The emerging role of targeted protein degradation to treat and study cancer.

The evolution of cancer treatment has provided increasingly targeted strategies both in the upfront and relapsed disease settings. Small-molecule inhibitors and immunotherapy have risen to prominence with chimeric antigen receptor T-cells, checkpoint inhibitors, kinase inhibitors, and monoclonal antibody therapies being deployed across a range of solid organ and haematological malignancies. However, novel approaches are required to target transcription factors and oncogenic fusion proteins that are central to cancer biology and have generally eluded successful drug development. Thalidomide analogues causing protein degradation have been a cornerstone of treatment in multiple myeloma, but a lack of in-depth mechanistic understanding initially limited progress in the field. When the protein cereblon (CRBN) was found to mediate thalidomide analogues' action and CRBN's neo-targets were identified, existing and novel drug development accelerated, with applications outside multiple myeloma, including non-Hodgkin's lymphoma, myelodysplastic syndrome, and acute leukaemias. Critically, transcription factors were the first canonical targets described. In addition to broadening the application of protein-degrading drugs, resistance mechanisms are being overcome and targeted protein degradation is widening the scope of druggable proteins against which existing approaches have been ineffective. Examples of targeted protein degraders include molecular glues and proteolysis targeting chimeras (PROTACs): heterobifunctional molecules that bind to proteins of interest and cause proximity-induced ubiquitination and proteasomal degradation via a linked E3 ligase. Twenty years since their inception, PROTACs have begun progressing through clinical trials, with early success in targeting the oestrogen receptor and androgen receptor in breast and prostate cancer respectively. This review explores important developments in targeted protein degradation to both treat and study cancer. It also considers the potential advantages and challenges in the translational aspects of developing new treatments. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Improving Access to Specialist Eye Care for Indigenous Australians via Telehealth: An Observational Cohort Study.

Background: Indigenous people are often neglected in eye health research and service delivery programs, despite having a greater burden of vision loss, most of which is avoidable. The objective of this work was to improve access to specialist eye care for Indigenous Australians living in rural and remote areas, by providing direct access to expert diagnostic services based in metropolitan areas through a tele-ophthalmology system. Methods: Over a four-year study period, 13 remote communities in Queensland and the Northern Territory were identified that had limited or no access to eye screening services. Relationships with health service providers in the communities were established to codesign a sustainable model of service delivery and referral pathways to ensure that patients identified with eye issues received appropriate treatment. Results: Over the course of the study, screening records from 378 patients were uploaded to a web-based telehealth system and diagnosed by ophthalmologists. From these examinations, 64 new cases of diabetic retinopathy (DR) were identified (including 2 cases of proliferative DR and 4 cases of severe nonproliferative DR), and diabetic macular edema was noted in 18 patients. The majority of participants screened had no eye problems, which enables the removal of these patients from the queues of overwhelmed specialist lists, improving service efficiency. The study also demonstrates capacity building of healthcare workers to perform eye screening and improved patient health awareness where the retinal cameras were used as an educational tool. Conclusions: A valuable screening service has been established in the target areas, where access to ophthalmic services has been improved for residents of the study screening locations. Routine eye examination (instead of opportunistic eye examination) is feasible for early detection of some eye diseases for remote and rural patients.