Identifying Mechanistic Similarities in Drug Responses
February 16, 2012
2:30 p.m.
Ivan Ivanov
Abstract
In early drug development it is beneficial to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit a desired response. One approach to do this is to quantify the degree of similarity between the responses that the same or different cells produce in response to drugs, so that consistencies in the regulation of cellular response processes that produce success or failure can be more readily identified.
We discuss a current technology for tracking drug response by means of fluorescent proteins as transcription activity reporters. Our basic assumption is that drugs inducing very similar alteration in transcriptional regulation will produce similar temporal trajectories and hence be identified as having similarities in their mechanisms of action (MOA). Thus, the main focus is to characterize similarity in temporal trajectories. To do so, we must first identify the key points that determine mechanistic similarity between two drug responses. Directly comparing points on the two signals is unrealistic, since it cannot handle delays and speed variations on the time axis. Hence, to capture the similarities between reporter responses, we propose an alignment algorithm that is robust to noise, robust to time delays, and able to find all the contiguous parts of signals centered about a core alignment (reflecting a core mechanism in drug response). Applying the proposed algorithm to a range of real drug experiments shows that the result agrees well with the prior drug MOA knowledge.