Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

Abstract

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

Depatuxizumab Mafodotin (Depatux-M) Plus Temozolomide in Recurrent Glioblastoma Patients: Real-World Experience from a Multicenter Study of Italian Association of Neuro-Oncology (AINO)

“…Yet, the randomized phase 2 REGOMA trial [ 7 ] showed a statistically longer OS in recurrent GBM patients when treated with regorafenib compared to standard lomustine: the 12m-OS rate was 38.9% versus 15.0%, respectively. Due to this important clinical benefit, regorafenib was included in the NCCN 2020 guidelines and was approved by the Italian Medicines Agency (AIFA) as the preferred treatment for the recurrent GBM population [ 2 ].…”

“…While chemoradiotherapy with temozolomide (TMZ) represents standard first-line therapy after surgery [ 1 ], the standard of care for second-line treatment has not been defined. Treatment options include re-surgery, re-irradiation and systemic pharmacotherapy—mostly nitrosoureas [ 2 , 3 ]. Bevacizumab demonstrated that it prolongs progression-free survival (PFS) without improving overall survival (OS) [ 4 ]; yet, immunotherapy with checkpoint inhibitors showed no efficacy in glioma patients [ 5 , 6 ].…”

“…Some recent studies have improved knowledge on molecular pathways and specific gene mutations driving the origin and progression of GBM; we are therefore seeing some promising results due to specific targeted therapies (i.e., BRAF inhibitors, TRK inhibitors and regorafenib) [ 2 , 7 , 8 ], even though the benefit of these new treatments needs further evaluation.…”

Viral Gene Therapy for Glioblastoma Multiforme: A Promising Hope for the Current Dilemma

“…However, the complete resection of GBM has been challenging due to the invasive growth pattern and the functional area involvement. It has been almost inevitable that the tumor-infiltrating parenchyma tissue eventually relapsed even after surgical resection (8,9). The resistance to chemotherapy drug temozolomide (TMZ) was mainly caused by O6-methylguanine-DNA methyltransferase over-expression, mismatch repair and base excision repair (10)(11)(12).…”

KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1

“…However, the intrinsic characteristics of GBM cells, which include rapid growth and infiltration into the normal brain tissues, hinder the successive removal of the primary lesion; it frequently leads to postoperative recurrence despite the advances in intraoperative imaging techniques that facilitate intraoperative analysis of tumor and normal brain tissues [ 3 , 4 ]. In addition, the emergence of chemo resistance, especially to temozolomide (TMZ), which is the most effective drug for GBM at present, further contributes to tumor recurrence, resulting in poor clinical outcomes [ 5 ]. Therefore, it is urgent to develop a new and effective drug for GBM based on a molecular mechanism that is different from that of TMZ.…”