Periodic Reporting for period 1 - KILNEV (Killing Senescent Cells as a Novel Method to Eliminate Nevi)
Reporting period: 2018-04-01 to 2020-03-31
The current project entails the elucidation and evaluation of novel genes which senescent nevus cells (pigmented moles) utilise to maintain survival. Nevus cells arise when skin cells called melanocytes enter a state of gorwth arrest termed 'senescence'. Nevus cells can eventually develop into malignant melanoma, a highly aggressive skin cancer. Therefore targeting cell death in nevus cells may act as a novel preventative measure against melanoma development. This is especially important considering rates of melanoma are increasing in most European countries and current therapies against melanoma such as chemotherapy and immunotherapy are highly invasive, expensive and can result in toxic side effects.
The objectives are:
1) Elucidate and validate new genes of interest which modulate survival in senescent melanocytes.
2) Investigate whether siRNA mediated knockdown of these genes induce death of nevus cells in mice.
The objectives are:
1) Elucidate and validate new genes of interest which modulate survival in senescent melanocytes.
2) Investigate whether siRNA mediated knockdown of these genes induce death of nevus cells in mice.
The first aim of the project was to evaluate which genes are used my senescent melanocytes for cell survival. We first found find that Bcl-w and Mcl-1 are survival proteins used by senescent melanocytes for survival due to their upregulation compared to non-senescent melanocytes.
We next validated whether these proteins do modulate survival by silencing their expression using genetic knockdown experiments, or by inhibiting their function using pharmacological drugs. We indeed find that knockdown of these proteins do cause death in senescent, but not proliferating, melanocytes. We also used two pharmacological compounds called ABT-263 (an inhibitor of Bcl-w) and S63845 (an inhibitor of Mcl-1). These two drugs act together to also specifically kill senescent melanocytes.
We then aimed to investigate whether these two drugs could be topically administered onto mice nevi, in order to kill the nevus cells. Experiments carried out so far show reduced number of pigmented nevi in treated mice.
We next validated whether these proteins do modulate survival by silencing their expression using genetic knockdown experiments, or by inhibiting their function using pharmacological drugs. We indeed find that knockdown of these proteins do cause death in senescent, but not proliferating, melanocytes. We also used two pharmacological compounds called ABT-263 (an inhibitor of Bcl-w) and S63845 (an inhibitor of Mcl-1). These two drugs act together to also specifically kill senescent melanocytes.
We then aimed to investigate whether these two drugs could be topically administered onto mice nevi, in order to kill the nevus cells. Experiments carried out so far show reduced number of pigmented nevi in treated mice.
The potential impacts from this project are the development of new topical ointments containing ABT-263 and S63845 that could be administered onto human nevi. This could be beneficial in reducing the burden melanoma places on society.