arXiv subjects

Abbi Abdel-Rehim

Publications and source records attributed to Abbi Abdel-Rehim.

5 recordsLinked to original sources

arXiv2026

Iterative AI-guided optimisation of selective triple-drug combinations for breast cancer

Personalised cancer therapy aims to tailor treatment to individual tumour profiles, yet tumour heterogeneity and adaptive resistance continue to limit clinical efficacy. Drug combinations offer a strategy to overcome resistance by simultaneously targeting multiple pathways, but their rational design is constrained by the vast combinatorial search space and experimental cost. Here, we present an AI-guided, QSAR-driven iterative optimisation framework that integrates machine learning with automated experimental screening to enable closed-loop discovery of selective multi-drug therapies. Starting from an initial random screen, the system iteratively predicts, tests, and refines three-drug combinations targeting MCF7 breast cancer cells. Incorporation of non-tumorigenic MCF10A cells enables explicit optimisation of tumour-selective efficacy, prioritising regimens that maximise cancer cell killing while sparing healthy cells. Across successive iterations, the framework rapidly enriched for highly selective, high-efficacy combinations, while maintaining chemical and mechanistic diversity and avoiding convergence on a narrow solution space. By continuously learning from experimental feedback, the approach efficiently navigates millions of combinations to identify a small set of validated, tumour-selective regimens. These results establish a scalable proof-of-concept for AI-driven, closed-loop optimisation of higher-order drug combinations, demonstrating how iterative integration of computation and experimentation can enable adaptive and potentially personalised therapeutic design in precision oncology.

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arXiv2025

Advancing Drug Development Through Strategic Cell Line and Compound Selection Using Drug Response Profiles

Early identification of sensitive cancer cell lines is essential for accelerating biomarker discovery and elucidating drug mechanism of action. Given the efficiency and low cost of small-scale drug screens relative to extensive omics profiling, we compared drug-response panel (DRP) descriptors against omics features for predictive capacity using gradient boosting tree models across the GDSC and CCLE drug response datasets. DRP descriptors consistently outperformed omics data across key performance metrics, with variable performance across different drugs. Using complementary explainability approaches, we confirmed known MAPK-inhibitor sensitivity signatures, and identified novel potential biomarker candidates for MEK1/2 and BTK/MNK inhibitors. Lastly, to demonstrate the utility of this approach in distinguishing phenotypes, we applied our models to the breast cancer line MCF7 versus the non-tumorigenic MCF10A, and successfully identified compounds that selectively inhibit MCF7 while sparing the non-tumorigenic MCF10A. This methodology, developed using focused drug and cell line panels, supports early-stage drug development by facilitating rational cell line selection and compound prioritisation, enabling more efficient biomarker identification and candidate assessment.

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arXiv2025

Scientific Hypothesis Generation by a Large Language Model: Laboratory Validation in Breast Cancer Treatment

Large language models LLMs have transformed AI and achieved breakthrough performance on a wide range of tasks In science the most interesting application of LLMs is for hypothesis formation A feature of LLMs which results from their probabilistic structure is that the output text is not necessarily a valid inference from the training text These are termed hallucinations and are harmful in many applications In science some hallucinations may be useful novel hypotheses whose validity may be tested by laboratory experiments Here we experimentally test the application of LLMs as a source of scientific hypotheses using the domain of breast cancer treatment We applied the LLM GPT4 to hypothesize novel synergistic pairs of FDA-approved noncancer drugs that target the MCF7 breast cancer cell line relative to the nontumorigenic breast cell line MCF10A In the first round of laboratory experiments GPT4 succeeded in discovering three drug combinations out of twelve tested with synergy scores above the positive controls GPT4 then generated new combinations based on its initial results this generated three more combinations with positive synergy scores out of four tested We conclude that LLMs are a valuable source of scientific hypotheses.

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arXiv2024

Personalised Medicine: Establishing predictive machine learning models for drug responses in patient derived cell culture

The concept of personalised medicine in cancer therapy is becoming increasingly important. There already exist drugs administered specifically for patients with tumours presenting well-defined mutations. However, the field is still in its infancy, and personalised treatments are far from being standard of care. Personalised medicine is often associated with the utilisation of omics data. Yet, implementation of multi-omics data has proven difficult, due to the variety and scale of the information within the data, as well as the complexity behind the myriad of interactions taking place within the cell. An alternative approach to precision medicine is to employ a function-based profile of the cell. This involves screening a range of drugs against patient derived cells. Here we demonstrate a proof-of-concept, where a collection of drug screens against a highly diverse set of patient-derived cell lines, are leveraged to identify putative treatment options for a 'new patient'. We show that this methodology is highly efficient in ranking the drugs according to their activity towards the target cells. We argue that this approach offers great potential, as activities can be efficiently imputed from various subsets of the drug treated cell lines that do not necessarily originate from the same tissue type.

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arXiv2023

Beating the Best: Improving on AlphaFold2 at Protein Structure Prediction

The goal of Protein Structure Prediction (PSP) problem is to predict a protein's 3D structure (confirmation) from its amino acid sequence. The problem has been a 'holy grail' of science since the Noble prize-winning work of Anfinsen demonstrated that protein conformation was determined by sequence. A recent and important step towards this goal was the development of AlphaFold2, currently the best PSP method. AlphaFold2 is probably the highest profile application of AI to science. Both AlphaFold2 and RoseTTAFold (another impressive PSP method) have been published and placed in the public domain (code & models). Stacking is a form of ensemble machine learning ML in which multiple baseline models are first learnt, then a meta-model is learnt using the outputs of the baseline level model to form a model that outperforms the base models. Stacking has been successful in many applications. We developed the ARStack PSP method by stacking AlphaFold2 and RoseTTAFold. ARStack significantly outperforms AlphaFold2. We rigorously demonstrate this using two sets of non-homologous proteins, and a test set of protein structures published after that of AlphaFold2 and RoseTTAFold. As more high quality prediction methods are published it is likely that ensemble methods will increasingly outperform any single method.

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