The Development of Therapies for Squamous Cell Carcinoma in RDEB Patients (Saville-Proby 1)Completed
|Project lead||Dr. Mark Saville|
|Organisation||University of Dundee School of Medicine, Ninewells Hospital and Medical School|
|Partner organizations & collaborators||Prof. Charlotte Proby from University of Dundee School of Medicine|
|Project budget||GBP 186,598.00|
|Start date / Duration||01. May 2015 / 36 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria, MSAP/EBEP Recommended|
|Research area||Skin cancer & fibrosis|
Short lay summary
The ubiquitin-proteasome system is important in controlling normal cells and defects in this system can contribute to cancer development. There is an ongoing international effort to target the ubiquitin-proteasome system for the treatment of many kinds of cancer. We aim to investigate whether this can be applied to the treatment of skin cancer (squamous cell carcinoma) that occurs in RDEB patients. We have used a technology called small interfering RNA (siRNA) to block each component of the ubiquitin-proteasome system individually to find which component would be a good target for chemotherapy. We have done this alone and in combination with the drug cetuximab which has already shown promise for the treatment of squamous cell carcinoma in RDEB patients. This has identified multiple targets of interest. We aim to carry out pre-clinical studies to investigate the therapeutic potential of inhibiting these targets. We believe that this will lead to the development of better skin cancer therapy for RDEB patients.
What did this project achieve?
The ubiquitin-proteasome system (UPS) regulates many important cellular processes. Alterations during tumour development can make tumours more sensitive than normal cells to suppression of components of the UPS. There is an ongoing international effort to inhibit this system for the treatment of many kinds of cancer. We carried out pre-clinical studies to investigate the therapeutic potential of targeting the UPS for the treatment of cutaneous squamous cell carcinoma (cSCC) in RDEB patients.
The UPS is made up of over a thousand proteins. We have used a technology called small interfering RNA (siRNA) to block each component of the ubiquitin-proteasome system individually in RDEB cSCC cells to find which components would be good targets for therapy. We have followed this up by suppressing promising targets using siRNA in additional cSCCs and in non-cancerous skin cells to facilitate the identification of tumour-selective effects. This identified three proteins and five complexes of proteins whose siRNA-mediated suppression kills cSCC cells more effectively than normal skin cells.
We have tested drugs that inhibit many of these targets in a panel of cells: normal skin cells, RDEB cSCC cells and for comparison non-RDEB cSCC cells. We have extensively compared different doses of drugs and also different times of drug exposure. We have found seven drugs that can selectively kill cSCC cells compared to normal cells.
To inform patient selection and drug development we investigated how suppression of the most promising targets kills cSCC cells and identified potential biomarkers for inhibitor sensitivity.
For some targets, we have identified ways to potentially improve on the effectiveness of drugs for treating cSCC. We have also found targets for which new drugs should be developed.
Targets identified in this study include the proteasome, ubiquitin E1s, the spliceosome, the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase 4 substrate receptor CDT2/DTL and components of the anaphase promoting complex/cyclosome (CDC20 and EMI1).
Small molecule inhibitors that selectively kill cSCC cells are bortezomib, ixazomib and carfilzomib (inhibitors of the proteolytic activities of the proteasome), MLN7243/TAK-243 (ubiquitin E1 inhibitor), pladienolide B (modulator of the spliceosomal subunit SF3B1), DUBs-IN-3/compound 22c (USP8 inhibitor) and MLN4924/pevonedistat (NEDD8 E1-activating enzyme/indirect cullin-RING ligase inhibitor). A number of these inhibitors are being used in the clinic for other cancers or are in trials for other cancers. We think that developing some of these inhibitors for direct delivery to cSCCs would be a good initial approach.