Exploring Mechanisms and Predictors of Treatment Response to Improve Outcome of Standard Chemotherapy in Non-Small Cell Lung Cancer
Abstract
About 85% of all lung cancer patients have a type of the cancer called non-small cell lung cancer (NSCLC). Among them, the majority of the cancers are described as non-squamous NSCLC. This type of cancer widely affects the general population, including military personnel and Veterans and people near and dear to them. In recent years, a chemotherapy drug called pemetrexed (PEM) has come to become widely used in such patients because it is generally better tolerated. However, whereas a minority of patients respond very well to this treatment, in many patients the tumors may be poorly responsive to PEM treatment or not at all. Having the ability to predict which patients would respond to PEM chemotherapy will enable the doctor not only to avoid futile treatments in many patients but also to offer other treatment that may be more effective. Moreover, understanding why many patients do not respond well to PEM could enable the use of PEM in those patients in a more effective manner. These issues are addressed in this research proposal. PEM causes severe and painful skin rash in about a third of patients treated with this drug. To alleviate this side effect, a standard steroid drug called dexamethasone (Dex) is typically given to patients beginning the day before giving PEM and ending the day after treatment with PEM. We have studied the effect of Dex on many model NSCLC cells to see what Dex might do to them and whether Dex may influence the effect of Dex on the cancer cells. We have discovered that in many cases, Dex protects the cancer cells against the very chemotherapy drug whose side effects it is meant to alleviate! We have also discovered how Dex could protect these lung cancer cells against PEM. Our studies show that Dex acts through a protein called the glucocorticoid receptor (GR) to temporarily prevent the cancer cells from multiplying by holding the cells in a state that is insensitive to PEM. In the laboratory, cancer cells with high levels of GR were resistant to treatment when Dex was given along with PEM, while those with low levels of GR were still sensitive. We have developed a method to image tumor growth using positron emission tomography (PET) with the radioactive tracer FLT. We have shown that FLT levels in cancer cells goes down when cells with high levels of GR protein are treated with Dex, but not in those with low levels of GR. Cells with decreased FLT uptake with Dex were resistant to PEM treatment. In this research project, we will study the ability of PET imaging with FLT to predict and monitor the effect of Dex on tumor resistance to PEM. In the first patient imaged as part of a pilot study, Dex decreased FLT uptake by up to 65%. We plan to study 20 patients by imaging them before and after Dex to test their sensitivity. We will also use FLT with PET to see if PEM is changing tumor metabolism as a measure of the effectiveness of treatment when given with Dex. We will compare the results with imaging to measurements of GR from biopsies already obtained from these patients as part of routine care. This may help us determine if GR levels can predict which patients should not receive Dex with PEM. Giving treatment that is not effective exposes the patient to toxicity, may delay more effective therapy, and PEM costs over $6000 per month. If this study yields the expected results, the findings will be immediately further validated to predict which patients with NSCLC will benefit from chemotherapy using a major drug (PEM) that is presently given to many patients. Patients predicted to non-responders when Dex is given with PEM may need to have their Dex delayed or be treated with alternative chemotherapies that do not require Dex. Future studies will establish which types of chemotherapy will work best in patients that predictably would not benefit from the currently used PEM treatment regimens. Those studies may also explore changing the Dex treatment regimen in PEM chemother
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510171
Entities
People
- Anthony F Shields
Organizations
- United States Army
- Wayne State University