SeqPerGlio

Glioblastoma (GB) is the most common malignant primary brain tumour and, with a 5-year survival rate of 6,9%, it is mostly incurable. Standard-of-care therapy consists of surgical resection followed by radiation therapy and concurrent chemotherapy with temozolomide. Still, while diffuse invasiveness precludes complete surgical resection, genetic heterogeneity contributes to chemo- and radio-resistance while localization beyond the blood-brain barrier limits drug penetration. Therefore, there is an unmet need for novel therapeutic approaches able to kill infiltrating cancer cells remaining in the parenchyma after resection of the primary tumour. The central hypothesis of this project is that personalised drug combination therapies will efficiently counteract intratumor molecular heterogeneity when locally administered at the tumour site by biocompatible drug-loaded gels. The aim of this project is, therefore, to demonstrate the feasibility of overcoming both intratumor heterogeneity and the obstacle imposed by the blood-brain barrier to intracranial drug accumulation, by first setting up a workflow for accurate intraoperative tumour profiling by ultrafast nanopore sequencing, which will allow to decipher key patient actionable targets and assemble appropriate combinations of targeted drugs into biocompatible thermogels. Next, we will intracranially administer these “therapeutic” thermogels before the end of surgical procedures.
Importantly, the efficacy of specific tumour-tailored drug combinations, targeting the multiple actionable targets that can be identified in each patient, will be assessed by using the most appropriate patient-derived models able to recapitulate the genetic and anatomic complexity of GB, both in vitro and in vivo. Also, our in vivo approach is closely related to the human pathological and therapeutic set-up and consists in the resection of the patient derived “primary” orthotopic GB from the mouse brain, followed by the filling of the resulting cavity with the appropriate “therapeutic” gel. Ultimately, we will evaluate a dose escalation, phase 1a clinical trial of the safety, tolerability and clinical activity of biocompatible gels containing targeted inhibitors, in patients with resectable recurrent GB.
We expect that delivering tailored combinations of targeted therapeutic drugs directly into the tumour site during surgery will allow to reach an efficient control of GB recurrences with low systemic toxicity. Our approach will indeed overcome two of the most critical problems preventing efficacious GB chemotherapy: drug resistance sustained by tumour heterogeneity and failure to pass the BBB. Overall, at the end of this 3-year project, we expect to demonstrate, by relevant preclinical models, the potential of our approach in effectively increasing survival and accelerating a cure for GB patients.