Background/rationale: Glioblastoma (GB) is the most common malignant primary brain tumour and, with a median survival time after diagnosis of 14 months and a 5-year survival rate of 6,9%, it is mostly incurable. Standard-of-care therapy consists in surgical resection followed by radiation therapy and concurrent chemotherapy with temozolomide (TMZ). However, diffuse invasiveness precludes complete surgical eradication, genetic heterogeneity contributes to chemo- and radio-resistance while localization beyond the blood brain barrier (BBB) limits drug penetration. Therefore, there is an unmet need for novel therapeutic approaches able to kill infiltrating cells remaining in the parenchyma after resection of the primary tumour.
Hypothesis: 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.
Aims: The aim of this project is to demonstrate the feasibility of overcoming both intratumor heterogeneity and the obstacle imposed by BBB to intracranial drug accumulation, by using the most appropriate patients derived in vitro and in vivo models, able to recapitulate the genetic and anatomic complexity of GB. To overcome the difficulties in performing preoperative intracranial tumour biopsies, we plan to use ultrafast nanopore sequencing-based tumour profiling during the surgery. This will allow us to decipher patient-specific actionable targets and assemble appropriate combinations of targeted drugs to be administered locally by biocompatible thermogels before the end of the surgical procedure.
Methods: We will develop a process for precise and ultrafast tumour profiling by nanopore sequencing. After determining multiple actionable targets for each patient, the efficacy of specific tumour-tailored drug combinations will be assessed in vitro in the same patient-derived organoids and explants, by evaluating cell proliferation, apoptosis and motility/invasion. Next, the efficacy of therapeutic gels carrying the same combinations of targeted drugs will be assessed in vivo using an approach closely related to the human pathological and therapeutic set-up, which consists in the resection of the patient-derived “primary” orthotopic GB and filling of the resulting cavity with the appropriate “therapeutic” gel. GB recurrences will be followed-up by in vivo imaging and Kaplan-Meier survival analysis of mice. Ultimately, based on preclinical results, we will evaluate a dose escalation, phase 1a clinical trial of the safety, tolerability and clinical activity of biocompatible gels containing selected targeted drugs, in patients with resectable recurrent GB.
Expected results and potential impact: We expect to address two of the most critical issues associated with recurrence in patients during GB treatment: drug resistance sustained by tumour heterogeneity and failure to overcome the BBB. Our approach of delivering, during surgery, combinations of targeted therapeutic drugs directly into the tumour site during surgery will enable truly personalized treatment strategies that are tailored to the molecular profile of each patient’s tumour and has a strong potential to reach an efficient control of GB recurrence with low systemic toxicity. At the end of this 3-year project, we expect to demonstrate the effectiveness of our approach in relevant preclinical models and evaluate a proof-of-concept phase 1a clinical trial for recurrent GB.