This is an interesting new paper from researchers at Yale, Massachusetts General Hospital, the Weizmann Institute of Science, and the University of Miami.

Using one of the largest longitudinal single-cell datasets in IDH-mutant glioma, the researchers showed that progression can occur through both genetic evolution and cell-state changes. In some tumors, acquired genetic alterations expand proliferative, stem-like cell populations. In others, tumors adopt a mesenchymal-like state associated with immune suppression and poorer outcomes, even without major new genetic changes.

Thus, treatment resistance is not necessarily driven solely by accumulating mutations. Instead, tumors under treatment pressure can evolve toward distinct biological trajectories, including stem-like or more glioblastoma-like programs. Two IDH-mutant gliomas could have similar DNA yet behave very differently because of the cell types and cellular programs active within the tumor. Single-cell sequencing is a powerful tool for capturing these differences, and as our understanding of these evolutionary trajectories improves, it may help identify early warning signs of resistance, predict treatment response, and potentially guide strategies to keep tumors on more treatment-sensitive paths.

In this study, another group of researchers reports a similar idea - that response to therapy in glioblastoma (GBM) may depend just as much on tumor cell state and the surrounding immune environment as on genetic mutations. The study analyzed 181 immune checkpoint inhibitor (ICI)-treated glioblastoma (GBM) samples using bulk DNA and RNA sequencing along with single-nucleus RNA sequencing to understand what predicts response in IDH-wildtype GBM.

The main finding was that the tumor’s baseline cell state, rather than its mutational burden, best predicted outcomes. Tumors with a mesenchymal (MES) subtype had better survival with ICIs compared to non-MES tumors, even though this same subtype did not benefit as much from standard chemoradiation. This MES state was linked to higher immune signaling (HLA class I expression) and more T cell infiltration, consistent with a more inflamed tumor environment. In contrast, overall mutation burden was not predictive, while specific genetic changes such as PDGFRA and CDKN2A were associated with worse outcomes after ICI but not standard therapy.

Long-term analyses suggested that ICI treatment may shift how tumors evolve over time, with selection of resistant subclones and changes away from MES-like states, suggesting that immunotherapy and chemoradiation may push tumors along different evolutionary paths.

The UNITED trial was a single-center phase 2 study testing MRI-guided adaptive radiotherapy for high-grade glioma using a 1.5T MR-Linac. Ninety-eight patients received standard chemoradiation, but with weekly MRI scans used to adjust radiation plans in real time. This allowed doctors to tighten treatment margins around the tumor while still accounting for microscopic spread.

The key concern with this approach had always been whether smaller margins would lead to more “missed” tumor at the edges. In this study, that did not happen. The rate of marginal failure was low (4%), meeting the study’s non-inferiority goal compared with historical outcomes. Treatment was generally well tolerated, with lymphopenia as the most common significant side effect. Overall, these results provide reassuring evidence that MRI-guided adaptive radiotherapy can safely reduce radiation margins in glioma, and support further testing in randomized trials.

A small, prospective pilot study from researchers at the University of Pennsylvania, including the Musella Foundation's Chief Scientific Advisor Dr. Steven Brem, evaluated machine learning-guided personalized precision radiation therapy (PPRT) in newly diagnosed IDH-wildtype glioblastoma (GBM). Twenty patients were enrolled after gross total resection, with efficacy analyses reported for 17 patients. The PPRT used an AI-based model to estimate patterns of microscopic tumor infiltration beyond what was visible on MRI to personalize radiation targeting, followed by standard temozolomide.

Compared with a matched historical control group, PPRT was associated with improved median progression-free survival (24.4 vs 11.6 months) and overall survival (35.4 vs 17.7 months). Treatment was generally well tolerated, with no grade ≥3 acute toxicities, but radiation necrosis was more frequent in the PPRT group. These findings will need further validation in larger studies, but we hope to see the survival gains replicated.

We are happy to share our brain tumor copayment assistance program is now open to new (and renewal) patients! This program can help cover the copay costs for: Optune Gio, Avastin, Temodar, Lomustine, and Modeyso, as well as their generics. If you think you may need help, apply ASAP as the program often closes quickly. Go to braintumorcopays.org for details and to apply.  

Researchers at the American Society for Clinical Oncology (ASCO) 2026 meeting reported results from the Phase 3 ROADS trial, which enrolled 230 patients with newly diagnosed brain metastases requiring surgery and randomized them to receive either GammaTile (115 patients) or standard postoperative stereotactic radiotherapy (115 patients).

