Department of Radiation Oncology

SOM logo


home » Division Information » Gary D. Kao, M.D., Ph.D.

Gary D. Kao, M.D., Ph.D.
Associate Professor

Gary Kao
University of Pennsylvania
Department of Radiation Oncology
180 H John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104


SELECTED PUBLICATIONS
LABORATORY MEMBERS

The overall goal of the Kao Laboratory is to understand aspects of cancer and normal cell biology that will ultimately allow us develop and refine anticancer treatment. We are attacking this goal via two interrelated approaches: (i) 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 (ii) 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:

  1. Expression and function of Class II histone deacetylases (HDACs) such as HDAC4.
  2. Defining the effects of novel anti-cancer treatment strategies on cancer cell viability and normal tissue development.
  3. High-throughput screening for novel compounds via zebrafish embryos.

1. 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.

2. 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.

3. 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! --

Selected References

» TOP

© University of Pennsylvania | School of Medicine | University of Pennsylvania Health System