Induction of the antigen presentation machinery using novel small molecules
Bibliographic record
Abstract
The immune system is crucial in the prevention and eradication of cancer. However, cancer genomes mutate more frequently than healthy cells and a commonly acquired phenotype is reduced expression of the antigen presentation machinery (APM) that is required for immunosurveillance. This phenotype can allow cancer cells to become invisible to the immune system and metastasize with limited inhibition. Since this phenomenon is seen across a wide variety of cancers discovering methods to reverse this immune evasion could lead to the development of widely applicable therapeutics. A compound, S-(+)-curcuphenol was previously identified as a novel candidate for restoring expression of the APM, however, its synthesis is greatly hindered due to chirality. Therefore, I investigated the ability of curcuphenol analogues to induce expression of the major histocompatibility complex I (MHC-I) in a murine metastatic lung carcinoma cell line in vitro. Two derivatives of curcuphenol, P02-113 and P03-97-1, showed improved outcomes in vitro and I further evaluated them in vivo, as anti-cancer therapeutics. Both compounds reduced tumour burden and increased immune cell infiltration into tumours. To explore a potential mechanism of P02-113 and P03-97-1, I evaluated them for histone deacetylase (HDAC) inhibition based on structural similarity to established HDAC inhibitors. Upon examination I observed a completely novel effect of enhanced class I/II HDAC activity. Furthermore to identify if this effect was direct and to uncover which HDAC enzymes were being affected, I evaluated individual HDAC enzymes. I discovered that HDAC8 was inhibited by both P02-113 and P03-97-1, however, the activities of HDAC 5 and 10 were enhanced upon treatment. While the field of cancer immunotherapy has grown, few therapeutics have been identified to target loss of immunogenicity through the up-regulation of the APM. In this thesis two analogues of curcuphenol P02-113 and P03-97-1 have been identified that up- regulate the APM in vitro and reduce tumour burden in vivo. With these effects P02-113 and P03-97-1 hold great potential as future therapeutics for cancers exhibiting an immunodeficient phenotype through loss of the APM. As well these compounds present ii the first class II HDAC enhancers, as they increase the enzymatic activity of HDAC 5 and 10.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".