mIHC, cyclic immunofluorescence-IF, and reverse phase protein array-RPPA). Results: Serial biopsies were obtained from all 3 enrolled patients, and the primary endpoint was achieved for all patients (Table). Treatment was well tolerated, and 2 patients achieved clinical benefit > 6 months. In one patient with a prolonged CR ( > 18 months), the on-tx sample exhibited dramatic changes in protein network rewiring by protein data analysis (RPPA, cyclic-IF), and an increase in immune infiltrate by mIHC. Conclusions: This pilot confirmed the feasibility of rapid real-time analysis to inform treatment decisions. This led to the development and initiation of biomarker driven olaparib combination trials in mTNBC at our institution. Clinical trial information: NCT03544125 . [Table: see text]
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- 2020
15. Multiomics profiling of longitudinal melanoma specimens unravels molecular mechanisms of resistance to sequential targeted and cancer immunotherapies
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Meenhard Herlyn, Jinho Lee, Gao Zhang, Suzanne McGettigan, Todd Camp, Georgia M. Beasley, Marilyne Labrie, Hongli Ma, Megan Grout, Donald M. O'Rourke, Christopher L. Corless, Wei Xu, Lynn M. Schuchter, Gen Yong, and Gordon B. Mills
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Protein profiling ,Cancer Research ,Oncology ,Metastatic melanoma ,business.industry ,Melanoma ,Cancer research ,Medicine ,business ,medicine.disease - Abstract
e22015 Background: We evaluated spatially-resolved protein profiling of longitudinal tumor specimens derived from two patients with metastatic melanoma who progressed on sequential therapies including targeted therapy (TT) and immune checkpoint blockade (ICB) therapy targeting T cell-surface antigens (CTLA-4 and PD-1). The purpose of this study was to identify molecular determinants of resistance to sequential TT and ICB therapies. Methods: We performed multiplexed and multidimensional spatial protein profiling using NanoString’s GeoMx Digital Spatial Profiling (DSP) platform and single-cell level imaging analysis with Cyclic Immunofluorescence (CycIF) to simultaneously determine dynamic changes in tumor intrinsic signaling pathways and immune response in the tumor microenvironment (TME). Results: The first patient presented with a BRAFV600E-positive brain metastasis. This patient was sequentially treated with ipilimumab (Ipi), the combination of dabrafenib and trametinib, and pembrolizumab (Pembro) and progressed despite of high expression of CD56 NK cell after all treatments. In addition, CycIF analysis revealed drug resistance in a subpopulation of cells that had continued activation of mTOR (pS6) and EGFR pathways. The second patient presented with dermal metastases on the flank with NRASQ61K mutation. This patient was sequentially treated with Pembo, Talimogene Laherparepvec, the combination of Ipi plus nivolumab, and two different investigational agents combined with Pembro. This patient displayed stable disease (SD) on Pembro but eventually progressed on the subsequent therapies. DSP analysis demonstrated CD68/CD40 myeloid cell infiltrates as well as HLA-DR and CD44 in the TME after the last treatment. CycIF analysis revealed dynamic changes in tumoral characteristics including DNA damage and proliferation during treatment. Furthermore, the analysis suggested that there might be a resistant subpopulation in the last tumor biopsy, which is in line with progression of the disease. Conclusions: In this study, we conducted detailed analyses on serial specimens from two patients to precisely define the spatial distribution of immune responses and cancer signaling pathways. The findings propose that concurrent proteomics analysis and immune monitoring of longitudinal tumor biopsies can be informative in clinical evaluation in order to identify salvage therapies to overcome drug resistance.
