Abstract 2504: Genetic and molecular profiles altering radiosensitivity in melanoma

Purpose/Objectives: Historically, melanoma has been considered a relatively radioresistant tumor. Newer data have challenged this viewpoint, and radiation therapy (RT) is now considered to be useful for treating patients with malignant melanoma. Most importantly, it can provide effective palliation for the 40 to 50 percent of patients who develop unresectable locally recurrent or metastatic disease producing bone pain, epidural spinal cord compression, central nervous system dysfunction due to brain involvement, and/or tumor hemorrhage. RT has also been applied after complete excision of a primary melanoma or after therapeutic lymphadenectomy for regional nodal disease as adjuvant therapy to reduce the rate of local recurrence for certain types of melanoma. Melanoma is the most lethal form of skin cancer and incidences in the United States have steadily increased over the past 30 years. According to the American Cancer Society, melanoma accounts for only 3 percent of all skin cancers, but is responsible for nearly 74 percent of the deaths resulting from skin cancer. Prognosis is particularly poor for patients with metastasis as only 15 percent of this patient population survives for more than 5 years. Melanoma has been regarded as resistant to most treatments including radiation therapy. Melanoma has been poorly studied from the perspective of radiation biology and it is our intentions to elucidate key molecular mechanisms that can improve the benefit of radiotherapy in melanoma. Materials/Methods: In this study we set out to study genes that are commonly mutated in melanoma: BRAF, N-RAS, CKIT, TP53, PTEN, etc. These genes were sequenced in our panel of melanoma cell lines for determination of mutational status. We then stratified the cell lines based on their response to radiation as measured in a clonogenic survival and other functional assays. Established (ATCC) and primary (OSUMC patients) cell lines were used in this study. From the radioresistant melanoma cell lines we were able to isolate a small subpopulation of cells which exhibited the properties of stem cells and currently we are conducting further studies to completely characterize this sub population. Results/Conclusion: Melanoma has been poorly studied from the perspective of radiation biology and it is our intentions to elucidate key molecular mechanisms that can improve the benefit of radiotherapy in melanoma. It appears that BRAF intact cell lines are radiosensitive, whereas a mutation in at least one of the BRAF alleles at codon 600 leads to a radioresistant phenotype. We have adapted a pathway based targeting approach rather than the conventional gene based methods. We will present our preclinical studies on how genetic and molecular signatures in melanoma play a pivotal role in radiosensitizing melanoma and which subset of melanoma patients would derive the benefit from RT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2504. doi:10.1158/1538-7445.AM2011-2504