Science brief
Structural Biology and Cellular Switches Upend Cancer Frontiers
Israeli research teams redesign T-cell spines, expose tumor self-destruct pathways, and uncover the metabolic impact of human company.
Science
Israeli biophysicists rebuilt the structural spine of T-cell receptors — turning fragile cellular therapies into durable treatments that stay active long enough to clear solid tumors.
BackgroundT-cell receptors are cell-surface proteins that direct white blood cells to hunt down abnormal cells carrying viral or cancerous markers. Synthetic receptors often degrade rapidly or fail to express stably in living tissue, which routinely undermines adoptive cell transfer treatments.
- Prof. Cyrille Cohen and Prof. Sarel Fleishman computationally redesigned structural regions of T-cell receptors, generating Structurally Enhanced TCRs that resist cellular degradation.
- In preclinical mouse trials with human tumors, SET-engineered T cells cut tumor volume by 35% and achieved 100% survival past day 120, versus under 50% in controls.
- The engineering platform demonstrated high receptor stability across diverse disease targets, including melanoma, Epstein-Barr virus, and common respiratory pathogens.
Science
Ben-Gurion researchers exposed the chemical escape hatch tumors use to endure cellular stress — giving drug developers a clear target to force resistant cancers to self-destruct.
BackgroundMalignant cells often survive cytotoxic chemotherapy by mobilizing internal stress-response proteins that buffer against severe intracellular damage. When these protective systems collapse, cells initiate apoptosis — programmed death — but mutated tumors frequently bypass ordinary genetic triggers like p53.
- Dr. Aeid Igbaria's laboratory discovered that endoplasmic reticulum cochaperones DNAJB12 and DNAJB14 act as an essential molecular shield that keeps stressed tumors alive.
- Under sustained oxidative pressure, rising glutathione levels break internal disulfide bonds, dismantling those protective chaperones and unleashing lethal pro-apoptotic enzyme cascades.
- Developing small molecules that artificially trigger this degradation pathway could force drug-resistant tumors into suicide during conventional chemotherapy regimens without damaging healthy tissue.
Science
Science
A 70-year-old cancer chemotherapy failed because medicine mistook a structural scaffold for an enzymatic catalyst — charting a clear path toward targeted protein degraders for resistant leukemia.
BackgroundSynthesized in the 1950s, 6-thioguanine remains an indispensable chemotherapy agent across pediatric and adult leukemia treatments globally. For seven decades, clinicians could not explain why patients with identical drug-metabolizing enzymes often showed wildly disparate clinical outcomes.
- Genetic knockout of NUDT5 completely shielded leukemia cells from 6-thioguanine toxicity, whereas chemical inhibitors targeting its enzymatic active site failed to change response rates.
- The protein drives drug toxicity exclusively by anchoring multi-protein metabolic complexes in place, behaving as an organizational scaffold rather than a chemical catalyst.
- The finding redirects pharmaceutical pipelines away from traditional catalytic inhibitors and toward targeted protein degraders capable of destroying the scaffold to overcome drug resistance.
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