GammaTile is a collagen implant containing radioactive cesium-131 seeds that is placed directly into the surgical cavity during tumor removal. Investigators reported that local recurrence occurred in just 1% of GammaTile patients, compared with 12% of patients receiving standard postoperative radiation.

The study also reported improvements in recurrence-free survival and overall survival, with an estimated 61.7% of GammaTile patients alive two years after diagnosis, compared with 35.7% in the control group. Importantly, these benefits were achieved without an increase in serious treatment-related side effects.

 For more neuro-oncology updates from the 2026 ASCO conference (e.g., DOC1021, NeoVax, Nan02, liposomal curcumin, CAR T trials), click HERE. 

Fantastic work from Dr. Rifaquat and colleagues, who showed that carefully matched external control data produced treatment effect estimates nearly identical to those obtained using the randomized control arm of the INSIGhT glioblastoma (GBM) trial. Their findings add to the growing evidence that external controls can, in appropriate scenarios, help reduce the number of patients who must be assigned to traditional control groups while still generating reliable results.

We have long advocated for this approach. Years ago, the Musella Foundation used its brain tumor registry to show that carefully curated and well-matched real-world GBM patient cohorts could approximate outcomes seen in traditional clinical trial control arms. (See HERE) We are very happy to see the neuro-oncology field advancing this concept, as it has great potential to improve the efficiency of clinical trials, increase trial enrollment, and meaningfully benefit patients.

Researchers at the University of Cincinnati and Johns Hopkins reported promising preclinical results for a novel 'NanoMesh' implant designed to deliver multiple anti-cancer drugs directly into the surgical cavity after glioblastoma (GBM) resection. In mouse models, the multi-layered nanofiber device released temozolomide, acriflavine, and PT2385 in a controlled fashion, significantly extending survival. While this technology is still in the preclinical stage, it's an interesting new approach to local drug delivery for GBM. 

This is a great blog post from long-term brain cancer survivor and practicing physician Courtney Burnett, explaining why many survivors continue to talk about and advocate for brain cancer even years after treatment. Her perspective will likely resonate with many survivors and patient families who live daily with the lasting impacts of a brain tumor diagnosis. 

The REGAIN study is a small feasibility/safety trial expected to enroll up to 10 patients with recurrent GBM. The trial is using Alpha DaRT, an investigational alpha-radiation therapy placed directly into the tumor tissue via a minimally invasive stereotactic procedure. Early interim results from the first 3 patients treated in the trial showed two complete MRI responses (using RANO criteria), and the third patient had stable disease with 30% tumor reduction. So far, there has only been one grade 3 adverse event in the trial: a treatment-related seizure with temporary paralysis that resolved with steroids.

While these initial objective imaging responses are exciting, the data should be interpreted cautiously. Longer follow-up will be needed to determine durability of response, survival impact, risks such as radiation necrosis, and whether results can be reproduced in a larger population. More information on the trial can be found HERE. 

This phase 1 trial investigated a personalized neoantigen DNA vaccine (GNOS-PV01) in 9 newly diagnosed MGMT-unmethylated glioblastoma patients. The vaccine was individually designed for each patient using up to 40 tumor-specific neoantigen targets (more than most prior GBM vaccine approaches). No serious treatment-related adverse events were reported. Vaccine-induced immune responses were seen in 8 of 9 patients, and the only non-responder was on steroids. Three of the 9 patients survived beyond 2 years, and 1 patient remains recurrence-free nearly 5 years after diagnosis. The study adds to growing evidence supporting vaccine strategies for GBM and especially supporting multi-target neoantigen vaccines. The Musella Foundation continues working to support the advancement of promising investigational vaccine approaches for brain tumors, with the strong hope that more patients will gain access to these therapies in the near future.

A new study is challenging assumptions about testosterone and glioblastoma (GBM). Some previous preclinical studies suggested testosterone or androgen receptor signaling might promote GBM growth, but many of those studies focused mainly on direct effects of testosterone on tumor cells themselves, often in cell cultures (“cells in a dish”) or simplified tumor models.

Our next educational webinar is tomorrow, Tuesday, May 12, at 7pm ET with Dr. Nicholas Blondin on "Harnessing Oxygen to Fight Brain Tumors." To join, visit virtualtrials.org/webinar. 

Dr. David Nathanson and his team at UCLA are developing an EGFR-targeted drug for glioblastoma (GBM) called KTM-101. About half of GBMs have EGFR alterations, so there have been many attempts to target EGFR, but EGFR-targeted monotherapies have repeatedly disappointed in GBM. Several likely reasons for these failures include poor blood-brain barrier penetration, the heterogeneity and adaptability of GBM tumors, and the ability of tumors to bypass a single blocked pathway or even lose the targeted EGFR alteration over time. We will be watching KTM-101 for further validation in larger studies, and we hope to see EGFR-targeted therapy increasingly explored as one component of rational combination approaches rather than as a stand-alone strategy.

