Resistance mechanisms to autophagy-modulating therapies

Summary

This project aims to understand mechanisms of resistance to autophagy-modulating therapies in cancer, specifically melanoma, by investigating lipid raft induction and cholesterol/sphingolipid salvage pathways (CSSP).

What they want

Aim 1: Define the mechanism by which autophagy modulation regulates the cholesterol and sphingolipid scavenging pathways (CSSP), determining the effects of chemical or genetic manipulation inhibition of key CSSP genes in lipid-depleted and precisely reconstituted media on tumor cell survival. Aim 2: Determine the role of UGCG as a driver of resistance across melanoma therapy combinations in in vivo models, utilizing a panel of patient-derived xenograft (PDX) models from BRAF mutant and NRAS mutant melanoma patients to assess if targeting UGCG results in decreased lipid raft assembly that overcomes resistance to clinically relevant therapies.

Deliverables

Uncover new therapeutic vulnerabilities in melanoma as well as other cancers.
Identify new therapeutic combinations incorporating CSSP inhibitors to be tested in future clinical trials.

Technical requirements

Use of lipid-depleted and precisely reconstituted media.
In vivo models.
Panel of patient-derived xenograft (PDX) models generated from BRAF mutant and NRAS mutant melanoma patients.
Humanized mouse model.
Bank of patient-derived xenografts.

Key personnel

Oncologist with autophagy expertise (Dr. Amaravadi)
Systems biology expert (Dr. Speicher)
Melanoma expert (Dr. Meenhard Herlyn) with experience in humanized mouse models and patient-derived xenografts
Biostatistician (Dr. Phyllis Ginotty) with prior collaboration experience with the team