Revival of TRAIL as a cancer therapeutic: Can pre-treatment analysis of biopsied tumors give hope for the clinical use of TRAIL?

The clinical evaluation and classification of biopsied tumors for genotypic and phenotypic characteristics allows for the application of appropriate anti-cancer treatments for specific tumor types.  Personalized cancer treatments are critical to tailor therapies to individuals resulting in more efficacious therapies while minimizing negative side effects.  Individualized cancer plans can be applied to the clinical utilization of the death ligand Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL). 

TRAIL has been given considerable attention due to its ability to selectively induce apoptosis in a wide range of tumor types while showing minimal toxicity to normal non-transformed cells.  The ability of TRAIL to exhibit significant anti-tumor activity without harming normal cells contrasts with traditional chemotherapy where all cells, normal and cancerous, are targeted for cell death.  Due to this non-specificity, patients experience numerous side effects that negatively influence their quality of life and prevents optimal drug-dosing.  TRAIL is selective for only cancer cells resulting in minimal side effects.  In Phase I studies, TRAIL was found to be safe and well-tolerated; however, Phase II studies showed that only a small cohort of patients responded to TRAIL therapy while others displayed resistance and as a result the clinical use of TRAIL has been discontinued. 

The selectivity of TRAIL is through its interaction with extracellular death receptors (DR), DR4 and DR5.  TRAIL binding to DR4 and DR5 leads to apoptosis (programmed cell death) in cancer cells.  Consequently, we propose the pre-treatment analysis of biopsied tumors for expression of DRs to determine a patient’s suitability for TRAIL treatment.  Membrane surface expression of DR4 and DR5 can be easily determined through the application of fluorescent antibodies specific for the receptors followed by FACS analysis. 

Our lab has provided preliminary evidence to support the pre-treatment analysis of biopsied tumors using a malignant melanoma model.  Three malignant melanoma cell lines, A375, MeWo and WM164 were analyzed for membrane expression of DR4 and DR5 and sensitivity to TRAIL.  Cell line A375 had the highest expression of both DR4 and DR5 with a mean fluorescence intensity (MFI) of 42.0±2.7 (n=9) and 1958.0±25.9 (n=9), respectively.  Compared to A375, MeWo and WM16 had a significantly less expression of DR4 with a MFI of 15.7±3.6 (n=9) and 18.0±1.4 (n=9), respectively, and DR5 with a MFI of 928.4±47.0 (n=9) and 552.7±10.8 (n=9), respectively.  Moreover, we found that A375 was sensitive to TRAIL as evidenced by the dose-dependent generation of apoptotic cells when treated with 5-1000 ng/ml of TRAIL.  MeWo and WM164 were highly resistant to TRAIL and there was no induction of apoptosis even at 1000 ng/ml of TRAIL.

Preliminary results show a direct correlation between DR expression and sensitivity to TRAIL-induced apoptosis.  TRAIL-resistant cells had 74.6%±2.9 less DR4 and 55.2%±3.1 less DR5 membrane expression compared to the TRAIL-sensitive cell line, A375.  These data provide the rationale to implement this cytometry technique to measure DR expression of biopsied tumors to predict their sensitivity to TRAIL-induced apoptosis and give TRAIL a fighting chance to act as an effective anti-cancer therapy by giving it to patients that are well suited for it.