419 Roger Adams Lab.
University of Illinois
600 S. Mathews Avenue
Urbana, IL 61801
Drug Discovery, Endocrinology, Protein-Nucleic Acid Interactions, Receptor Biochemistry, Regulation of Gene Expression, Signal Transduction
Disease Research Interests
Cancer, Drug Discovery, Neurological and Behavioral Disorders, Trauma, Bleeding & Tissue Regeneration
Identification and use of small molecule biomodulators as novel anticancer drugs and probes for new regulatory pathways
ErSO, a novel small molecule biomodulator uses a recently unveiled pathway to eradicate advanced breast cancer
More than 90% of deaths due to cancer are due to metastases, or spread, of the cancer. Nearly all metastatic cancers are incurable. Metastatic estrogen receptor a (ERa) positive breast and ovarian cancer are presently incurable and most patients die within a few years. Therefore, our goal is to use our expertise in high throughput screening, cell line development, endocrinology and animal models to identify new pathways in cancer and small molecules that target them.
From a program with Chemistry Professor, Paul Hergenrother, we identified a novel small molecule that acts through ERa to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases and near complete regression of highly lethal brain metastases. Although, complete regression with no recurrence over 4-6 months without treatment was common, tumors that did recur remained fully sensitive to ErSO re-treatment; in >150 mice, we have never seen an ErSO-resistant tumor. ErSO’s unprecedented activity against advanced primary and metastatic ERα-positive breast cancers is achieved by exploiting our finding that estrogen-ERa activates an extranuclear tumor-protective, signaling pathway, termed the anticipatory unfolded protein response (a-UPR). We repurposed this tumor protective pathway by targeting it with ErSO. ErSO kills cancer cells by acting non-competitively through ERa to induce lethal hyperactivation of the anticipatory UPR (a-UPR), triggering rapid necrotic cell death. This game-changing turn-on strategy contrasts with widely used inhibition strategies.
A new essential action of hormones: Anticipatory activation of the Unfolded Protein Response (a-UPR)
The endoplasmic reticulum (EnR) stress sensor, the unfolded protein response, was known as a pathway that reacts to diverse forms of stress by activating signaling pathways that reduce protein production and increase protein-folding capacity. We, and others, identified an alternative type of UPR pathway in which mitogenic hormones, such as estrogen and epidermal growth factor (EGF), act through their receptors to preactivate the UPR in anticipation of future needs for increased protein folding and transport. Our bioinfomatic analysis of tumor data showed that elevated expression of a UPR gene signature at diagnosis is a powerful prognostic marker tightly correlated with subsequent breast cancer recurrence, therapy resistance and poor survival. This recently unveiled pathway of hormone action is conserved from insects to humans and between steroid hormones and peptide hormones.
B.S. 1967 Brooklyn College
Ph.D. 1972 Purdue University
Postdoc. 1972-1973 Stanford University Medical School, 1973-1974 Stanford University
1985 - 1986 Guggenheim Fellow, Center for Cancer Research MIT
Awards and Honors
Representative Recent Awards and Media Coverage
2016 – Present Eugene Howe Scholar in Biochemistry
08/2021 Scripps TV interview (60 stations) “Researchers develop breakthrough compound that kills breast cancer in animals”
08/2021 Nature Reviews Drug Discovery: “UPR activator eliminates breast tumours”
07/2021 Fierce Biotech: “Bayer’s drug that turns a cancer-protective pathway toxic eradicates breast tumors in mice”
07/2021 Medical News Today: “Drug rapidly shrinks metastatic breast cancers in mice”
07/2021 inews.co.UK: “New breast cancer drug shrinks tumours by 99% in three days in mice”
07/2021 BioTech Scope: “New ‘turn-on’ anticancer strategy eradicates breast cancer in days”
Boudreau, M.W., Duraki, D., Wang, L., Mao, C., Kim, J.E., Henn, M.A., Tang, B., Fanning, S.W., Kiefer, J., Tarasow, T.M., Bruckheimer, E.M., Moreno, R., Mousses, S., Greene, G.L., Roy, E.J., Park, B.H., Fan, T.M. Nelson, E.R., Hergenrother. P.J. and Shapiro D.J. 2021. A Small Molecule Activator of the Unfolded Protein Response Eradicates Human Breast Tumors in Mice. Science Translational Medicine, online July 21, 2021. DOI: 10.1126/scitranslmed.abf1383
Yu, L., Wang, L., Kim, J.E., Mao, C., and Shapiro, D.J. (2020) Src Couples Estrogen Receptor to the Anticipatory Unfolded Protein Response and Regulates Cancer Cell Fate Under Stress. Biochim Biophys Acta Mol Cell Res. DOI: 10:1016/j.bbamcr2020.118765, PMCID: PMC 7653967
Yu, L., Wang, L., Mao, C., Duraki, D., Kim, J.E. Huang, R. Helferich, W.G. Nelson, E.R., Park, B.H. and Shapiro D.J. (2019) Estrogen-Independent Myc Overexpression Confers Endocrine Therapy Resistance on Breast Cancer Cells Expressing ERαY537S and ERαD538G Mutations, Cancer Letters, 442: 373-382.
