Introduction:

Pharmacogenomics deals with inherited differences in the response to drugs. Genomic information may allow more accurate prediction of an individual's drug response and selection of the appropriate drug dosage. Information for Phase I trial are limited to define maximum tolerated dose and define toxicity of drugs. To optimize the objectives of Phase I trials we decide to propose concomitant screenings of anticancer drugs on yeast.

Methods: Our pharmacogenomic tool uses yeast as first step to identitfy gene(s) that potentially affect(s) pharmacodynamics of anticancer drugs. Yeast has proven to be a powerful instrument to this purpose: its small, compact genome has completely been sequenced showing that many yeast proteins share similarity to human ones. Several of these are involved in human diseases (Hartwell et al., 1997), making this simple organism very appealing for anticancer drug discovery. We intend to use yeast Saccharomyces cerevisiae as a model system to identify drug responsive genes that will be then validated in human cells and tissues (second step).

A concomitant screening on yeast model/phase I trial will be performed in IFOM /IEO in order to identify mutants that exhibit resistance or hypersensitivity to drug treatments. Mechanistic studies will be carried out when applicable.

Results: From 2006 at IFOM a pharmacogenomic platform is operative and devoted to the identification of the chemical genetic profiles of several anticancer drugs. Several drugs have been tested on the 6000 yeast mutants grown on solid medium. We will screen for those mutants exhibiting sensitivity or resistance to the drugs. This will be carried out by using a Virtek robotic station to replica-plate the mutant libraries. Mechanistic studies are also ongoing aimed at elucidating the mechanistic aspects of drug activity. In particular, the results concerning genes involved in pharmacosensitivity and resistance to cisplatin will be presented at the Meeting (Ferrari E et al). Furthermore, we will proceed by investigating the “status” of the genes of interest in human tissues. Frozen tissues will be microdissected by Laser Capture Microdissection in order to obtain purified cell populations from tumor. The cDNA from these tissues will be used to retrospectively understand whether there is a correlation between the expression of the genes identified, measured by RT-PCR, and tumor response to chemotherapy. The DNA of the genes of interest will also be sequenced to investigate the presence of mutation or polymorphisms.

Conclusions:

The yeast system allows analysing of gene knock-out and mutations, whereas in the mammal cell lines we can study only gene knock-out. An additional advantage is that many of these model systems use cell lines and associated genomic data that are publicly available.

Furthermore co-studies will be exploring on animal models the sequencing of drugs for phase I trials.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2193.