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  • American Association for Cancer Research (AACR)  (21)
  • Korkut, Anil  (21)
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  • American Association for Cancer Research (AACR)  (21)
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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-01-06-P6-01-06
    Abstract: PURPOSE Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer. Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) predicts better survival. Early prediction of the treatment response can potentially triage non-responding patients to alternative protocol treatments, spare them of the unneeded toxicity, and improve pCR. We evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on the dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI) MRI images obtained early during NAST to predict pCR. MATERIALS AND METHODS This IRB-approved prospective study (NCT02276443) included 182 patients with biopsy proven stage I-III TNBC who had multiparametric MRIs at baseline (BL), post 2 cycles (C2), and post 4 cycles (C4) of NAST before surgery. Tumors and peritumoral regions of 5 mm and 10 mm in thickness were segmented on the 2.5 minutes DCE subtraction images and on the b=800 DWI images. Ten histogram-based first order texture features including mean, minimum, maximum, standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentile, and 300 radiomic Grey Level Co-occurrence matrix (GLCM) features along with their absolute and relative differences between the 3 imaging time points were extracted from the tumors and from the peritumoral regions with an in-house Matlab toolbox. Treatment response at surgery (pCR vs non-pCR) was documented. The samples were divided into training and testing datasets by a 2:1 ratio. Area under the receiver operating characteristics curve (AUC ROC) was calculated for univariate analysis in predicting pCR. Logistic regression with elastic net regularization was performed for texture feature selection. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. RESULTS Of 182 TNBC patients, 88 (48%) had pCR and 94 (52%) did not achieve pCR. Eight multivariate models combining radiomic features from both DCE and DWI tumoral and peritumoral regions had AUC & gt; 0.8 (0.807-0.831) with p-value & lt; 0.001 in both training and testing sets. The highest AUC=0.831 was obtained from a model consisting of 15 radiomic features: tumor DWI (5 GLCM features) at C2, peritumoral region on DCE (skewness) at C2, tumor DCE (1st, 5th percentile) at C4, tumor DWI (3 GLCM features) at C4, peritumoral region DWI (1 GLCM feature) at C4, and the relative difference between C4/C2 on DCE (5th, 95th percentile and mean). CONCLUSION Multi-parametric MRI-based radiomics models from the tumor and the peritumoral regions showed high accuracy as potential early predictors of NAST response in TNBC patients. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3382-3382
    Abstract: Background: TGF-β/SMAD signaling is a crucial, often contradictory regulator in multiple stages of liver disease that include inflammation, cirrhosis and development of HCC as well as other cancers. The context-specific role of this pathway in treatment strategies has yet to be clarified. Therefore, understanding the multiple context-specific roles of the pathway across broad cancer types is critical towards deciphering the complexities of the pathway. Methods: We followed our previous analysis of HCCs, by extending and examining TGF-β pathway across 33 TCGA tumor types and 9125 samples to address this question. We focused on 43 core genes that encode components that regulate signaling by the TGF-β superfamily with 50 target genes collectively identified through a consensus among TCGA network members. In addition, we extended our analyses to functional studies in mouse mutants and human cell lines with alterations of TGF-β signaling. Results: Focusing on 43 core TGF-β pathway genes, we found at least one of them was genomically altered in 39% of samples (mutations: 24%, homozygous deletions: 10%, or amplifications: 14%). We observed the highest alteration frequencies with hotspot mutations, 65% of which were in liver and GI cancers. We identified hotspots in 6 genes, with new discoveries in TGFBR2 and BMP5. Interestingly, with all 6 hotspot mutations we observed increased expression of TERT, HMGA2, IL6, MMP9, COL1A1/1A2/3A1, MYC, and FOXP3. Surprisingly, CDH2, and ALDH1A1expression levels were markedly reduced in liver and GI cancers. Alterations in the core genes correlated positively with expression of metastasis-associated genes, and poor patient survival. Epigenetic silencing and miRNA expression were associated with limited activity of the pathway in a cancer dependent manner. Using proteomics data, elevated TGF-β pathway activity showed positive correlation activity of DNA damage repair and EMT pathways (R=0.24, p & lt; 0.0001), while the cell cycle and apoptosis pathways showed strong negative correlation (R= -0.3, and -0.15, p & lt; 0.0001). Functional analyses reveal that disruption of TGF-β leads to increased sensitivity to cisplatin and other DNA cross linking agents as well as radiation. Conclusions: Our data suggest that TGF-β superfamily indices when combined with specific genes, such as HMGA2 and TERT, may represent strong prognostic markers, and targets in some cancer types such as HCC. This study provides a rich resource and broad molecular perspective that could guide future functional and therapeutic studies of the diverse set of cancer pathways mediated by TGF-β superfamily. In addition, when the pathway is disrupted, epithelial cells are more susceptible to transformation and invasion, potentially identifying specific populations that are more sensitive to chemotherapy such as cisplatin and 5FU, as well as radiation therapy. Citation Format: Kazufumi Ohshiro, Sobia Zaidi, Anil Korkut, Jian Chen, Shuyun Rao, Shoujun Gu, Wilma Jogunoori, Bibhuti Mishra, Rehan Akbani, Lopa Mishra. A pan-cancer analysis reveals high frequency genetic alterations in mediators of signaling by the TGF-β superfamily [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 3382.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1759-1759