Our next webinar will take place on Tuesday, May 12 at 7pm ET. The topic is "Harnessing Oxygen to Fight Brain Tumors" with Dr. Nicholas Blondin. To join, visit virtualtrials.org/webinar.

The annual Tumor Takedown fundraiser is coming up this Saturday, May 2nd from 4-7pm at Millennial Brewing Company in Fort Myers, Florida. This event is put on by Zachary, brain tumor survivor and thriver, to raise local awareness of brain cancer. 100% of the donations go to the Musella Foundation to help brain tumor patients through emotional and financial support, education, advocacy and raising money for brain tumor research. For more info, click here! 

The phase 2/3 GBM AGILE platform trial has now reported final results for the regorafenib (Stivarga) arm. In the study, regorafenib was tested in both recurrent glioblastoma (against lomustine) and newly diagnosed unmethylated glioblastoma (against standard chemoradiation). The trial did not find an overall survival benefit in either group, and regorafenib was associated with more toxicity compared to control. These findings are not entirely surprising given the modest survival signal seen in the earlier phase 2 REGOMA trial for recurrent GBM.

While disappointing, the GBM AGILE platform continues to represent an important advance in GBM drug development by enabling rapid, randomized testing of drug candidates within an adaptive framework, allowing ineffective agents to be deprioritized more efficiently.

From a broader perspective, these results also reinforce a recurring theme in GBM: monotherapy approaches, particularly with targeted kinase inhibitors, have repeatedly failed to translate early-phase signals into durable clinical benefit. This underscores the need for rational combination strategies that address the multiple redundant resistance pathways that drive GBM progression.

A new study has identified miR-181d, a naturally occurring microRNA that regulates gene expression, as a potential mediator of glioblastoma (GBM) treatment sensitivity. The study team found that higher miR-181d levels were associated with GBM “exceptional responders,” the rare patients who experience unusually durable responses to therapy.

The data suggest miR-181d improves treatment response by suppressing multiple resistance pathways. Prior work showed miR-181d suppresses MGMT, a key mediator of temozolomide resistance. In this study, the authors show that miR-181d also suppresses RAD51, a critical DNA repair protein, thereby increasing tumor sensitivity to radiation and other DNA-damage therapy. Lower RAD51 expression in patient tumors was associated with longer survival, consistent with prior reports.

In preclinical models, intracranial delivery of miR-181d prior to radiation improved tumor control and survival. In an immunocompetent recurrent GBM mouse model, median survival increased from 41 days with radiation alone to 58 days with the addition of miR-181d, with roughly half of treated animals surviving beyond three months. Re-implantation of GBM cells into long-term survivors resulted in lower tumor burden by bioluminescence imaging, consistent with durable anti-tumor immune recognition.

These findings support the concept that miR-181d may both enhance tumor sensitivity to standard therapy and help sustain anti-tumor immunity. The authors are now working toward a clinical trial evaluating local delivery of miR-181d during surgery.

This UCSF preclinical study reaffirms IL-6 as an important regulator of the glioblastoma (GBM) immune tumor microenvironment (TME) and a potential target for combination therapy. Using integrated spatial and single-cell analyses of patient-matched human GBM samples, the authors show that lower baseline IL-6 is associated with the rare clinical responses seen with immune checkpoint inhibitors (ICIs), while higher IL-6 correlates with poorer outcomes. These findings are consistent with prior observations by Dr. Steven Brem and others linking IL-6 to glioma progression, senescence-associated genes, immune suppression and prognosis in GBM.

In the current study by Jacob Young, et al., using preclinical models, IL-6 blockade alone was not sufficient for durable tumor control, but it shifted the tumor immune microenvironment to a more immunoresponsive TME by reducing regulatory T cells, activating dendritic cells, and increasing antigen presentation and effector CD8+ T-cell activity. When combined with immune checkpoint inhibition and radiotherapy, IL-6 blockade translated into more durable anti-tumor responses. This work further supports a combination strategy of targeting cytokine-driven resistance pathways by blocking IL-6, and potentially other immunosuppressive cytokines, to overcome immunotherapy resistance in GBM. Currently, an NRG multicenter trial (NCT04729959), combining anti-IL6R antibody (tocilizumab) with an ICI (atezolizumab) and fractionated radiotherapy has completed accrual and the data is being analyzed. We will share those results when they become available!