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- 2020
16. Abstract NT-098: WINDOW OF OPPORTUNITY TRIAL: ASSESSING THE ADAPTIVE RESPONSE OF HGSOC TO PARPI FOR INFORMED COMBINATION THERAPIES
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Marilyne Labrie, GB Mills, Sanghoon Lee, Zhenlin Ju, Yiling Lu, Ken Chen, Tae-Beom Kim, and Shannon N. Westin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Window of opportunity ,business.industry ,Internal medicine ,medicine ,Adaptive response ,business - Abstract
At least 50% of high grade serous ovarian cancer (HGSOC) patients display defects in the components of the homologous recombination (HR) DNA repair pathway, which is the only high fidelity DNA repair mechanism for double strand breaks (DSB). This provides an exciting opportunity for targeted therapies using drugs such as poly (ADP-ribose) polymerase inhibitors (PARPi). PARP is an important component of the base excision repair and alternative non-homologous recombination DNA repair pathways. Therefore, inhibition of PARP enzymatic activity induces DNA damage and leads to synthetic lethality in HR defective tumors. Several clinical trials with PARPi have shown an improvement of progression-free survival in patients but have only shown a limited effect on overall survival. As for many other targeted therapies, the cancer cells rapidly adapt to the stress induced by the drug and develop resistance. Resistance can either be genomic or adaptive. In adaptive resistance the cellular networks are rewired in the absence of genomic changes to mediate resistance. To overcome this resistance, several groups, including ours, suggested the use of PARPi-based combination therapies. Several clinical trials are currently testing PARPi combinations with drugs targeting the immune checkpoint, the DNA damage checkpoint, the PI3K pathway, and the MAPK pathway. Although several of these combinations are promising, the main challenge remains in finding the right drug combination for the right patient since each tumor has the potential to adapt differently to PARPi. We thus implemented a window of opportunity trial to determine whether it is possible to identify different adaptive responses to PARPi by comparing pre and post-treatment tumor samples from multiple sites in the peritoneal cavity. We used reversed phase protein array (RPPA) analysis to measure the expression of over 300 proteins in each tumor samples and compared pathways activity in pre and post treatment samples from individual patients. We also compared the adaptive response detected in cancer patients with the one observed in cell lines. Base on pathway scores, we developed an approach to predict which combination with PARPi would be most likely to benefit a specific patient. Overall, our results indicate that the adaptive response to PARPi treatment can be detected early during treatment and that individual patients utilize different pathways to adapt to the stress induced by the drug. This study reinforces the need and opportunity for informed combination therapies to improve outcomes in this devastating disease. Citation Format: Marilyne Labrie, Tae-Beom Kim, Zhenlin Ju, Sanghoon Lee, Yiling Lu, Ken Chen, Gordon B. Mills and Shannon N. Westin. WINDOW OF OPPORTUNITY TRIAL: ASSESSING THE ADAPTIVE RESPONSE OF HGSOC TO PARPI FOR INFORMED COMBINATION THERAPIES [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-098.
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- 2019
17. Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy
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Ken Chen, Yongsheng Li, Christopher P. Vellano, Chaoyang Sun, Kang Jin Jeong, Mark J. O'Connor, Shiaw Yih Lin, Zhiyong Ding, Timothy A. Yap, Imelda Mercado-Uribe, Steven W. Wang, Jinsong Liu, Gordon B. Mills, Nidhi Sahni, Xiaohua Chen, Marilyne Labrie, Jiyong Liang, Daniel J. McGrail, Tae-Beom Kim, Hui Dai, Zhenlin Ju, Yiling Lu, Yong Fang, Sanghoon Lee, Dong Zhang, Shannon N. Westin, and Guang Peng
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0301 basic medicine ,Cancer Research ,Time Factors ,DNA damage ,Poly ADP ribose polymerase ,Mice, Nude ,Mitosis ,Cell Cycle Proteins ,Mice, SCID ,Poly(ADP-ribose) Polymerase Inhibitors ,Drug Administration Schedule ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,biology ,business.industry ,G2-M DNA damage checkpoint ,Protein-Tyrosine Kinases ,medicine.disease ,Tumor Burden ,G2 Phase Cell Cycle Checkpoints ,Mice, Inbred C57BL ,Wee1 ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,PARP inhibitor ,Toxicity ,biology.protein ,Cancer research ,Heterografts ,Female ,business ,Ovarian cancer ,DNA Damage ,Signal Transduction - Abstract
We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.