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1759-1759
    Abstract: Adaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of anti-apoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress. Citation Format: Augustin Luna, Heping Wang, Gonghong Yan, Xubin Li, Ozgun Babur, Gordon Mills B. Mills, Chris Sander, Anil Korkut. Targeting adaptation to cancer treatment by drug combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1759.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2226-2226
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2226-2226
    Abstract: Introduction: Development of colorectal cancer (CRC) is associated with alterations in key driving pathways, which include Wnt (APC-βcatenin), TGF-β members, p53 and pathways that regulate Ras activity. Members of the TGF-β superfamily regulate colon inflammation, have both tumor-suppressing and tumor-promoting activities, while colon cancer formation has been observed in TGF-β deficient mouse models. Through earlier studies, using mouse models followed by functional studies in human cell lines and tissues, we identified candidate set of TGF-β regulated biomarkers for early detection of CRC, that were altered in tissues from patients with adenomas, and could represent signs of early cancer stem cell development (J Clin Invest 2016;126(2); PLoS One 2016;11(4)). These markers are CEACAMs 1, 5 and 6; TGFBR2, SMAD4, Smad adaptor, SPTBN1. Here, we took an integrated approach to extend and validate these potential markers for early detection of CRC. Methods and Results: 1) Analyzing the TCGA cohort of 9,125 samples and 33 cancer types, including CRC, revealed alterations in TGF-β members in ~40% of samples. 2) cBioportal cancer genomics data reveal reduced overall survival in CRC patients with decreased TGFBR1 and TGFBR2, together with increased CEA (CEACAM5). 3) TCGA analyses also reveal significant tendency of co-occurrence of genomic alterations in TGFBR1 and CEA. 4) mRNA stemness index score in 33 cancers types in TCGA, reveals increased transcriptome levels of a cancer stem cell signature in specific cancers, that concomitantly have decreased levels of TGF-β pathway members, supporting the mouse models revealing that TGF-β suppresses cancer stem cells. 5) Cluster analysis for miRNAs in the 33 cancers suggest a role for these in suppression of TGF-β pathway, depending on the cancer type. miRNA 92a-3p that targets 3 core genes, BMPR2, TGFBR2, and SMAD7, is overexpressed in many cancers. Colon cancer with high frequencies of hotspot mutations in BMPR2 and TGFBR2 did not have high expression of 92a-3p, perhaps indicating that there is little selective pressure for a second mechanism of inactivation. 6) We further identified hotspot mutations in the B3 domain of the CEA that interacts with TGFBR1, supporting a mechanism for previously observed CEA inactivation of TGF-β tumor suppressor function. Conclusions: CEACAMs with TGF-β signaling members as a group could represent strong prognostic indicators of high-risk adenoma-carcinoma progression and invasive disease. Citation Format: Sobia Zaidi, Anil Korkut, Wilma Jogunoori, Jian Chen, Shoujun Gu, Shuyun Rao, Kazufumi Ohshiro, Rehan Akbani, Chuxia Deng, Bibhuti Mishra, Lopa Mishra. TGF-β and CEACAMs regulated biomarkers detect early colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2226.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2102-2102
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2102-2102
    Abstract: Systematic perturbation of cells followed by comprehensive measurements of molecular and phenotypic responses provides an informative data resource for constructing computational models of cell biology. Models that generalize well beyond training data can be used to identify combinatorial perturbations of potential therapeutic interest. Major challenges for machine learning on large biological datasets are to find global optima in an enormously complex multi-dimensional solution space and to mechanistically interpret the solutions. To address these challenges, we introduce a hybrid approach that combines explicit mathematical models of dynamic cell biological processes with a machine learning framework, implemented in Tensorflow. We tested the modeling framework on a perturbation-response dataset for a melanoma cell line after drug treatments. The models can be efficiently trained to accurately describe cellular behavior, as tested by cross-validation. Even though completely data-driven and independent of prior knowledge, the resulting de novo network models recapitulate known interactions. The main predictive application of our work is the identification of combinatorial candidates for cancer therapy. This approach is readily applicable to a wide range of kinetic models of cell biology. Citation Format: Judy Shen, Bo Yuan, Augustin Luna, Anil Korkut, Debora Marks, John Ingraham, Chris Sander. Interpretable machine learning for perturbation biology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2102.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. B126-B126
