Kendall J. Blumer, Ph.D.

Professor
Cell Biology and Physiology

Molecular Cell Biology Program
Cancer Biology Program
Biochemistry, Biophysics, and Structural Biology Program

  • 314-362-1668

  • 314-362-1662

  • 314-362-7463

  • 506 McDonnell Medical Sciences Building

  • kblumer@wustl.edu

  • cancer, signal transduction, drug development

  • Precision targeting of signal transduction for drug development in cancer

Research Abstract:

Our research seeks to develop precision therapy for cancer and other diseases by identifying and exploiting abnormal signal transduction mechanisms, and developing pharmacological agents to target them.

One major focus of our current research is uveal (ocular) melanoma (UM), the most common intraocular tumor in adults. Half of UM patients develop liver metastases, and typically survive only a few months due to lack of effective therapy. Our research addresses this crucial, unmet clinical need by focusing on mutant constitutively active G protein alpha-subunits of the Gq/11 class, the oncogenic drivers in ~90% of UM tumors. We discovered that mutant Gq/11 can be trapped in inactive states by targeting GDP/GTP exchange with a bioavailable inhibitor called FR900359 (FR). Furthermore, we found that FR inhibits growth ex vivo of primary and metastatic UM tumor cells from patient biopsies, and arrests growth of UM tumor xenografts in mice. Ongoing research is aimed at investigating FR in mouse models of metastatic disease, developing methods to synthesize FR in quantity sufficient for clinical trials, producing FR analogs for tumor-directed delivery, and elucidating novel vulnerabilities of UM tumor cells that can be combined with FR to regress UM tumors.

The second major objective of our research is to develop a panel of FR-like molecules, each of which selectively targets specific subclasses of G proteins in cancer or other diseases. Such inhibitors will reveal how G protein dysfunction causes disease, and provide novel lead compounds for therapeutic development. Our research is developing these inhibitors by combining synthetic organic chemistry, computational and biophysical analyses of G protein structure and drug binding, with biochemical and cell-based studies of G protein function

Selected Publications:

Onken MD, Makepeace CM, Kaltenbronn KM, Choi J, Hernandez-Aya L, Weilbaecher KN, Piggott KD, Rao PK, Yuede CM, Dixon AJ, Osei-Owusu P, Cooper JA, Blumer KJ. (2021). Targeting primary and metastatic uveal melanoma with a G protein inhibitor. J Biol Chem. Feb 9:100403. doi: 10.1016/j.jbc.2021.100403. Online ahead of print. PMID: 33577798

Onken MD, Blumer KJ, Cooper JA. (2021). Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium. Mol Biol Cell. Jan 6:mbcE20040241. doi: 10.1091/mbc.E20-04-0241. Online ahead of print. PMID: 33405963

Truong A, Yoo JH, Scherzer MT, Sanchez JMS, Dale KJ, Kinsey CG, Richards JR, Shin D, Ghazi PC, Onken MD, Blumer KJ, Odelberg SJ, McMahon M. (2020). Clin Cancer Res. 26(23):6374-6386. doi: 10.1158/1078-0432.CCR-20-1675. Epub 2020 Sep 15. PMID: 32933997

Sun, X., Sing, S., Blumer, K.J., and Bowman, G.R. (2018). Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding. eLife. Oct 5;7. pii: e38465.

Onken, M.D., Makepeace, C.M., Kaltenbronn, K.M., Kanai, S.M., Todd, T.D., Wang, S., Broekelmann, T.J., Rao, P.K., Cooper, J.A., Blumer, K.J. (2018). Targeting nucleotide exchange to inhibit constitutively active G protein alpha-subunits in cancer cells. Sci Signaling. 11: eaao6852
http://stke.sciencemag.org/content/11/546/eaao6852

Last Updated: 2/15/2021 3:11:57 PM

Uveal melanoma, the large green mass pictured, is a cancer of the eye that has no targeted therapies. Research from the Blumer lab shows that a natural plant compound shuts down uveal melanoma cell growth in human tumor cells.
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