1. Chemoproteomics and associated bioinformatics.
We have coupled our chemical tools with sensitive mass spectrum-based techniques and bioinformatics to develop a method that provides the cellular complement of proteome alterations associated with a specific stress phenotype. We have conducted several proof-of-principle studies to demonstrate the power of this chemoproteomics approach: identification of an altered signalosome in chronic myeloid leukemia (Nature Chem Biol 2011 and Cell Reports 2015), the viral oncoproteome in AIDS-related lymphomas (Blood 2013), implication of the methyltransferase CARM1 in CML, novel mechanism of activation of STAT5 in cancer (Nature Chem Biol 2011), identification of unanticipated combination therapies for cancer (JCI 2015), novel cancer survival mechanism (Nature 2016), protein networks altered early in the course of Parkinson’s disease (Nature Communications 2018).
Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol. 2011;7(11):818-26. PubMed PMID: 21946277; PMCID: PMC3265389.
- Nature News&Views October 20, 2011, Darby JF, Workman P. Chemical biology: Many faces of a cancer-supporting protein. Nature. 2011;478(7369):334-5. PubMed
- 2xRecommended F1000Prime, https://f1000.com/prime/13363971
- Ojala PM. Naughty chaperone as a target for viral cancer. Blood. 2013;122(16):2767-8. PubMed [PMID: 24136075] http://www.bloodjournal.org/content/bloodjournal/122/16/2767.full.pdf
- Science News. Tumor-targeting compound points the way to new personalized cancer treatments. December 3, 2011, https://www.sciencedaily.com/releases/2011/12/111201163558.htm
- Adam Bonislawski. ProteoMonitor. Sloan-Kettering Scientists Using Cancer Drug Candidate to Study Aberrant Protein Pathways. Proteomics & Protein Research, Sep 30, 2011
2. Diagnostic assays
These assays are based on our finding that PU-H71 specifically interacts with the tumor HSP90-incorporating epichaperome complexes, such as expressed in certain cancer cells, and other cells under pathogenic stress. We have developed a positron emission tomography based assay that incorporates a radiolabeled version of PU-H71 to detect such epichaperome-positive cells. For liquid tumors we have developed a flow cytometry based assay that incorporates a fluorescently labeled PU-H71, designed for this purpose. The PU-FITC assay for liquid tumors was developed in collaboration with the Guzman lab and the PU-PET assay for solid tumors in collaboration with the Lewis and Larson labs. All assays are currently in clinical evaluation.
3. Compound testing strategies
The distinct nature of the stress chaperome cannot yet be recapitulated biochemically, in a test tube, and we tailor our chemical tools for selectivity towards the CSC through the use of novel, in-house designed and developed, batteries of in silico and in vitro and in vivo phenotypic assays