    Abstract: Background: Zanidatamab is a bispecific HER2-targeted antibody in clinical development which has demonstrated antitumor activity in a broad range of HER2 amplified/expressing solid tumors.  We report the antitumor activity of zanidatamab in vivo by utilizing patient-derived xenograft (PDX) models developed from pre-treatment or post-progression biopsies from the first-in-human zanidatamab phase I study (NCT02892123). Methods: PDXs were established by implanting 1-2 core biopsies from HER2 expressing tumors into immunodeficient mice.  The PDXs that developed were expanded and treated with zanidatamab monotherapy or novel combinations targeting co-alterations and the relevant treatment controls. PDXs models were also characterized by DNA and RNA sequencing, HER2 IHC, and reverse phase protein arrays (RPPA).  Antitumor activity in patients was assessed by RECIST1.1. Antitumor activity in PDXs was assessed by change in tumor volume from baseline, objective response, and event-free survival defined as time to tumor volume doubling (EFS-2). Results: From the thirty-six patient tumors implanted, 19 PDX models were established (52.7% take rate) from 17 individual patients.  Established PDXs represented a broad range of HER2-expressing cancers; however, a higher take-rate was observed in gastrointestinal (GI) tumors (64.0%) compared to non-GI tumors (27.3%).   Patients whose biopsies grew as PDXs had shorter median progression-free survival (PFS) and overall survival (OS) than patients whose biopsies did not grow as PDXs (PFS: 58 days vs 112 days; OS: 92 days vs. 574 days). PDXs were developed from patients with a range of objective responses to zanidatamab. In vivo testing in PDXs demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested.  We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab in 2 of 4 post-progression PDXs and demonstrated that MET inhibitors have single agent activity and enhance zanidatamab activity in vitro and in vivo in a post- zanidatamab progression model. Conclusions: Our findings provide evidence that PDXs can be developed from pre-treatment biopsies in clinical trials and may provide insight into mechanisms of resistance. Citation Format: Timothy P DiPeri, Kurt W Evans, Bailiang Wang, Ming Zhao, Argun Akcakanat, Maria Gabriela Raso, Yasmeen Q Rizvi, Xiaofeng Zheng, Anil Korkut, Kaushik Varadarajan, Burak Uzunparmak, Ecaterina E Dumbrava, Shubham Pant, Jaffer A Ajani, Paula Pohlmann, V Behrana Jensen, Milind Javle, Jordi Rodon, Funda Meric-Bernstam. Co-clinical trial of novel bispecific anti-HER2 antibody Zanidatamab in Patient-Derived Xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B126.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 6 ( 2021-03-15), p. 1681-1694
    Abstract: Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA approved for HER2-overexpressing/amplified (HER2+) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2+ cancers in vitro and in vivo. Experimental Design: Cell viability, colony formation assays, and Western blotting were used to determine the effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDX): two breast, two colorectal, and one esophageal cancer (with HER2 mutations). Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through reverse phase protein arrays and network-level adaptive responses were assessed through Target Score algorithm. Results: In HER2+ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors everolimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Kα inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2+ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1/4) and 60% (3/5) of models, respectively, while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR, and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib. Conclusions: Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR, and MEK inhibitors for the treatment of HER2+ cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 11 ( 2021-06-01), p. 3243-3252
    Abstract: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. Experimental Design: Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. Results: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor–positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody–drug conjugate targets LIV-1 and B7-H3. Conclusions: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2838-2838
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2838-2838
    Abstract: Drug resistance to targeted therapies, either intrinsic (existing before treatment) or acquired (resulting from adaptation to therapy), is a major challenge in patient care. Drug combinations offer a possible solution to prevent drug resistance by blocking multiple routes to tumor proliferation. Discovery of effective combinations remains a challenging task due to complexity of the underlying biological processes and inter-tumor heterogeneity. Here, we developed a statistical pathway analysis method that (i) reveals pathways involved in drug response and adaptive resistance and (ii) nominates combination targets and therapies to down-regulate the resistance pathways. The method is based on the rationale that (i) use of therapies targeting specific genomic aberrations can lead to compensatory responses (e.g. through feedback loop activation in the short term or the development of oncogenic alterations in the long term) leading to drug resistance, and (ii) collective changes in pathway activities are better predictors