AIRC 2021-The dark side of BRAFi: hampering pigmentation to boost the efficacy of targeted therapy in melanoma (DSB.AD001.219)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of clinical physiology (IFC)

Project manager

LAURA POLISENO
Phone number: 0503152780
Email: laura.poliseno@ifc.cnr.it

Abstract

Background
Selective inhibitors of the constitutively-active BRAFV600E kinase (BRAFi, such as vemurafenib and dabrafenib)
have become a valid example of molecularly-driven precision medicine, contributing to increase life
expectancy of patients with a metastatic melanoma that is rapidly progressing and immediately lifethreatening.
However, there are still many drawbacks associated with their use. Therefore, the hunt for drugs
to be combined with BRAFi in order to improve their performance as first line treatment option is still on.
Hypothesis
Having previously demonstrated in vitro that pigmentation is an adaptive cellular response that limits
vemurafenib efficacy, in this project we want to dig further into its mechanism of action and to show that its
inhibition can be exploited for therapeutic purposes.
Aims
We aim to:
-gain insights into the molecular mechanism(s) by which pigmentation limits BRAFi activity in melanoma cells
(TASK 1);
-use a tissue-specific and inducible melanoma model in zebrafish to confirm in vivo that pigmentation has a
negative impact on sensitivity to BRAFi (TASK 2);
-perform a drug screening in zebrafish embryos to identify new combinations of one BRAFi

Goals

Aims
We aim to:
-gain insights into the molecular mechanism(s) by which pigmentation limits BRAFi activity in melanoma cells
(TASK 1);
-use a tissue-specific and inducible melanoma model in zebrafish to confirm in vivo that pigmentation has a
negative impact on sensitivity to BRAFi (TASK 2);
-perform a drug screening in zebrafish embryos to identify new combinations of one BRAFi plus one
pigmentation inhibitor (PIGMi) (TASK 3);
-test Lmat (attenuated Listeria monocytogenes) anti-cancer vaccine as a platform for the selective delivery of
the best-performing BRAFi+PIGMi combinations inside melanoma tumors that develop in Braf/Pten mice (TASK
4).

Start date of activity

02/01/2022

Keywords

Melanoma, Drug response and/or resistance, Combination therapy

Last update: 04/12/2023