Establishing a Preclinical Multidisciplinary Board for Brain Tumors

Abstract

SUMMARY Purpose Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. Experimental Design A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic and efficacy studies were used to triage active compounds for combination preclinical trials with ‘standard-of-care’ surgery and radiotherapy. Results Mouse models displayed distinct patterns of response to surgery, irradiation and chemotherapy that varied with tumor subtype. Repurposing screens identified three hour infusions of gemcitabine as a relatively non-toxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Post-irradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma

“…Mice bearing G3 HD-MB03 tumors were randomized into treatment groups 4–7 days after implantation, and those with SHH-MB 28 days after implantation. A published protocol for fully-fractionated whole-brain irradiation was used (10). In brief, a planar posterior–anterior (PA) beam was delivered at 2 Gy/day, 5 days on and 2 days off, for a total of 40 Gy for G3 HD-MB03 and 36 Gy for SHH-MB PDOXs (10).…”

Challenges to curing primary brain tumours

“…Nascent attempts to unify the brain tumour research pipeline are underway. The international paediatric brain tumour community has demonstrated remarkable levels of collaborative activity over many years and is now working to discover and define the genomic subtypes of paediatric brain tumours and form multi-disciplinary teams in order to design preclinical studies that better inform the design of clinical trials 11,12 . However, the community must go further, by forming international collaborations that extend beyond the borders of traditional research disciplines and by engaging the entire breadth of expertise available within the biological and physical sciences (see Challenge 2).…”

“…Of particular note, although patients with brain tumours receive complex, multimodality therapy, mice in pre-clinical studies typically receive monotherapies that are rarely comparable to the standard of care for the malignancy that is being modelled. Thus, efforts to establish preclinical ‘mouse hospitals’, in which potential new therapies are tested in the context of combination with neurosurgery, fractionated radiotherapy and/or conventional chemotherapy, should become the new standard 11 . Researchers with access to such preclinical hospitals should also perform robust pharmacokinetic (with particular attention to BBB penetration), pharmacodynamic and biomarker (tumour, liquid biopsy and imaging) studies for novel agents, thus maximizing the speed and likelihood of success of clinical translation (FIG.…”

“…These short-term culture systems have enormous potential for studying interactions between different cells and drug sensitivities and for interrogation using genome-wide interference and/or editing techniques 20,55–58 . Preclinical pipelines that deploy these novel screening approaches, together with the use of matched GEMMs and PDX models (ideally in humanized mice), should provide a more comprehensive and more accurate means of delivering optimized drugs and their associated biomarkers into clinical trials 11 .…”

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

“…Approaches to use PDX models as avatars for individual patients that are parallelly being treated in the clinic are possible in principle, but typically hampered by time-consuming model establishment and variable engraftment rates [ 176 ]. Nimmervoll et al further introduced the concept of a mouse clinic, aiming to more closely resemble the multimodal clinical therapy, including chemotherapy, radiotherapy, and local resection for testing the application of new targeted treatments [ 177 ]. While this elaborate approach will likely be to too complex and resource-intensive for general use, one should carefully consider the combination of new targeted treatments and immunotherapies with mainstays of current therapy, including local resection and radiation.…”