Interaction of combined administration of multi-targeted kinase inhibitors with ionizing radiation
Bibliographic record
Abstract
Along with surgery and chemotherapy, radiation therapy is one of the three cancer treatment modalities to treat patients. Over the recent decades, thanks to technological progress, radiation techniques have been improved drastically. However, the same effort has not been put into the biology of the tumours and how different tumours interact with radiation beams. Moreover, it has been only recently that attention has been drawn towards the chemo-radiation or combination of radiation with molecular targeting agents. In this thesis we have studied the combination of ionizing radiation with a class of small molecule inhibitors that target defects in the MAPK/PI3K pathway in breast cancer cells. These pathways are often over-activated in human malignancies including breast cancer. Two of the multiple receptors involved in these pathways are EGFR and VEGFR, which have been shown to be over-expressed in cancerous tumours and have been associated with poor prognosis as well as drug and radiation resistance. The two inhibitors we have used in this study are ZRBA1, a combi-molecule that targets EGFR and also induces DNA lesions, and Sorafenib (Nexavar), which is an inhibitor of several RTKs including VEGFR and also Raf kinase. Using breast cancer cells, we have shown that these multi-functional inhibitors increased the sensitivity of cancer cells towards radiation as they induced a strong G2/M cell cycle arrest and apoptosis. Our in vivo results show that ZRBA1 and Sorafenib, if combined with radiation, can significantly increase tumour growth delay. When radiation is administered concurrently with ZRBA1, a significant tumour growth delay of 47 days is observed. Moreover, ZRBA1 in combination with radiation not only induced the DNA single and double strand breaks, but also delayed DNA repair process contributing to its higher potency against breast cancer cells. Interestingly, Sorafenib when it is combined with radiation has more persistent anti-tumour effect in our in vivo model.Overall, our results suggest that the combined administration of multi-targeting molecular inhibitors, a systemic targeted therapy, with radiation, a local and regional therapy, could be beneficial for patients as they potentiate the radiation response while not increasing adverse side effects.The results of these preclinical studies contribute to a better understanding of how radiation interacts with small molecule inhibitors such as ZRBA1 and Sorafenib and provide the rational basis for further preclinical and clinical studies.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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) | 0.002 | 0.000 |
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".