Paradigms for Precision Medicine

Understanding mechanisms driving the stressor-to-phenotype phenomena and controlling these maladaptive responses in the wake of stressor presentation may lead to the development of rational therapeutic approaches to abrogate dysfunction from interactomes to connectomes.

schematic therapy
The combination of drug (e.g., PU-H71), companion diagnostic (e.g., [124I]-PU-H71 for solid tumors (Pillarsetty et al. 2019; Jhaveri et al. 2020) and PU-FITC for hematologic malignancies (Merugu et al. 2020; Sugita et al. 2021) and biomarker (e.g., epichaperome levels (Rodina et al. 2016)) enables a precision medicine approach in epichaperome therapy that is based of stressor-induced molecular dysfunctions rather than genetics or pathology. Taking lessons from oncology paradigms, a similar platform was also designed for neurodegenerative disorders (Inda et al. 2020; Bolaender et al. 2021).

cancer cell cover

On the cover: Essential to normal cellular function is the interaction among proteins and their organization in well-defined networks. Pillarsetty et al. (pp. 559–573) introduced a positron emission tomography-based assay called PU-PET to visualize pathologic protein-protein interaction networks termed epichaperomes in human cancer patients. They demonstrate epichaperome engagement by the drug candidate PU-H71 in patients’ tumors at single-lesion resolution and show how information derived from PU-PET provides a platform for precision medicine targeting of the aberrant properties of protein networks. Artwork by Samantha Welker and Samantha Gore. [courtesy of Cancer Cell]

Chiosis G, Digwal CS, Trepel JB, Neckers L. Structural and functional complexity of HSP90 in cellular homeostasis and disease. Nat Rev Mol Cell Biol. 2023. doi: 10.1038/s41580-023-00640-9. https://pubmed.ncbi.nlm.nih.gov/37524848/

Ginsberg SD, Sharma S, Norton L, Chiosis G. Targeting stressor-induced dysfunctions in protein-protein interaction networks via epichaperomes. Trends Pharmacol Sci. 2023;44(1):20-33. doi: 10.1016/j.tips.2022.10.006. https://pubmed.ncbi.nlm.nih.gov/36414432/

Ginsberg SD, Joshi S, Sharma S, Guzman G, Wang T, Arancio O, Chiosis G. The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders. J Neurochem. 2021;159(6):958-79. https://pubmed.ncbi.nlm.nih.gov/34657288/ 

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.