Molecular Radiation Therapeutics Branch

The Molecular Radiation Therapeutics Branch (MRTB) was initiated in June of 2001 with the goal of developing target based strategies for enhancing tumor sensitivity and protecting normal tissue during radiotherapy. Towards this end, we have three general aims:

1. Identify molecules/processes that regulate the radioresponse of tumors and normal tissue, i.e., define novel molecular targets for radiation modifiers. With respect to tumor cell radiosensitizers, these fundamental studies will not only address causal relationships between a given molecule and radiosensitivity, but also the therapeutic feasibility of a molecule to serve as a target for radiosensitization. Investigations will thus define the "death process" affected by a molecule, the genetic context under which a regulatory molecule operates, and the potential for tumor selectivity.
2. Evaluate currently available agents for their ability to enhance tumor cell radiosensitivity and protect normal tissue. There are now agents in clinical trial or about to enter clinical trial that have been designed against a specific molecular target. The putative target for a number of these agents has also been associated with radioresistance. Such agents will be evaluated for their ability to modify tumor cell radiosensitivity. Critical to these studies will be the establishing a causal relationship between the agent-induced modification of the target and radiosensitization. This will serve to validate (or invalidate) a given molecule as a target for radiosensitization (target credentialing) and establish a "marker" for the use in the potential design of a clinical trial. Although initial studies will be performed using tumor cell lines and normal cells in vitro, agents found to be effective in vitro will then be evaluated using in vivo models.
3. Develop high throughput screening procedures for identifying novel radiation modifiers and for evaluating analogues of lead compounds as defined in Aim 2. High throughput screening (HTS) has been used for a number of years by academia and the pharmaceutical industry as a means of drug discovery. The goal of this aim is to apply these basic approaches to the discovery of radiation modifiers. Processes that correspond to a specific aspect of cellular radioresponse such as proliferation, apoptosis, G2 arrest and gene expression will serve as parameters for assays amenable to high throughput analysis. Through the use of libraries composed of synthetic small molecules and/or natural products HTS can be used for de novo modifier discovery, which will not only identify novel modifiers, but also lead to the identification of novel targets. With the potential for a more rapid impact, HTS will also be used to evaluate derivatives of modifiers identified in Aim 2.