Roots of Resistance

Overview
Cancer cells survive treatment through fundamental biological barriers—genetic mutations, altered cell kinetics, adaptive signaling, and microenvironmental stresses such as hypoxia. In this branch, we convert these invisible resistance drivers into measurable, mechanistic variables that can be targeted and translated into practice. From hypoxia‑responsive gene systems to resistance signaling maps, our work dismantles resistance at its roots to improve radiotherapy precision.

Focus Areas

• Hypoxia biology & therapy: Mechanisms, biomarkers, and gene‑directed strategies targeting hypoxic compartments.

• Resistance signaling: Notch, STAT5A, YB‑1 and other pathways that modulate radioresponse.

• DNA repair & dose‑response: Mismatch repair, MGMT/O6MeG, low‑dose hypersensitivity.

• Microenvironment & vesicles: Vascular and extracellular vesicle (EV) responses to RT.

• Radiosensitizers & modulators: Small molecules (e.g., metformin, statins, melatonin) to enhance RT response.

Flagship Publications (Selected)

• Concept & Mechanism

  • Hypoxia in prostate cancer: a powerful shield against tumour destruction? (Cancer Treat Rev, 2008) — Framing of hypoxia as a clinical resistance driver.

  • Time, location and function of hypoxia‑inducible factors are critical to therapeutic tumour response (BMJ Oncol, 2024) — Explores how HIF dynamics shape treatment sensitivity.

• Gene‑Directed Strategies

  • Hypoxia response element‑driven CD/5‑FC gene therapy enhances radiosensitivity in vitro (J Gene Med, 2009).

  • Tissue plasminogen activator promoter: a novel tool for radiogenic gene therapy (J Gene Med, 2008).

  • Radiation to control gene expression in tumors (Cancer Biol Ther, 2007).

• Resistance Signaling & miRNA

  • Notch, hypoxia signaling and prostate cancer (Nat Rev Urol, 2013) & Notch‑3 receptor: a molecular switch to tumorigenesis? (Cancer Treat Rev, 2017).

  • Multiplex profiling identifies clinically relevant signalling proteins in an isogenic prostate cancer model of radioresistance (Sci Rep, 2019).

  • miR‑31 modulates tumor sensitivity to radiation in esophageal cancer (J Mol Med, 2012); Low miR‑187 promotes resistance and correlates with failure (Mol Med, 2016).

• DNA Repair & Dose Response

  • MSH2 dictates survival after low‑dose radiation in endometrial carcinoma (Cancer Lett, 2013).

  • Recognition of O6MeG lesions… prerequisite for low‑dose radiation hypersensitivity (Radiat Res, 2009).

  • DNA mismatch repair and DDR to ionising radiation (Cancer Treat Rev, 2010).

• Microenvironment, EVs & Vascular

  • Vascular responses to RT and ADT in experimental prostate cancer (Radiat Oncol, 2012).

  • Extracellular vesicles and the “six Rs” in radiotherapy (Cancer Treat Rev, 2024).

• Theranostics & Radiomics

  • [64Cu][Cu(elesclomol)] as a theranostic for hypoxic solid tumours (EJNMMI, 2023).

  • Exploring hypoxia in prostate cancer with MRI radiomics & pimonidazole (Anticancer Res, 2023).

• Radiosensitizers & Modulators

  • Metformin and improved RT outcomes: review (Cancer Treat Rev, 2017).

  • Clinical potential of statins in prostate cancer RT (Anticancer Res, 2017).

  • Melatonin for breast cancer RT patients (Int J Radiat Biol, 2018).

Methods & Tooling

• Hypoxia‑responsive gene constructs (HRE‑driven systems) and promoter engineering.

• Multiplex signalling/omics profiling in isogenic resistance models.

• Radiomics and theranostic tracers to localize functional resistance.

• Preclinical and translational assays linking mechanism to measurable biomarkers.

Impact

• Made hypoxia actionable: From concept to gene‑based intervention and biomarker‑guided strategies.

• Mapped resistance circuitry: Identified practical targets (Notch, STAT5A, YB‑1; miRNA axes) and dose‑response rules.

• Laid translational groundwork: Brought microenvironmental and EV insights into the “six Rs” framework.

Get Involved

• We welcome collaborations in hypoxia imaging, theranostic development, and mechanistic radiosensitization. Contact us to co‑develop assays, trials, and translational pipelines.