Gary D. Kao, M.D., Ph.D.
Smilow Translational Research Center
8th Floor, Suite 8-134
Univ. of Pennsylvania Perelman School of Medicine
3400 Civic Center Blvd.
Philadelphia, PA 19104-5156
The overall goal of the Kao Laboratory is to understand aspects of cancer and normal tissue biology that will ultimately allow us develop and refine anticancer treatment. We have attacked this goal via interrelated approaches that have included: (i) novel assays to study the integrity of the blood:brain:barrier (BBB) as a determinant of malignant brain tumor treatment success (ii) investigating the biology of histone deacetylases in cancer and normal tissues, its role in development and cellular growth, and in the response to histone deacetylase inhibitors and other treatment modifiers, and (iii) developing novel vertebrate-based systems to investigate the relative effects of treatment on cancer cell viability as well as normal tissue development and function. We believe the understanding resulting from these investigations will enable us to optimize the "therapeutic ratio" --developing more effective yet less toxic treatment strategies.
Specific Projects in the Kao Laboratory:
- Integrity of the central nervous system and tumor blood:brain:barrier (BBB) as a determinant of malignant brain tumor treatment efficacy.
- Expression and function of Class II histone deacetylases (HDACs) such as HDAC4.
- Defining the effects of novel anti-cancer treatment strategies on cancer cell viability and normal tissue development.
- High-throughput screening for novel compounds via zebrafish embryos.
HDACs are best known for the ability to deacetylate specific lysines in the tails of core histones, thereby contributing to chromatin remodeling. These enzymes are intimately involved in diverse activities including carcinogenesis, gene expression, cell cycle control, differentation, and much more. HDAC inhibitors are currently being intensely studied in clinical trials, including for treating cancer. The HDACs are divided into classes based on sequence homology. The Class II HDACs, which include HDAC4, are especially intriguing because it is increasingly apparent that the target(s) of these enzymes may extend to nonhistone proteins, with diverse and complex mechanisms of function and regulation. For example, caspase mediated cleavage of HDAC4 generates a bioactive amino-terminal fragment that may not even need its deacetylase domain to affect the expression of downstream targets. The regulation of HDAC4 in term may involve mRNA and protein instability, as well as the Sp1-family of transcription factors. These mechanisms together may facilitate precise control of its regulatory functions (i.e. HDAC4 can be quickly turned “off” and “on”). In addition to its role in controlling gene expression and viability of cancer cells, HDAC4 has also been linked to the development of normal tissues such as the CNS, cardiac and musculoskeletal. However, how HDAC4 expression is regulated during development is unknown and is one of our current interests.
The ideal anticancer treatment combines high efficacy with the least amount of toxicity to normal tissues. Ionizing radiation (IR, i.e. radiation therapy or radiation oncology) is a treatment that the majority of cancer patients will receive at some point in their lives. In most cases, the treatment is successful and incurs few or no complications. Complications do occur sometimes and vulnerable populations such as children are at higher risk. Surprisingly little is known, however, regarding the pathogenesis of such complications. Our goal is to develop novel vertebrate model systems with which to investigate the efficacy and normal tissue effects of anticancer treatment. We have helped pioneer the zebrafish (danio rerio) for such studies, especially those involving IR. The zebrafish offers logistical, technical, genetic and physiological advantages, which include but are not limited to: high genetic and physiologic homology to mammals, rapid development, optical clarity, experimental accessibility of the embryo and juveniles and opportunities for genetic and biochemcial screens and manipulations.
The low cost, easy care, and small dimensions of the zebrafish embryo renders it the ideal (and perhaps the only) vertebrate amenable to high-throughput screening (HTS). Up to 20 embryos can easily fit within individual wells of a 96-well microplate. The aqueous environment of the zebrafish faciliates drug treatment and uniform radiation dosimetry.
