Program Project Grant

Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy (P01 CA186866)

This PPG focuses on grp94, a molecule that is highly expressed in cancer cells, whose atomic structure has been resolved and whose “drug-like” inhibitors have been discovered by the leaders of this project. Completion of the proposed studies will enrich the knowledge of grp94, uncover its cancer-specific roles, and identify its targeted inhibitors for eventual clinical development of novel cancer therapeutics.

This PPG represents an unprecedented opportunity to enable continued collaboration between three leading laboratories in GRP94 research – biology and immunology (Zihai Li), chemical biology and translational research (Gabriela Chiosis) and structural biology (Daniel T. Gewirth) – to understand GRP94 biology in cancer and to develop GRP94 anti-cancer therapeutics. The projects’ synergy is illustrated in the shared interests of its project leaders, scientific track record of collaboration, and the complementary expertise that each project leader brings to the program.

Projects and Cores

Project 1: Definition of the grp94-GARP-TGFβ Axis in Cancer Biology and Clinical Significance

The OSUCCC – James, Pelotonia Institute for Immuno-Oncology (PIIO)

Bei Liu, MD, MPH (Project 1 Co-Leader)

This project addresses how a chaperone molecule called grp94 controls breast cancer. Preliminary studies have revealed that grp94 orchestrates a number of important pathways for cancer development and progression, including the pathway of transforming growth factor beta (TGFβ). Findings from this proposal should lead to a better understanding of the biological and clinical significance of grp94-TGFβ interaction and eventual development of novel cancer therapeutics for breast cancer.

Project 2: Development of grp94-selective Inhibitors for Cancer

Memorial Sloan Kettering Cancer Center
Gabriela Chiosis, PhD (Project Leader)

This project will address an unmet research and medical need by developing novel chemical tools to enable a spatiotemporal investigation of grp94-regulated cancer mechanisms in endogenous cancer phenotypes. This chemical biology/pharmacology approach complements the genetic and structural approaches of other research components in this integrated program. Importantly, it will help address the biology of grp94 in the cellular environment where grp94 is limited but not absent, and this also aims to improve the drug-like characteristics of grp94 ligands towards the ultimate goal of identifying leads with therapeutic potential for clinical translation.

Project 3: Structural Basis for grp94 Drug Development and Chaperone Function

The Hauptman-Woodward Medical Research Institute

This project attempts to understand the structure and function of grp94, a master-activator protein that helps other proteins in the cell become active. Given that many grp94-dependent proteins have been implicated in cancers, the ability to selectively stop their function by stopping their master activator, grp94, could open a powerful new route to treating cancer. Stopping the activity of grp94 requires that we understand what it looks like, how it works and what makes it unique; to achieve this understanding, we will visualize the 3-dimensional structure of grp94, identify and test the structural features that make grp94 special, and ultimately use this knowledge to design drug inhibitors that have fewer side effects.

Core 1: (Administration & Biostatistics Core)

The Admin and Biostats Core, housed at OSUCCC – James, PIIO, has two essential functions: (1) Administration, including program integration; resource prioritization and allocation; meeting arrangements, minutes and follow-up; fiscal reporting and budgetary management, communications and resource sharing; and coordination of all interactions with internal and external advisors; and (2) Bio-statistical Support, including experimental design; power analysis and sample size; data management, analysis and interpretation; and assistance with manuscript preparation, project reports and grant applications.

Core 2: (Medicinal Chemistry Core)

Gabriela Chiosis, PhD (Core Leader)

The Medicinal Chemistry Core, housed at Memorial Sloan Kettering, makes the chemical tools needed by the three projects to carry out investigations of grp94 in cancer. Specifically, this core will generate sufficient amounts of grp94-related small molecule materials, characterize these materials for judicious in vitro and in vivo use, and provide information on their proper use, handling, and storage. The materials and knowledge provided will facilitate the studies described throughout this PPG.

Selected Publications

Huck JD, Que NL, Hong F, Li Z, Gewirth DT. Structural and Functional Analysis of GRP94 in the Closed State Reveals an Essential Role for the Pre-N Domain and a Potential Client-Binding Site. Cell Rep. 2017;20(12):2800-9. Epub 2017/09/21. doi: 10.1016/j.celrep.2017.08.079. PubMed PMID: 28930677; PMCID: PMC5608278.

Wang T, Rodina A, Dunphy MP, Corben A, Modi S, Guzman ML, Gewirth DT, Chiosis G. Chaperome heterogeneity and its implications for cancer study and treatment. J Biol Chem. 2019;294(6):2162-79. Epub 2018/11/10. doi: 10.1074/jbc.REV118.002811. PubMed PMID: 30409908; PMCID: PMC6369301.

Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016;538(7625):397-401. Epub 2016/10/21. doi: 10.1038/nature19807. PubMed PMID: 27706135; PMCID: PMC5283383.

Joshi S, Wang T, Araujo TLS, Sharma S, Brodsky JL, Chiosis G. Adapting to stress - chaperome networks in cancer. Nat Rev Cancer. 2018;18(9):562-75. Epub 2018/05/26. doi: 10.1038/s41568-018-0020-9. PubMed PMID: 29795326; PMCID: PMC6108944.

Kishinevsky S, Wang T, Rodina A, Chung SY, Xu C, Philip J, Taldone T, Joshi S, Alpaugh ML, Bolaender A, Gutbier S, Sandhu D, Fattahi F, Zimmer B, Shah SK, Chang E, Inda C, Koren J, 3rd, Saurat NG, Leist M, Gross SS, Seshan VE, Klein C, Tomishima MJ, Erdjument-Bromage H, Neubert TA, Henrickson RC, Chiosis G, Studer L. HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nat Commun. 2018;9(1):4345. Epub 2018/10/21. doi: 10.1038/s41467-018-06486-6. PubMed PMID: 30341316; PMCID: PMC6195591.

Staron M, Yang Y, Liu B, Li J, Shen Y, Zuniga-Pflucker JC, Aguila HL, Goldschneider I, Li Z. gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood. 2010;115(12):2380-90. Epub 2009/12/08. doi: blood-2009-07-233031 [pii] 10.1182/blood-2009-07-233031. PubMed PMID: 19965672; PMCID: 2845896.

Metelli A, Wu BX, Fugle CW, Rachidi S, Sun S, Zhang Y, Wu J, Tomlinson S, Howe PH, Yang Y, Garrett-Mayer E, Liu B, Li Z. Surface Expression of TGFbeta Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res. 2016;76(24):7106-17. Epub 2016/12/04. doi: 10.1158/0008-5472.CAN-16-1456. PubMed PMID: 27913437; PMCID: PMC5504525.

Rachidi S, Metelli A, Riesenberg B, Wu BX, Nelson MH, Wallace C, Paulos CM, Rubinstein MP, Garrett-Mayer E, Hennig M, Bearden DW, Yang Y, Liu B, Li Z. Platelets subvert T cell immunity against cancer via GARP-TGFbeta axis. Sci Immunol. 2017;2(11). Epub 2017/08/02. doi: 10.1126/sciimmunol.aai7911. PubMed PMID: 28763790; PMCID: PMC5539882.

Salem M, Wallace C, Velegraki M, Li A, Ansa-Addo E, Metelli A, Kwon H, Riesenberg B, Wu B, Zhang Y, Guglietta S, Sun S, Liu B, Li Z. GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon. Cancer Res. 2019;79(6):1178-90. Epub 2019/01/25. doi: 10.1158/0008-5472.CAN-18-2623. PubMed PMID: 30674536; PMCID: PMC6420855.