Implementing targeted therapies in the treatment of glioblastoma: Previous shortcomings, future promises, and a multimodal strategy recommendation

Abstract

The introduction of targeted therapies to the field of oncology has prolonged the survival in several tumor types. Despite extensive research and numerous trials, similar outcomes have unfortunately not been realized for glioblastoma. For more than 15 years, the standard treatment of glioblastoma has been unchanged. This review walks through the elements that have challenged the success of previous trials and highlight some future promises. Concurrently, this review describes how institutions, through a multimodal and comprehensive strategy with four essential components, may increase the probability of finding a meaningful role for targeted therapies in the treatment of glioblastoma. These components are (1) prudent trial designs, (2) considered drug and target selection, (3) harnessed real-world clinical and molecular evidence, and (4) incorporation of translational research.

The Glioma-IRE project − Molecular profiling in patients with glioma: steps toward an individualized diagnostic and therapeutic approach

“…‘Basket trials’ allow the inclusion of patients presenting with a specific driver mutation irrespective of the underlying tumor type, while in ‘platform trials’, patients are screened for a broad range of driver mutations and assigned to a particular treatment based on the results of the genetic testing. These innovative strategies could help overcome the limitations of current clinical trials in glioma, which are constrained by a low number of prospectively treated patients, thus accelerating the development of targeted treatments in patients with primary CNS tumors [ 45 ].…”

The Neurogenome study: Comprehensive molecular profiling to optimize treatment for Danish glioblastoma patients

“…However, second-line treatments, including experimental agents, have shown limited activity. 39 Therefore, we find it important to perform sequencing early on, ideally at diagnosis, making evaluation for experimental treatment available as soon as possible, either as add-on to standard treatment or in the adjuvant setting. This can increase the treatment options for this patient group, and might also prompt companies and/or investigators to initiate more clinical trials for brain tumor patients.…”

Adult brain tumour research in 2024: Status, challenges and recommendations

“…• Underpin initiatives like the GCGR and GlioModel with infrastructure funding that widens accessibly and ensures longevity [52] (SE)…”

“…GlioModel [53] is a UK‐based initiative to develop a preclinical modelling resource, specifically for target validation in glioblastoma and make it accessible through fee‐for‐service, although self‐sustainability remains uncertain. Recommendations : •Underpin initiatives like the GCGR and GlioModel with infrastructure funding that widens accessibly and ensures longevity [52] (SE) •Standardise model characterisation with regard to molecular profiles, phenotypes and response to current SOC (IM) •Tiered approaches to target validation and drug screening are needed, with cascades of models and assays on a range of scales and complexities, based on the strength of evidence for, or biology underlying, the specific target or drug (IM) •Evolve academic recognition. Researchers focused on model development should be credited on outputs where their models are used whilst retaining the primacy of the molecule, mechanism or hypothesis being tested (LD) …”

“…In 2021, the BNOS completed a UK survey of preclinical neuro‐oncology models to identify commonly adopted approaches and highlight groups that are willing to collaborate with and train other researchers [51]. However, barriers to cross‐institutional working, difficulty in retaining ownership (intellectual property) and a lack of infrastructure and resource funding vastly reduce the impetus to share models across research groups [52]. GlioModel [53] is a UK‐based initiative to develop a preclinical modelling resource, specifically for target validation in glioblastoma and make it accessible through fee‐for‐service, although self‐sustainability remains uncertain.…”