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Discovery of molecular markers for the inverse relationship between platinum and taxane resistance in cancer

Final Report Summary - CISTAX (Discovery of molecular markers for the inverse relationship between platinum and taxane resistance in cancer)

An EACR travel fellowship allowed me to spend a week at the laboratory of my collaborators Dr. Jean-Pierre Gillet and Prof. Michael Gottesman at the National Cancer Institute (NCI).
My research investigates patterns of resistance and sensitivity in cancer cell lines to two chemoterapy drugs, cisplatin and paclitaxel. When cisplatin resistance is developed in the laboratory 68% of cells lines are not resistant to paclitaxel and some even become more sensitive to paclitaxel. The reverse is also true of paclitaxel-resistant cell lines. 66% showed no resistance to cisplatin or were more sensitive to cisplatin. This research suggests that two-thirds of cancer patients would benefit from receiving chemotherapy which alternates between cisplatin and paclitaxel, because developing resistance to one could make their cancer more sensitive to other drug.

The challenge for me is how to identify which patients will respond to alternating therapy between cisplatin and paclitaxel. While two-thirds of cancer patients may respond well to this treatment strategy, the other third would respond poorly and need to be treated differently. Through collaboration with the Gottesman lab and several other groups I have put together a panel of drug-resistant cell lines which either have the inverse resistance phenotype between cisplatin and paclitaxel or are cross resistant to both drugs. I will be looking for "molecular markers": genes and proteins which correspond with the inverse resistance pattern. I will determine wheter these molecular markers change in the same way in samples from ovarian cancer patients. Once validated in clinical samples, these molecular markers could be used as a clinical test to determine if an individual patient is likely to respond to cisplatin or paclitaxel and therefore model the smaller group of patients who are cross-resistant to both agents. We took a targeted approach to examining gene expression by performing profiling with a custom TLDA array designed by the Gottesman group. This assays the expression of 380 genes previously associated with drug resistance and response to chemoterapy. Gene families examined included; ABC transporters, DNA repair genes, apostosis-associated genes, glutathione metabolism, copper metabolism and many others.