55 Quick summary: Researchers in Israel have discovered that an experimental compound can reverse chemotherapy resistance in glioblastoma, which is the most aggressive and deadly form of brain cancer. By targeting nitrosative stress and blocking the molecular pathways that protect cancer cells, this treatment restores tumour sensitivity to standard drugs and significantly slows disease progression in preclinical models. For healthcare practice and patient well-being, these findings open up a vital new path towards developing effective combination therapies that could overcome treatment resistance and offer profound hope to individuals facing a devastating diagnosis. Researchers in Israel have identified a potential breakthrough in treating glioblastoma, the most aggressive form of brain cancer, by targeting the biological mechanisms behind chemotherapy resistance. The study, led by postdoctoral fellow Dr Mallikarjuna Nimgampalle and Professor Haitham Amal of the Hebrew University of Jerusalem (HUJI) and Harvard Medical School, was published in Cancer Medicine. It shows that an experimental compound, BA-101, can make drug-resistant glioblastoma cells vulnerable again to the standard chemotherapy drug temozolomide (TMZ), significantly slowing tumour growth in preclinical models. First author Dr Nimgampalle worked alongside co-authors Shashank Kumar Ojha, Maryam Kartawy, and Michelle Feivelson, all from the Institute for Drug Research at the HUJI. Glioblastoma is notoriously difficult to treat. Although surgery, radiation, and temozolomide are the current standard of care, many tumours either fail to respond or quickly develop resistance, leaving patients with few effective options. Median survival remains around 12–15 months for most patients despite aggressive therapy, according to established medical understanding of the disease. The cancer accounts for a significant proportion of malignant brain tumours in adults and is known for its rapid growth and infiltration into healthy brain tissue, which makes complete surgical removal challenging. Standard protocols typically involve maximal safe resection followed by radiotherapy and concurrent temozolomide chemotherapy, but resistance that develops through various molecular pathways, including DNA repair mechanisms, remains a critical barrier. Targeting nitrosative stress The researchers focused on a process called nitrosative stress, an imbalance caused by excessive production of nitric oxide molecules that helps tumours survive, spread, and evade treatment. They found that blocking this pathway with BA-101, a selective inhibitor of neuronal nitric oxide synthase (nNOS), substantially reduced the aggressive behaviour of drug-resistant glioblastoma cells. The treatment was found to slow cancer cell growth, reduce the cells’ ability to invade surrounding tissue and migrate, lower markers of nitrosative stress, and trigger cancer cell death. Combining BA-101 with temozolomide produced a stronger anti-cancer effect than either treatment alone, including a significant reduction in tumour growth in mice. “Temozolomide resistance remains one of the biggest obstacles in treating glioblastoma,” said Professor Amal, who led the study. “Our findings suggest that targeting nitrosative stress can restore the tumour’s sensitivity to treatment. While additional studies are needed before this approach can reach patients, these results open an exciting new direction for developing more effective therapies against one of the deadliest cancers.” The team believes the findings could pave the way for a new class of combination therapies aimed at overcoming treatment resistance rather than simply replacing existing drugs. Because BA-101 targets a mechanism that helps cancer cells survive chemotherapy, it may enhance the effectiveness of current treatments while potentially delaying the development of resistance. BA-101 has been exclusively licensed from Yissum, the Technology Transfer Company of the HUJI, by NeuroNOS, a biotechnology company co-founded by Professor Amal. NeuroNOS is advancing BA-101 as a potential first-in-class therapy for glioblastoma, aiming to translate these preclinical findings into future clinical development. The researchers stress that BA-101 remains experimental and that further preclinical studies and clinical trials will be needed before it can be evaluated as a treatment for patients. Experts not involved in the study have noted that while the early results are encouraging, the path from preclinical success to patient benefit in glioblastoma is often long and complex, given challenges such as the blood-brain barrier and tumour heterogeneity. Even so, approaches that address resistance mechanisms are considered particularly valuable in this field. The development comes amid continued global efforts to improve outcomes for brain cancer patients, where progress has historically been incremental. If successfully translated, combination strategies like this one could offer renewed hope for those facing this devastating diagnosis.