Johann Brandes M.D., Ph.D.

Recipient of the LUNGevity Foundation/Joan’s Legacy Research Grant. Funded equally by Joan's Legacy and the LUNGevity Foundation.

Lay Description

About 170 000 patients are yearly diagnosed with NSCLC, most of these with advanced stages. The 5 year survival is about 14%. About 10% of lung cancers arise in never-smokers. About half of these carry a recently defined genetic change, a mutation in the Epithelial Derived Growth factor Receptor, which is responsible for tumor growth, but also serves as a target for therapy. As a result, patients with mutations in the EGFR have a significantly better prognosis than those without. Consequently one of the major challenges in the treatment of advanced adenocarcinoma of the lung and lung cancer in general is the improvement in therapy in those patients whose tumors do not carry an EGFR mutation. We have new and exciting preliminary data that loss of function of the gene “Checkpoint with Forkhead and Ringfinger Domain” (CHFR) correlates with improved response and survival following therapy with a commonly used chemotherapeutic class called taxanes. Loss of CHFR is observed in about 15% of non-small cell lung cancers. Response rates to taxanes are in the same range. If CHFR could be targeted in the remaining 85% of patients, a dramatic impact on response rates to taxanes could be expected. Previous work suggests that CHFR function can be inhibited pharmacologically by targeting a modification called poly-ADP ribosylation (PARP). A class of inhibitors of this modification is currently under clinical investigation. We have preliminary data showing that PARP-inhibitors potentiate the effects of taxanes in adenocarcinoma cell lines of the lung and we hypothesize that the mechanism is by targeting CHFR. In the proposed study we determine the expression of CHFR and will examine the effects of the combination of PARP-inhibitors and taxanes in adenocarcinomas derived from non-smokers and compare these to those derived from smokers. We will also address the question if PARP-inhibition can overcome acquired taxane resistance. The study is highly relevant since it could lead to a dramatic improvement in response rates and clinical outcomes in those lung cancer patients who currently do not benefit from novel targeted therapies.

Scientific Abstract

Treatment options for nonsmokers with NSCLC without EGFR mutation remain poor. The IPASS trial recently suggested that combination chemotherapy with carboplatin and paclitaxel remains the most active therapy. Response rates for these patients are a disappointing 15-20%. The identification and targeting of pathways that confer resistance to commonly used chemotherapy is of the utmost importance to improve response rates and outcomes. By showing that methylation and silencing of the mitotic checkpoint gene CHFR is associated with a dramatic improvement in survival following taxane based combination therapy, we have identified CHFR expression as a mechanism to confer intrinsic resistance to taxanes. Previous work has shown that CHFR has a poly-ADP-ribosylation site and that its checkpoint function can be inhibited by inhibiting PARP. We have preliminary data showing that PARP-inhibition sensitizes the adenocarcinoma cell line A549 to the effects of paclitaxel, leading us to hypothesize that PARP-Inhibitors can overcome intrinsic and acquired resistance to taxanes by inhibiting CHFR function. We will address this question in a panel of adenocarcinoma cell lines of smokers and non-smokers. We will determine the effects of taxanes alone or in combination with PARP-inhibition in CHFR positive and negative cell lines, which are either chemotherapy naïve or made resistant to taxanes by prior exposure. In addition, we will determine in CHFR expressing cell lines by CHFR shRNA knockdown if the effects of PARP-inhibition are as strong as a near-complete loss of CHFR function. Experimental endpoints are a) the determination of IC50 values and apoptosis b) determination of CHFR poly-ADP-ribosylation by immunoprecipitation and Western Blot and c) determination of the mitotic index as an indicator for CHFR’s checkpoint function. The study is highly relevant since it could lead to a dramatic improvement in response rates and clinical outcomes in those lung cancer patients who currently do not benefit from novel targeted therapies.