Katherine L. Schaefer, Ph.D.

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Katherine L. Schaefer

Assistant Professor

Department of Medicine, Gastroenterology and Hepatology

 

Microtubule function in colorectal cancer and novel chemotherapeutic agents that target microtubules

Microtubules are key components of the cytoskeleton, and their proper function is essential for maintenance of cell shape, polarity, migration, intracellular transport, and cell division. Given the importance of migration and division to cancer cells, microtubules are a prime target in cancer therapy. However, current microtubule-targeting agents have side effects that occur at least in part because the drugs interfere with microtubule function in normal cells, and drug resistance is a serious problem.

Work in my laboratory centers on determining how microtubule function in normal cells differs from that in colorectal cancer cells, and in developing therapeutic compounds targeting microtubules that exploit these differences. To approach this problem, we are identifying microtubule-associated proteins whose regulation is altered in colorectal cancer cells, and determining whether reversal of these changes is detrimental to cancer cell growth. A variety of experimental systems are being used, including colorectal cancer cell lines, cancer stem cells derived from human tissue, and mouse models.

We have recently discovered a class of compounds that affects microtubule function differently from all known anti-microtubule therapies. Rather than binding directly to microtubules or their constituent alpha/beta tubulin proteins and altering microtubule polymerization, these compounds cause a progressive loss of tubulin proteins, as well as cell cycle arrest and apoptosis. In a mouse model, they reduce tumor burden without causing leucopenia or damage to the intestinal epithelium. Experiments are in progress to determine the basis of this seeming tumor specificity as well as to determine the mechanisms underlying apoptosis and tubulin loss.

Relevant Publications:

1. Schaefer, KL. PPAR-gamma inhibitors as novel tubulin-targeting agents. Expert Opin Investig Drugs, 16: 923-6 (2007).

2. Schaefer KL#, Takahashi H, Morales VM, Harris G, Barton S, Osawa E, Nakajima A, and Saubermann LJ. PPARgamma inhibitors reduce tubulin protein levels by a proteasome-independent post-transcriptional mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. Int. J. Cancer 120:702-13 (2007). # corresponding author

3. Schaefer, KL#, Wada, K, Takahashi, H, Matsuhashi, N, Ohnishi, S, Wolfe, MM, Turner, J R, Nakajima, A, Borkan, SC, and Saubermann, LJ. Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells. Cancer Res., 65: 2251-2259 (2005).

# corresponding author

 

Current Appointments

• Assistant Professor - Department of Medicine (SMD)

Education
PhD Biological Science	Carnegie-Mellon Univ	1996
BS Biochemistry	Univ of Illinois-Urbana	1988

Post-Doctoral Training & Residency
postdoctoral fellow Lawrence Saubermann, MD Boston Medical Center Boston, MA 02118	2002 - 2005
postdoctoral fellow Leslie Berg, PhD University of Massachusetts Medical School Worcester, MA 01655	1997 - 2002
postdoctoral fellow Leslie Berg, PhD Harvard University Cambridge, Massachusetts 02138	1996 - 1997

Fellowship Awards
NIH/NIDDK NRSA 1F32 DK66928-01 3/1/04-3/31/07 postdoctoral training grant	2004 - 2007
National Institutes of Health; NIGMB 1T32 GM08067-10 predoctoral training fellowship	1990 - 1993
American Society for Microbiology Summer Research Grant salary support and supply money for an undergraduate research project	1988 - 1988

Recent Journal Articles
Showing the 5 most recent journal articles. (12 available)
Harris, G.; Schaefer, K.L. "The Microtubule-Targeting Agent T0070907 Induces Proteasomal Degradation of Tubulin". Biochem Biophys Res Commun 388 (2009): 345-9.
Schaefer KL. "PPARgamma Inhibitors as Novel Tubulin-Targeting Agents." PPAR research. 2008; 2008():785405.
Schaefer KL; Takahashi H; Morales VM; Harris G; Barton S; Osawa E; Nakajima A; and Saubermann LJ. "PPAR³ inhibitors reduce tubulin protein levels by a proteasome-independent post-transcriptional mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells". International Journal of Cancer 120 (2007): 702-13.
Schaefer KL. "PPAR-gamma inhibitors as novel tubulin-targeting agents." Expert opinion on investigational drugs. 2007; 16(7):923-6.
Takahashi H; Fujita K; Fujisawa T; Yonemitsu K; Tomimoto A; Ikeda I; Yoneda M; Masuda T; Schaefer K; Saubermann LJ; Shimamura T; Saitoh S; Tachibana M; Wada K; Nakagama H; Nakajima A. "Inhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties." Cancer science. 2006; 97(9):854-60. Epub 2006 Jun 29.