Melanocytes are the pigment-producing cells that protect and color the skin. Cancer of melanocytes is called malignant melanoma and is the most deadly form of skin cancer. Primary melanoma is characterized by growth of melanocytes on the skin surface, following by invasion of cells deep into the skin, which can result in spread of the cancer cells throughout the body. Once melanoma has spread to other parts of the body, it is referred to as metastatic melanoma and is highly resistant to conventional cancer treatments. Unfortunately, recent therapies that provide patient benefit often result in rapid relapse of disease because melanoma cells become resistant to the drug. Therefore, novel approaches and drug targets are critically needed.
Melanoma is thought to arise from a combination of genetic mutations in the cell that alter the DNA sequence in such a manner to drive cancer growth, invasion, and survival. DNA is wrapped around a core of proteins, and it is stored and regulated as a complex called chromatin. Alterations to chromatin, which do not affect the sequence of the genetic code (referred to as 'epi'genetics), are also involved in driving tumor formation. Thus, it is now believed that cancer progression occurs through a series of genetic and epigenetic events. However, the epigenetic players involved in melanoma progression and drug resistance remain unclear.
We favor the hypothesis that melanoma treatment should be guided by the tumor biology, which includes both genetic and epigenetic alterations. Our previous work has highlighted a role for histone variant proteins, which help to package and regulate chromatin, as a barrier to the progression of melanoma. However, the chromatin level alterations that participate in melanoma drug resistance remain poorly explored. Here we propose a combination of innovative and novel approaches to (1) map the changes in the chromatin structure of melanoma cells that have acquired resistance to melanoma therapies, particularly those that target genetic mutations (such as the commonly mutated BRAF gene) and (2) identify novel epigenetic regulators that mediate this resistance.
We expect that such studies will provide insight into the changes that occur at the chromatin level upon resistance, as well as genes and pathways that may be activated or suppressed in resistant cells. Such studies may also reveal differences between different types of resistant melanoma cells, which may suggest differential targets for distinct modes of resistance. This approach is highly clinically relevant, as it will provide rationale for combining therapy targeted against identified epigenetic modulators with current therapies, such as BRAF inhibitors. The study outlined here will also greatly facilitate our mechanistic understanding of melanoma drug resistance and provide critical information for rationally guided therapies for this highly aggressive disease.
|Effective start/end date||1/01/13 → …|
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