Advances Against Small Cell Lung Cancer

January 1, 2015

Translating basic science into clinical impact

Innovations in Cancer - Winter 2015 - View Full PDF
 

Afshin Dowlati, MD

Director, Phase I & Thoracic Oncology Program, University Hospitals Seidman Cancer Center; Lucile and Robert H. Gries Endowed Director, Center for Cancer Drug Development, UH Seidman Cancer Center; Rosalie and Morton A. Cohen Chair in Lung Cancer; Professor of Medicine, Case Western Reserve University School of Medicine; and Co-Leader, Developmental Therapeutics Program, Case Comprehensive Cancer Center

During the past 30 years, little progress has been made in the treatment of small cell lung cancer (SCLC), which accounts for about 13 percent of all lung cancers. Approximately 20,000 to 25,000 cases are diagnosed each year in the United States, but many more SCLC cases occur worldwide. Virtually all cases are linked to cigarette smoking. SCLC is one of the most aggressive and fastest-growing solid tumors. Without treatment, survival is only about four to eight weeks. 

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University Hospitals Seidman Cancer Center is a center of excellence in the diagnosis and treatment of SCLC, with considerable expertise not only on the clinical side, but also in basic and translational research.

IDENTIFYING RET MUTATIONS IN SCLC

In my laboratory, we have focused on finding new targets for the treatment of SCLC. We recently identified a mutation in the RET (rearranged during transfection) protein in the tumor of one of our patients, and we found this same mutation in a small number of other SCLC patients.

When we artificially implant this mutation into SCLC lines growing in the laboratory, those cells become extremely sensitive to RET inhibitors. This tells us that we must think about whether patients with SCLC have RET mutations. If they do, they should be considered for treatment with RET inhibitors.

Based on this work, a multicenter trial has been proposed that will identify and treat the subset of patients who have RET mutations present in their SCLC tumors, and UH will participate.

PINPOINTING POTENTIAL DRUGS

We have also used resources from the bioinformatics group at UH Case Medical Center and Case Western Reserve University School of Medicine to identify additional molecular targets for SCLC treatment.

We analyzed biologic data from a large series of SCLC cell lines and identified three molecular targets and three corresponding groups of drugs that may be very effective in treating SCLC. The drugs
are polokinase (PLK) inhibitors, heat shock protein inhibitors and cyclin-dependent kinase inhibitors, none of which has been studied previously in SCLC.

To validate the work further, we looked more closely at the responses of individual cell lines to PLK inhibitors. We found that approximately 50 percent of SCLC cell lines are sensitive to this class of drugs at very low, nanomolar concentrations.

PERSONALIZING MEDICINE

Because only half of the SCLC lines were sensitive to PLK inhibitors, we developed a genomic signature to personalize our approach, determining which patients may benefit from this class of drugs.

We then looked prospectively at human SCLC tumors to determine whether the same genomic predictor that we found in the cell lines also exists there. It does. This paves the way to start clinical trials of PLK inhibitors in patients whose SCLC contains this genomic signature. This study is being proposed as a national trial in which UH will participate.

Our progress in SCLC is an excellent example of practical research that translates directly into improved patient care. Additional genomic studies in SCLC are ongoing.

For more information on our SCLC clinical trials, please contact me at Afshin.Dowlati@UHhospitals.org.

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