Solid tumors: latest on treaments and research pathways

A UCL-sponsored clinical trial for patients newly diagnosed with glioblastoma, an aggressive form of brain cancer, has opened at UCLH's National Hospital for Neurology and Neurosurgery and Clinical Research Facility, in memory of Baroness Margaret McDonagh. Led by Dr. Paul Mulholland from UCL Cancer Institute and consultant medical oncologist at UCLH, the Win-Glio trial will recruit 16 patients over an 18-month period.

The blood-brain barrier-a feature of blood vessels that protects the brain from harmful substances-is so good at its job that it poses a serious obstacle to treating brain cancer. To deliver therapeutic treatments across the blood-brain barrier (BBB), researchers at Mass General Brigham have been working for decades on a technique known as focused ultrasound, which uses low-power ultrasound technology combined with microbubbles. In a new study, researchers at Mass General Brigham collaborated with colleagues at University of Maryland School of Medicine (UMSOM) to analyze results from ultrasound treatments delivered to 23 patients. Results published in Device identify a key metric-known as acoustic emission dose-which can predict how well the BBB opened, identifying a sweet spot that the team used for treating patients.

La inclusión de los TTFields en la cartera común abre la puerta a que nuestros pacientes tengan acceso a una terapia innovadora que ya forma parte del estándar en muchos países de referencia. El reto ahora está en que el estudio de monitorización se ponga en marcha de manera ágil y con la participación de centros de todo el país, para garantizar que el beneficio llegue a todos los pacientes que lo necesiten. Además, debemos aprovechar esta oportunidad para seguir impulsando la investigación clínica y traslacional en tumores cerebrales porque solo a través de la ciencia podremos seguir mejorando el pronóstico de estas personas.

In a groundbreaking study poised to redefine therapeutic strategies for one of the most aggressive brain tumors, researchers have uncovered a pivotal molecular mechanism by which ROCK inhibition suppresses glioblastoma progression. This research highlights the intricate relationship between ROCK signaling and the tumor suppressor PTEN, shedding light on a cascade that ultimately downregulates the notorious PI3K/AKT pathway, a critical driver of glioblastoma malignancy. The findings not only offer promising therapeutic avenues but also deepen our molecular understanding of glioblastoma’s resilience and invasiveness.

Despite triumphs in blood cancers, the application of CAR T therapy in solid malignancies remains fraught with barriers. Solid tumors pose a complex immunosuppressive microenvironment that hinders T-cell infiltration and persistence. Moreover, the antigenic heterogeneity and physical stromal barriers limit effective targeting by CAR T-cells. Unlike hematologic tumors, the lack of a universally expressed tumor-specific antigen presents a challenge in avoiding on-target off-tumor toxicity, where normal tissues expressing low levels of the target antigen could be damaged. Sophisticated CAR designs targeting multiple antigens or employing logic-gating methods are under investigation to improve specificity and reduce adverse effects.

In recent years, the revolutionary field of immunotherapy has drastically reshaped the landscape of cancer treatment, pushing the boundaries of what modern medicine can achieve. Among these advancements, Chimeric Antigen Receptor (CAR) T-cell therapy stands out as one of the most promising strategies that could redefine the future of cancer eradication. Building upon decades of immunological research, this innovative therapy harnesses the very cells of the immune system to specifically target and eliminate malignant cells, offering new hope to patients with otherwise refractory cancers.

The meta-analysis evaluates the impact of pituitary stalk preservation during craniopharyngioma surgery on pituitary function, resection extent, and recurrence. Preservation reduces diabetes insipidus risk but may increase incomplete resection risk in pediatric patients. Results are cautious due to small study sizes and reporting biases.

The team used techniques called single-cell sequencing and spatial transcriptomics to study the regulation of infiltrating glioblastoma cells. By analyzing which genes were active, chemical modifications to the DNA, how open or closed different regions of DNA were, and how tumour cells physically and molecularly interacted with nearby neurons, they identified key developmental pathways that invasive glioblastoma cells hijack to spread through the brain.
One such pathway is called NOTCH signaling – a cell communication system used by multicellular organisms to control cell fate decisions, such as differentiation, proliferation and apoptosis. The tumour cells hijack this pathway to activate oligodendrocyte lineage programs, effectively masquerading as normal OPCs.
The findings suggest that targeting this pathway and the regulatory programs involved may help limit tumour spread.

Despite no visible tumor growth, new research finds that the artificial sweetener aspartame reshapes gut bacteria and upregulates cancer-linked genes in glioblastoma.

Results indicated a statistically significant prolongation of progression-free survival among vaccinated patients, with a hazard ratio of 0.64 (p < 0.001). This suggests that vaccination therapies can reduce the risk of tumor progression by approximately 36% compared to controls. More intriguingly, a modest but highly significant improvement in overall survival was noted, with an HR of 1.09 (p < 0.00001). While the absolute survival benefit observed might appear modest, even incremental gains in glioblastoma are clinically meaningful, given the disease’s aggressive course and grim median survival times.