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- 2018
18. Abstract P1-07-16: Galectin-7 increases resistance of breast cancer cells to drug-induced apoptosis and promotes tumor escape by killing T cells
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Donald Gagné, Maria-Claudia Vladoiu, Yves St-Pierre, Nicolas Doucet, Marilyne Labrie, Andrée-Anne Grosset, and Louis Gaboury
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Cancer Research ,Tumor microenvironment ,business.industry ,Cancer ,medicine.disease ,Metastatic breast cancer ,Breast cancer ,Oncology ,Apoptosis ,Cancer cell ,Immunology ,otorhinolaryngologic diseases ,Cancer research ,Medicine ,business ,CD8 ,Galectin - Abstract
Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 was recently shown to be specifically expressed in basal-like and HER-2 positive but not in luminal subtypes of human breast cancer. Galectin-7 also increases the metastatic behavior of breast cancer cells since overexpression of this protein in poorly metastatic breast cancer cells increases their ability to metastasize to the bone and to the lung. This pro-tumoral activity of galectin-7 in breast cancer is surprising since galectin-7 had been previously associated with activation of p53 and breast cancer cells often harbor a transcriptionally inactive form of p53. We have recently reconcile this apparent contradiction by showing that elevated levels of galectin-7 in breast cancer cells occurs via a gain-of-function mechanism of mutant p53. In p53-null breast cancer cells, we have shown that C/EBPβ-2 (also known as LAP2), the most transcriptionally active of the C/EBPβ isoforms, is responsible for the upregulation of galectin-7. How galectin-7 contributes to the progression of breast cancer remains unclear. Up to now, regulation of apoptosis by intracellular galectins has been largely attributed to their ability to translocate to mitochondria, possibly following their interaction with bcl-2. Here, we report that a mutant of galectin-7 that is unable to translocate to mitochondria induces resistance of human breast cancer cells to apoptosis induced by etoposide or by hypoxia-mimicking conditions. Surprisingly, this mutant and the wild-type form of galectin-7 bind equally well to bcl-2 in vitro and in vivo. Interestingly, both forms decreases the translocation of p53 to the nucleus and reduce the expression of p21 following treatment with doxorubicin. We also found that galectin-7 was released by breast cancer cells and that recombinant galectin-7 increased apoptosis of monocytes, T CD4+ and T CD8+ cells. This suggests that galectin-7 contributes to the establishment of an immunosuppressive tumor microenvironment by killing helper and effector T cells. Taken together, these results challenges the current paradigm that mitochondrial galectins are important for resistance to apoptosis and call for a greater focus on the role of galectin-7 in breast cancer. They also indicate that targeting both cytosolic and extracellular galectin-7 could improve the efficacy of anti-cancer drugs for the treatment of aggressive forms of breast cancer. Citation Format: Yves St-Pierre, Andrée-Anne Grosset, Marilyne Labrie, Donald Gagné, Maria-Claudia Vladoiu, Louis Gaboury, Nicolas Doucet. Galectin-7 increases resistance of breast cancer cells to drug-induced apoptosis and promotes tumor escape by killing T cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-16.
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- 2015
19. Abstract 2070: Exploration of markers of synergistic lethality of PARP and PI3K-Akt-mTOR inhibitors in women's cancers
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Ken Chen, Shannon N. Westin, Michael Frumovitz, Tae-Beom Kim, Anil K. Sood, Amir A. Jazaeri, Robert L. Coleman, Karen H. Lu, Marilyne Labrie, Stacy L. Moulder, Zhenlin Ju, Larissa A. Meyer, Sanghoon Lee, Jennifer K. Litton, Gordon B. Mills, and Pamela T. Soliman
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0301 basic medicine ,Cancer Research ,Combination therapy ,business.industry ,Cancer ,mTORC1 ,Synthetic lethality ,medicine.disease ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Triple-negative breast cancer - Abstract
Introduction: The objective was to identify molecular mechanisms and protein networks involved in synthetic lethality as well as mechanisms of adaptive changes to the combination of olaparib (O) combined with inhibitors of the PI3K-AKT axis. Methods: 110 patients with recurrent ovarian, endometrial, and triple negative breast cancer were treated with a combination of O and vistusertib (V) or capivasertib (C) (mTORC1/2 and AKT inhibitors, respectively). We have previously reported durable clinical efficacy of these combinations, regardless of BRCA status. Tumor samples were collected pre-treatment and 30 days post-treatment and reverse-phase protein array (RPPA) was performed. Baseline expression was assessed and change in expression was calculated. Bioinformatics and statistical methods were developed to assess activity of signaling pathways. Pathway scores were determined based on the expression of sets of proteins known to be involved in a specific pathway, including PI3K, RAS/RAF, and DNA damage repair. Association between protein expression and treatment efficacy was determined. Results: We analyzed a total of 55 paired samples from patients treated with O/V (n=25) and O/C (n=30). These