-- You are most welcome to write, call, or visit us. We'd love to show you what we do! --
- Kao G, McKenna WG and Yen TJ. Detection of repair activity during the DNA Damage-induced G2 Delay. Oncogene, (27): 3486-96, 2001. PDF
- Kao GD, McKenna MG, Guenther MG, Muschel RJ, Lazar MA, Yen TJ. Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response. J Cell Biol. Mar 31;160(7):1017-27, 2003. PDF
- Daniel R, Kao G, Taganov K, Greger JG, Favorova O, Merkel G, Yen TJ, Katz RA, Skalka AM. Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response. Proc Natl Acad Sci U S A. Apr 15;100(8):4778-83, 2003. PDF
- Lee EA, Keutmann MK, Dowling M, Harris E, Chan E, Kao GD. Inactivation of the mitotic checkpoint targets human cancer cells to killing by microtubule-disrupting drugs. Molec Cancer Ther, 3(6):661-9, 2004. PDF
- Liu F, Dowling M, Yang XJ, Kao GD. Caspase-mediated specific cleavage of human histone deacetylase 4 (HDAC4). J Biol Chem, 279(33):34537-46, 2004. PDF
- Dowling M, Voong KR, Kim MJ, Keutmann M, Harris E, Kao GD. Mitotic spindle checkpoint inactivation by Trichostatin A defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents. Cancer Biol Ther, 4:2. e86-e95, EPUB ahead of print, 2005 PDF
- Kim M, Murphy K, Liu F, Parker S, Dowling ML, Baff W, Kao GD. Caspase-mediated specific cleavage of BubR1 is a determinant of the mitotic spindle checkpoint. Molecular and Cellular Biology, 25(21):9232-48, 2005. PDF
- Liu F, Pore N, Kim M, Voong KR, Dowling M, Maity A, Kao GD. Regulation of histone deacetylase 4 expression by the SP family of transcription factors. Molecular Biology of the Cell. Feb; 17(2):585-97, 2006. PDF
- Kim IA, Shin JH, Kim IH, Kim JH, Kim JS, Wu HG, Chie EK, Ha SW, Park CI, Kao GD. Histone deacetylase inhibitor-mediated radiosensitization of human cancer cells: class differences and the potential influence of p53. Clin Cancer Res. Feb 1; 12(3 Pt 1): 940-9, 2006. PDF
- Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Research. Mar 15; 66(6): 3197-204, 2006. PDF
- Farkash EA, Kao GD, Horman SR, Prak ET. Gamma radiation increases endonuclease-dependent L1 retrotransposition in a cultured cell assay. Nucleic Acids Res. Feb 28; 34(4):1196-204, 2006. PDF
- Geiger G, Parker S, Beothy A, Tucker J, Mullins MC, Kao GD. Zebrafish as a ‘‘Biosensor’’? Effects of ionizing radiation and amifostine on embryonic viability and development. Cancer Research, 66: (16), August 15, 2006. PDF
- Li Y, Kao GD, Garcia BA, Shabanowitz J, Hunt DF, Qin J, Phelan C, Lazar MA. A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity. Genes and Development, 20 (18): 2566-2579, 2006. PDF
- Yu J, Palmer C, Alenghat T, Li Y, Kao GD, Lazar MA. The Corepressor SMRT facilitates cellular recovery from DNA double-strand breaks. Cancer Research,Sep15;66(18):9316-22., 2006. PDF
- Huang H, Feng J, Famulski J, Rattner JB, Liu ST, Kao GD, Muschel R, Chan GKT, Yen TJ. Tripin/hSgo2 recruits MCAK to the inner centromere to correct defective kinetochore attachments. J Cell Biol., 2007 May 7;177(3):413-24. PDF
- Kao GD, Jiang Z, Fernandes AM, Gupta AK, Maity A. Inhibition of PI3K/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem., 2007 Jul 20;282(29):21206-12. PDF
- Lally BE, Geiger G, Kridel S, Wheeler K, Peddi P, Georgakilas A, Kao GD, Koumenis C. Identification and preclinical characterization of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library. Cancer Research, 2007 Sep 15;67(18):8791-9. PDF