In a groundbreaking study poised to redefine our understanding of glioblastoma biology, researchers have uncovered a paradoxical role of Gasdermin E (GSDME) in this aggressive brain cancer. Traditionally recognized as a crucial mediator of pyroptosis—a highly inflammatory and lytic form of programmed cell death—GSDME has now been found to contribute to glioblastoma’s notorious resistance to pyroptosis, simultaneously promoting tumor progression. This unexpected duality challenges existing paradigms around cell death pathways in cancer and opens novel avenues for therapeutic intervention.

The study finds that using Tumor Treating Fields therapy (TTFields), which delivers targeted waves of electric fields directly into tumors to stop their growth and signal the body's immune system to attack cancerous tumor cells, may extend survival among patients with glioblastoma, when combined with immunotherapy (pembrolizumab) and chemotherapy (temozolomide).

This systematic review and meta-analysis examined the impact of pituitary stalk sacrifice during craniopharyngioma surgery. It found that sacrificing the stalk significantly increases the risk of postoperative endocrine dysfunction without reducing tumor recurrence or progression, highlighting the importance of preserving the stalk when possible.

CAR-T activity is still modest in GBM, and there are multiple limitations to its use in this setting, said Elena Garralda, MD, PhD, of Vall d'Hebron Institute of Oncology in Barcelona, who served as ASCO session study discussant.

Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM.

In a study published in May in Cell Death and Disease, researchers identified a previously unknown trait of cancer cells that shows promise for therapeutic intervention. The group outlined the mechanism of action and effectiveness of the experimental drug known as JM2, revealing its potential as a peptide therapy to target cancer cells that can renew and regrow, even after chemotherapy and radiation.

In the relentless fight against glioblastoma, the most common and lethal form of primary brain cancer, new research is shedding light on a previously hidden collaborator within the tumor microenvironment—astrocytes. These star-shaped glial cells, traditionally known for their supportive roles in the central nervous system, have now been implicated in actively orchestrating immune evasion strategies that allow glioblastomas to thrive despite aggressive treatments. Groundbreaking work led by Faust Akl and colleagues unravels a complex molecular dialogue where tumor-derived signals reprogram astrocytes into suppressors of anti-tumor immunity, revealing promising therapeutic avenues that could reshape glioblastoma treatment paradigms.

Our study investigated the role of astrocytes, an abundant cell type in the brain, in regulating an immune response against glioblastoma (GBM)-a highly aggressive brain cancer. We found a subset of astrocytes that limits the immune response and can be targeted with therapeutics.

In a groundbreaking study poised to shift the paradigm of glioblastoma treatment, researchers have unveiled compelling evidence that gabapentinoids, a class of drugs traditionally employed in neuropathic pain and seizure management, confer a significant survival advantage in human glioblastoma patients. This revelation arises from an extensive, multifaceted investigation that meticulously combines clinical data, molecular biology, and pharmacological insights, potentially opening new therapeutic avenues for one of the deadliest brain cancers known to medicine.

In the relentless battle against gliomas, a notoriously aggressive and often deadly form of brain cancer, the quest for effective immunotherapy targets remains a paramount scientific challenge. Gliomas’ ability to evade immune detection has historically hindered the development of T-cell mediated therapies, largely due to the scarcity of identified tumor-specific antigens that effectively trigger immune responses. However, an innovative study is poised to change this narrative by unveiling a new reservoir of potential immunogenic targets derived from the aberrant transcriptomic landscape of glioma cells. This breakthrough work not only broadens our understanding of tumor antigenicity but also illuminates a promising avenue toward personalized immunotherapies.

The phase 2B SURVIVE trial testing SurVaxM, a cancer vaccine for glioblastoma, will continue as planned following an interim analysis showing sufficient promise to proceed. SurVaxM, combined with standard treatments like surgery, radiation, and chemotherapy, aims to extend survival and improve quality of life for patients with this aggressive brain cancer.
The vaccine targets survivin, a protein that helps tumor cells evade death, and has shown a strong safety profile and encouraging survival rates in earlier studies. While specific results remain confidential due to trial regulations, the decision to continue marks a hopeful step in the development of more effective glioblastoma therapies.

In a groundbreaking advancement that promises to reshape the landscape of glioblastoma research and treatment, a team of researchers led by Yu, Basu, Baquer, and their colleagues have unveiled a novel investigative approach utilizing needle core biopsies to enable comprehensive multimodal deep-data generation. 

GSK is licensing an ABL Bio technology that yields bispecific antibodies engineered to leverage a certain transmembrane receptor to cross the blood-brain barrier to treat neurodegeneration. GSK is already partnered with Alector, which has monoclonal antibodies in clinical development for Alzheimer’s disease.

In a Phase I clinical trial reported in Nature Communications, two researchers from UT Southwestern and their colleagues showed this strategy was safe and effective. The team worked with 21 patients at medical centers, including UTSW, who had recurrent glioblastoma. They were divided into six groups, each of which received a different dose of radiation-emitting nanoparticles through CED. Patients who received the highest doses had tolerable side effects and lived an average of 17 more months after treatment, significantly longer than expected for patients with recurrent glioblastoma. The authors suggest this strategy shows promise for improving treatments for these patients.