included 20 endometrial (37% PR, 31.5% SD, 31.5% PD), 21 ovarian (10% PR, 55% SD, 35% PD) and 14 triple negative breast (15% PR, 23% SD, 62% PD) tumors. Response to O/V was associated with low pre-treatment mTOR pathway activity and led to altered immune activity based on decreased CD4 and PD1 expression. Resistance to O/V was associated with high pre-treatment cell proliferation (high CCNB1, CDK1 and PLK1 protein expression). In contrast, response to O/C was associated with adaptive responses indicated by decreased mTOR activity and induction of the DNA damage checkpoint (high phospho-CHK1, -WEE1 and -CDC2). Resistance was associated with high pre-treatment RTK activity levels (high phospho-HER3, -EGFR, -IGFR, -MET) and AKT-independent activation of mTOR in the on-treatment samples. Conclusion: Analysis of pre- and on-treatment samples from responders and non-responders to PARP and PI3K pathway combination therapy identified biomarkers of patients likely to benefit from therapy and helps to understand molecular mechanisms involved in response and resistance to these drug combinations. Citation Format: Marilyne Labrie, Zhenlin Ju, Jennifer K. Litton, Tae-Beom Kim, Sanghoon Lee, Ken Chen, Pamela T. Soliman, Michael Frumovitz, Larissa A. Meyer, Stacy Moulder, Amir A. Jazaeri, Karen H. Lu, Anil K. Sood, Robert L. Coleman, Gordon B. Mills, Shannon N. Westin. Exploration of markers of synergistic lethality of PARP and PI3K-Akt-mTOR inhibitors in women's cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2070.
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- 2019
20. Exploration of markers of synergistic lethality of PARP and PI3K-akt-mTOR inhibitors in women’s cancers
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Marilyne Labrie, Ken Chen, Anil K. Sood, Michael Frumovitz, Shannon N. Westin, Jennifer K. Litton, Karen H. Lu, GB Mills, Amir A. Jazaeri, Stacy L. Moulder, Sun Joo Lee, Zhenlin Ju, Pamela T. Soliman, Robert L. Coleman, Larissa A. Meyer, and Tae-Beom Kim
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Oncology ,business.industry ,Poly ADP ribose polymerase ,Cancer research ,Obstetrics and Gynecology ,Medicine ,Lethality ,business ,Discovery and development of mTOR inhibitors ,Protein kinase B ,PI3K/AKT/mTOR pathway - Published
- 2019
21. Abstract 448: Expression of Galectins in high grade serous ovarian cancer
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Laudine Communal, Yves St-Pierre, Anne-Marie Mes-Masson, Marilyne Labrie, Pascal Dupont, and Maria-Claudia Vladoiu
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Oncology ,Cancer Research ,medicine.medical_specialty ,Tumor microenvironment ,Tissue microarray ,Taxane ,business.industry ,Serous carcinoma ,Cancer ,medicine.disease ,Internal medicine ,Cancer cell ,medicine ,business ,Ovarian cancer ,Galectin - Abstract
Ovarian cancer (OC) is the 5th leading cause of cancer-related deaths in the Western world. Despite improvements in various treatments, the five-year survival of patients with advanced stage disease remains less than 40%. Approximately 70% of malignant OCs are attributed to the high-grade serous carcinoma (HGSC) histological subtype, which is typically treated by a surgical tumor debulking followed by platinum/taxane chemotherapy. Unfortunately, although approximately 80% of patients respond well to the initial chemotherapy treatment, a large portion of patients develop drug resistance during subsequent cycles of chemotherapy. The non-uniformity of response to therapy complicates the clinical decision-making process and reflects the genetic complexity that gives rise to intra-tumor heterogeneity. Clearly, there is an urgent need to develop reliable clinical biomarkers to identify patients at different levels of risk for specific outcomes. Here, we have investigated the expression of galectins (gal) in HGSC and examined their potential as biomarkers. Galectins have been shown to play a dual role in cancer progression. When released in the extracellular space by cancer cells, they are particularly efficient in creating an immunosuppressive tumor microenvironment, both locally and systemically. Inside cancer cells, they provide cancer cells with increased resistance to apoptosis induced by chemotherapeutic agents. Using tissue microarrays constructed from formalin fixed paraffin embedded tissues from 209 patients with HGSC, we have identified a new protein signature that takes into account the expression of galectins in both cancer and stromal cells. Our study showed that increased protein expression of stromal gal-1 and epithelial gal-8/9 in primary tumors was associated with a poor response to treatment in patients with HGSC. This signature also increased the predictive value of CA-125 on five-year disease-free survival, chemotherapy treatment response and five-year overall survival. Univariate and multivariate analyses revealed that gal-8 and gal-9 were both independent predictors of chemoresistance and overall survival, respectively. From a fundamental point of view, our project also contributes to better define the heterogeneity of the disease. Overall, these data provide a rational for further studies of Galectins in OC. Citation Format: Marilyne Labrie, Laudine Communal, Maria-Claudia Vladoiu, Pascal Dupont, Anne-Marie Mes-Masson, Yves St-Pierre. Expression of Galectins in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 448.
