Using femtosecond pump-probe microscopy to improve detection of early-stage metastatic melanoma

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Melanoma, the skin cancer originating from melanocytes, is by far the most dangerous type of skin cancer because of its high metastatic potential. In 2019, about 100,000 new melanoma incidences are expected in the United States, and about 7,000 are expected to die from it. These numbers are comparable to most western countries; in Germany, for example, about 21,000 new incidences and about 3,000 deaths are caused by melanoma per year. Primary tumors of melanoma are “staged” from 0 to IV; tumors staged II and below do not have detected metastases and are almost always left untreated after excision. Yet, more people die from melanoma after a stage I diagnosis than after a stage IV diagnosis, because the current diagnostic gold standard (histopathological evaluation and, where appropriate, lymph node biopsy) is not suitable to assess the metastatic potential. A decade ago, measuring metastatic potential would have been not useful, because no effective treatments were available. Since then, adjuvant therapies have made great strides, but are only approved for melanoma with metastases (stage III-IV). Toxicity, side effects, and resistance development currently limit the broad use of adjuvant therapies, but they could be much more effective if applied to early stage tumors with high risk of metastases, given a reasonable marker for identifying them. Here we propose optical femtosecond pump-probe microscopy of primary tumor biopsies for identification of melanoma with a high risk for metastases. Analysis of the ultrafast electronic and vibrational dynamics of melanin, the tumor-intrinsic pigment, provides a powerful biomarker. Preliminary retrospective studies, done by the Warren lab at Duke University, have shown that the characteristic pump-probe signature of melanin changes with increased metastatic potential. We will further develop pump-probe microscopy of melanoma with the goal of clinical application. First, we will characterize the spectroscopic properties of the tumor-intrinsic pigment melanin and develop metrics to quantify their properties to metastatic potential. We will build a compact and turn-key microscope that can be deployed in a diagnostic lab and operated by pathologists and, as a last step, we will use around 600 archived melanoma biopsy samples (from the Duke Medical Center) to rigorously benchmark our method. This technology can directly impact patient treatment and prognosis by assisting pathologists in quantifying the metastatic potential of melanoma. It could guide appropriate usage of lymph node biopsy, thereby avoiding unnecessary diagnostic surgical procedures, and, in the long run, this technology has the potential to deliver a reliable biomarker to decide which early stage, high-risk melanoma should be treated with adjuvant therapy.