of resistance and mitigation strategies than individual responses. We construct a pathway model of signaling interactions for measured molecular species through automated extraction of pathway information from Pathway Commons plus manual expert curation. Next, we combine the pathway model with the cell-type-specific drug response data to calculate a TargetScore (TS) for each protein. The score quantifies the adaptive pathway responses to a perturbation by integrating the change in the level of a (phospho)protein along with its pathway neighborhood in response to the single drug. A high TS corresponds to involvement in adaptive response (e.g. upregulation of RTK expression by MEK inhibitor via a feedback loop) and a low TS corresponds to the activity of the drug (e.g. inhibition of ERK phosphorylation by MEK inhibitor). Finally, by identifying the sub-pathways with enriched, high TS values, we determine the adaptive resistance pathways. We test the resulting predictions (combinations of the original single drug with drugs targeting members of the resistance pathways) experimentally. TargetScore is amenable to calculations for hundreds of samples treated with individual (or combinations of) drugs in multiple doses and/or time points and assayed for hundreds to thousands of molecular entities (mRNA or proteomic). Analysis of longitudinal data may allow us to trace the evolution of drug resistance and, potentially, the optimum time points for intervention. The current protocol is defined with a focus on proteomic RPPA data, but can be adapted to other kinds of molecular data associated with adaptive responses. We applied our method to BET-BRD inhibition in ovarian cancer to compare resistance/response pathways in cells with varying degrees sensitivity. The analysis nominated cell-type-specific, anti-resistance combinations involving BET inhibitors. Citation Format: Augustin Luna, Özgün Babur, Gonghong Yan, Emek Demir, Chris Sander, Anil Korkut. Discovery of adaptive resistance pathways and anti-resistance combination therapies in cancer from phosphoproteomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2838.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 410466-3
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3820-3820
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3820-3820
    Abstract: Introduction. Resistance to targeted therapies, either intrinsic (pre-existing at the time of treatment) or acquired (emerges as the tumor adapts to therapy), is a major challenge in oncology. Blocking multiple escape routes using drug combinations is the best solution to drug resistance. However, the discovery of effective combinations remains a challenging task due to complexity of the underlying biological processes and inter-tumor heterogeneity. Here, we developed a statistical pathway analysis method that (i) reveals pathways involved in drug activity and adaptive resistance and (ii) nominates combination therapies to down-regulate the resistance pathways. The method is based on the rationale that (i) targeting a specific genomic aberration may lead to activation of compensatory pathways (e.g. via feedback loops in the short term) and subsequent resistance, and (ii) collective changes in pathway activities are better predictors of resistance and mitigation strategies than abundances of individual molecules. Method. We construct a network model of signaling interactions using an adjusted graphical LASSO (GLASSO) algorithm from RPPA data. This is supplemented with prior pathway information from multiple signaling databases (using Pathway Commons) to estimate sparse directed graphical models. Next, we combine the network with the cell- type-specific drug response data to calculate a target score (TS) for each protein. The TS quantifies the adaptive pathway responses to a perturbation by integrating the change in the level of a (phospho)protein and its pathway neighborhood in response to a perturbation. A high TS corresponds to involvement in adaptive response (e.g. RTK upregulation by MEK inhibitor via a feedback loop) and a low TS corresponds to the activity of the drug (e.g. ERK phosphorylation inhibition by MEK inhibitor). Finally, by identifying the subnetworks with enriched, high TS values, we determine the adaptive resistance pathways. We validate the resulting predictions (combinations of the original drug perturbation with drugs targeting the resistance pathways) experimentally. Applications. The method is amenable to calculations for hundreds of samples treated with individual (or combinations of) drugs in multiple doses and/or time points and interrogated for thousands of molecular entities (mRNA or proteomic). With longitudinal data, we will be able to explain the evolution of drug resistance and potentially the optimum time points for intervention. The protocol is defined with a focus on RPPA data, but can be adapted to other kinds of molecular data associated with adaptive responses. We applied our method to BET-BRD inhibition in ovarian and breast cancers to compare resistance/response pathways in cells with varying sensitivity. The analysis nominated cell-type-specific anti-resistance combinations involving BET inhibitors. Citation Format: Augustin Luna, Heping Wang, Ozgun Babur, Chris Sander, Anil Korkut. Discovery of adaptive resistance pathways and anti-resistance combination therapies from phosphoproteomic data using graphical models [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 3820.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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