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- 2016
22. Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells
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Andrée-Anne Grosset, Yves St-Pierre, Maria Claudia Vladoiu, Louis Gaboury, Donald Gagné, Nicolas Doucet, Marilyne Labrie, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), and Supported in part by grants to Y.S-P. from the Canadian Institute for HealthResearch (Grant No. MOP-89697) and a Discovery grant to N.D. from theNatural Sciences and Engineering Research Council of Canada (RGPIN402623–2011). A.A.G. and M.L. are supported by a Ph.D. studentship andN.D. by a Research Scholar Career Award (Junior 1) from the Fonds deRecherche du Québec-Santé (FRQS). D.G. is supported by a Ph.D. studentshipfrom the Fondation universitaire Armand-Frappier de l’INRS. N.D. alsoacknowledges support from the FRQNT Strategic Cluster RegroupementQuébécois de Recherche sur la Fonction, la Structure et l’Ingénierie desProtéines (PROTEO) and the FRQS Strategic Cluster Groupe de Recherche Axésur la Structure des Protéines (GRASP
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Models, Molecular ,p53 ,Pathology ,medicine.medical_specialty ,Cancer Research ,Arginine ,Protein Conformation ,[SDV]Life Sciences [q-bio] ,Galectins ,Mutant ,Intracellular Space ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Breast Neoplasms ,Apoptosis ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Mitochondrion ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Cell Line, Tumor ,Genetics ,Humans ,Medicine ,Galectin-7 ,030304 developmental biology ,Galectin ,0303 health sciences ,business.industry ,Wild type ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,Protein Transport ,Cytosol ,Oncology ,Drug Resistance, Neoplasm ,Cell culture ,Localization ,030220 oncology & carcinogenesis ,Mutation ,Female ,Tumor Suppressor Protein p53 ,business ,Research Article - Abstract
Background Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 (gal-7) was recently shown to be specifically expressed in basal-like but not in luminal subtypes of human breast cancer. Methods We generated a mutant form of gal-7 (R74S). Arginine 74 is the structural equivalent of arginine 186 found in human galectin-3. Mutation R186S was previously shown to abolish the biological function of galectin-3. Results Mutation of arginine 74 induced only limited and local changes to the gal-7 fold. Recombinant forms of R74S and wtgal-7 were also equally effective at forming dimers in solution. Analysis of the thermodynamic parameters by isothermal titration calorimetry (ITC) indicated, however, that binding of lactose to gal-7 was inhibited by the R74S mutation. Using confocal microscopy and electron microscopy, we confirmed the expression of gal-7 in the cytosolic and nuclear compartments of breast cancer cells and the ability of gal-7 to translocate to mitochondria. The mutation at position 74, however, greatly reduced the expression of gal-7 in the nuclear and mitochondrial compartments. Interestingly, cells expressing mutated gal-7 were equally if not even more resistant to drug-induced apoptosis when compared to cells expressing wtgal-7. We also found that both wtgal-7 and R74S inhibited dox-induced PARP-1 cleavage and p53 protein expression. The inhibition of p53 correlated with a decrease in p21 protein expression and CDKN1A mRNA. Furthermore, analysis of nuclear and cytoplasmic fractions showed that both wild type and R74S mutant gal-7 inhibited p53 nuclear translocation, possibly by increasing degradation of cytosolic p53. Conclusions These findings pose a challenge to the paradigm that has guided the design of galectin-specific inhibitors for the treatment of cancer. This study suggests that targeting CRD-independent cytosolic gal-7 in breast cancer cells may be a valuable strategy for the treatment of this disease. Our study will thus complement efforts towards improving selectivity of targeted anticancer agents. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-801) contains supplementary material, which is available to authorized users.
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