Universitätspublikationen
Refine
Document Type
- Article (1)
- Doctoral Thesis (1)
Language
- English (2) (remove)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- Cancer therapy (2) (remove)
Institute
- Medizin (2) (remove)
Cancer is one of the leading causes of death across all countries and its diagnosis still yields fear for the affected patient. Although treatment of cancer has made marvelous progress compared to the agents available thirty years ago, a cure for cancer, however, is still a distant prospect. Modern therapy still is a burden for many patients due to heavy side effects. With the development of agents targeting specific molecular targets on cancer cells, a new field of cancer therapy was opened and a small success story in the history of cancer began.
Aurora kinases represent a relatively new target in cancer therapy. The kinase is a essential part of mitosis and cell cycle progression and its overexpression has been shown to be related to many kinds of malignancies. Allosteric inhibition of a kinase is an increasing pre-clinical approach not yet established in the treatment of patients. In this thesis, we combine allostery with another innovative approach that is drug repurposing. If repurposed, a drug can be permitted to fast track drug admission to clinical trials.
I set up a screening of 1280 FDA approved drugs to identify small molecule compounds that affect the binding of Aurora kinase A and its main physiologic binding partner, TPX2. Further, I characterized the positive hits in vitro for their capabilities to displace TPX2 from Aurora A, to inhibit Aurora kinase activity, to thermally stabilize the protein and performed assays to determine their dissociation constant. Last but not least, I tested the compounds in cells for their effect on the cell viability and cell cycle via flow cytometry. Comparing the hit-compounds with controls I found that ATP-competitive AurA inhibitor MLN 8237 strongly displaces the interaction of Aurora A with TPX2.
Summarized, we identified eight hit compounds allosterically affecting Aurora A, but no compound proved to be active in all assays. Just one compound, PS 731, identified in another screening performed by our group and further characterized in this thesis remains interesting, especially when put in context with recent publications released in the time between the start of experiments for this thesis and its finalization.
Background: The most recent overall survival (OS) and adverse event (AE) data have not been compared for the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treatment alternatives.
Methods: We performed a systematic review and network meta-analysis focusing on OS and AE according to the most recent apalutamide, enzalutamide, and darolutamide reports. We systematically examined and compared apalutamide vs. enzalutamide vs. darolutamide efficacy and toxicity, relative to ADT according to PRISMA. We relied on PubMed search for most recent reports addressing prospective randomized trials with proven predefined OS benefit, relative to ADT: SPARTAN, PROSPER, and ARAMIS. OS represented the primary outcome and AEs represented secondary outcomes.
Results: Overall, data originated from 4117 observations made within the three trials that were analyzed. Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order. In the subgroup of PSA-doubling time (PSA-DT) ≤ 6 months patients, enzalutamide ranked first, followed by darolutamide and apalutamide in that order. Conversely, in the subgroup of PSA-DT 6–10 months patients, darolutamide ranked first, followed by apalutamide and enzalutamide, in that order. Regarding grade 3+ AEs, darolutamide was most favorable, followed by enzalutamide and apalutamide, in that order.
Conclusion: The current network meta-analysis suggests the highest OS efficacy and lowest grade 3+ toxicity for darolutamide. However, in the PSA-DT ≤ 6 months subgroup, the highest efficacy was recorded for enzalutamide. It is noteworthy that study design, study population, and follow-up duration represent some of the potentially critical differences that distinguish between the three studies and remained statistically unaccounted for using the network meta-analysis methodology. Those differences should be strongly considered in the interpretation of the current and any network meta-analyses.