Livezey, M., Huang, R., Hergenrother, P.J., and Shapiro, D.J. (2018) Strong and Sustained Activation of the Anticipatory Unfolded Protein Response Induces Necrotic Cell Death. Cell Death and Differentiation, 25:1796-1807 (C. Wraight Award: Dept. of Biochem., The Outstanding Graduate Student Paper of 2018)
Zheng, X., Andruska, N., Lambrecht, M., He, S., Parissenti, A., Hergenrother, P,, Nelson, E.R., and Shapiro, D.J. (2016) Targeting Multidrug Resistant Ovarian Cancer Through Estrogen Receptor α Dependent Hyperactivation of the UPR. Oncotarget, 9: 14741-14753 (C. Wraight Award: Dept. of Biochem., The Outstanding Graduate Student Paper of 2016)
Andruska, N., Zheng, X., Yang, X., Mao, C., Cherian. M., Mahapatra, L,, Helferich, W.G. and Shapiro, D.J. (2015) An estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis and induces tumor regression. Proc. Nat.l Acad. Sci. USA, 112(15) 4737-4742 (highlighted paper)
Boudreau, M. W., Mulligan, M. P., Shapiro, D. J., Fan, T. M., & Hergenrother, P. J. (2022). Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer. Journal of Medicinal Chemistry, 65(5), 3894-3912. https://doi.org/10.1021/acs.jmedchem.1c01730
Zuo, Q., Mogol, A. N., Liu, Y. J., Casiano, A. S., Chien, C., Drnevich, J., Imir, O. B., Kulkoyluoglu-Cotul, E., Park, N. H., Shapiro, D. J., Park, B. H., Ziegler, Y., Katzenellenbogen, B. S., Aranda, E., O’Neill, J. D., Raghavendra, A. S., Tripathy, D., & Erdogan, Z. M. (2022). Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy. Molecular Cancer Research, 20(6), 923-937. https://doi.org/10.1158/1541-7786.MCR-21-0781
Boudreau, M. W., Duraki, D., Wang, L., Mao, C., Kim, J. E., Henn, M. A., Tang, B., Fanning, S. W., Kiefer, J., Tarasow, T. M., Bruckheimer, E. M., Moreno, R., Mousses, S., Greene, G. L., Roy, E. J., Park, B. H., Fan, T. M., Nelson, E. R., Hergenrother, P. J., & Shapiro, D. J. (2021). A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice. Science Translational Medicine, 13(603), [eabf1383]. https://doi.org/10.1126/scitranslmed.abf1383
Hergenrother, P., Shapiro, D. J., & Boudreau, M. W. (2021). Activators of the unfolded protein response. (U.S. Patent No. 11046647).
Cotul, E. K., Zuo, Q., Santaliz-Casiano, A., Imir, O. B., Mogol, A. N., Tunc, E., Duong, K., Lee, J. K., Ramesh, R., Odukoya, E., Kesavadas, M. P., Ziogaite, M., Smith, B. P., Mao, C., Shapiro, D. J., Park, B. H., Katzenellenbogen, B. S., Daly, D., Aranda, E., ... Madak-Erdogan, Z. (2020). Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers. Cancers, 12(9), 1-22. . https://doi.org/10.3390/cancers12092397