Techniques, Diagnostic assays

1. Epichaperomics for stressor-to-phenotype investigations:

Development of new strategies to study changes within interactome networks linking stressors to specific phenotypes remains an unmet need. To enable systems level evaluation of proteome-wide changes in PPIs in disease, we developed an ‘omics platform called chemical chaperomics or epichaperomics. Epichaperomics profiling in cancer (Nature 2016), Parkinson’s disease (Nature Comm 2018), and AD (Nature Comm 2020) demonstrated this approach provides insights into human disease biology unavailable through other platforms.

 

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“Epichaperomics can identify disease-related changes in protein-protein interaction networks”

Epichaperomics can identify disease-related changes in protein-protein interaction networks

2. Non-invasive assays for detection of the epichaperome in humans.

These assays are based on our finding that PU-H71 and PU-AD specifically interact with the tumor HSP90-incorporating epichaperomes. We have developed a positron emission tomography-based assay that incorporates a radiolabeled version of PU-H71 to detect such epichaperome-positive tumors; and 124I-PU-AD to detect epichaperomes in the AD brain . For liquid tumors we have developed a single-cell flow cytometry-based assay that incorporates a fluorescently labeled PU-H71. The PU-FITC assay for liquid tumors was developed in collaboration with the Guzman lab and the PU-PET assay for solid tumors and the PU-AD PET for Alzheimer’s disease in collaboration with the Lewis and Larson labs. These 3 assays are currently in clinical evaluation.

Diagnostic assays

 

 

Rodina A, Xu C, Digwal CS, Joshi S, Patel Y, Santhaseela AR, Bay S, Merugu S, Alam A, Yan P, Yang C, Roychowdhury T, Panchal P, Shrestha L, Kang Y, Sharma S, Almodovar J, Corben A, Alpaugh ML, Modi S, Guzman ML, Fei T, Taldone T, Ginsberg SD, Erdjument-Bromage H, Neubert TA, Manova-Todorova K, Tsou MB, Young JC, Wang T, Chiosis G. Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation. Nat Commun. 2023;14(1):3742. doi: 10.1038/s41467-023-39241-7. https://www.nature.com/articles/s41467-023-39241-7

Sharma S, Kalidindi T, Joshi S, Digwal CS, Panchal P, Burnazi E, Lee SG, Pillarsetty N, Chiosis G. Synthesis of (124)I-labeled epichaperome probes and assessment in visualizing pathologic protein-protein interaction networks in tumor bearing mice. STAR Protoc. 2022;3(2):101318. doi: 10.1016/j.xpro.2022.101318. https://pubmed.ncbi.nlm.nih.gov/35496791/

Alam A, Wang T, Chiosis G. Cytoscape files—Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation [Data set]. Zenodo https://doi.org/10.5281/zenodo.7433980 (2022). https://zenodo.org/record/7433980

Wang T, Digwal CS, Alam A, Chiosis G. R Script Epichaperomics—Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation. Zenodo https://doi.org/10.5281/zenodo.7416220 (2022). https://zenodo.org/record/7416220 

Ginsberg SD, Neubert TA, Sharma S, Digwal CS, Yan P, Timbus C, Wang T, Chiosis G. Disease-specific interactome alterations via epichaperomics: the case for Alzheimer’s disease. FEBS J. 2021 May 24. doi: 10.1111/febs.16031. Epub ahead of print.

Sugita M, Wilkes DC, Bareja R, Eng KW, Nataraj S, Jimenez-Flores RA, Yan L, De Leon JP, Croyle JA, Kaner J, Merugu S, Sharma S, MacDonald TY, Noorzad Z, Panchal P, Pancirer D, Cheng S, Xiang JZ, Olson L, Van Besien K, Rickman DS, Mathew S, Tam W, Rubin MA, Beltran H, Sboner A, Hassane DC, Chiosis G, Elemento O, Roboz GJ, Mosquera JM, Guzman ML. Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia. NPJ Precis Oncol. 2021 May 26;5(1):44. doi: 10.1038/s41698-021-00183-2.

Jhaveri KL, Dos Anjos CH, Taldone T, Wang R, Comen E, Fornier M, Bromberg JF, Ma W, Patil S, Rodina A, Pillarsetty N, Duggan S, Khoshi S, Kadija N, Chiosis G, Dunphy MP, Modi S. Measuring Tumor Epichaperome Expression Using [124I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer. JCO Precis Oncol. 2020 Nov 17;4:PO.20.00273. doi: 10.1200/PO.20.00273.

Pillarsetty N, Jhaveri K, Taldone T, Caldas-Lopes E, Punzalan B, Joshi S, Bolaender A, Uddin MM, Rodina A, Yan P, Ku A, Ku T, Shah SK, Lyashchenko S, Burnazi E, Wang T, Lecomte N, Janjigian Y, Younes A, Batlevi CW, Guzman ML, Roboz GJ, Koziorowski J, Zanzonico P, Alpaugh ML, Corben A, Modi S, Norton L, Larson SM, Lewis JS, Chiosis G, Gerecitano JF, Dunphy MPS. Paradigms for Precision Medicine in Epichaperome Cancer Therapy. Cancer Cell. 2019 Nov 11;36(5):559-573.e7. doi: 10.1016/j.ccell.2019.09.007. Epub 2019 Oct 24.

Dunphy MPS, Pressl C, Pillarsetty N, Grkovski M, Modi S, Jhaveri K, Norton L, Beattie BJ, Zanzonico PB, Zatorska D, Taldone T, Ochiana SO, Uddin MM, Burnazi EM, Lyashchenko SK, Hudis CA, Bromberg J, Schöder HM, Fox JJ, Zhang H, Chiosis G, Lewis JS, Larson SM. First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer. Clin Cancer Res. 2020 Oct 1;26(19):5178-5187. doi: 10.1158/1078-0432.CCR-19-3704. Epub 2020 May 4.