Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma

Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.

Section: Increased Fatty Acid Synthesismentioning

confidence: 99%

Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors

Gupta,

Das,

Taneja

2024

“…Specifically, they preferentially utilize short-chain FAs to facilitate its absorption and acquire a growth advantage when compared to normal brain cells [ 78 , 84 ]. Supporting the critical role of FASN in the carcinogenesis of brain tumors, a recent phase II clinical study of relapsed high-grade astrocytoma showed an objective response rate of 56%, complete response rate of 17%, plus partial response rate of 39% in patients receiving FASN inhibition in combination with bevacizumab [ 85 ]. Progression-free survival at 6 months (PFS6) with the combination of FASN inhibition and bevacizumab was 31.4%, which was statistically significant when compared with historical controls of bevacizumab as monotherapy (BELOB trial; PFS6: 16%) [ 86 ].…”

Section: A New Strategy Of Tailored Therapy For Radioresistant Brain ...mentioning

confidence: 99%

Biological Insights and Radiation–Immuno–Oncology Developments in Primary and Secondary Brain Tumors

Gregucci,

Beal,

Knisely

et al. 2024

Malignant central nervous system (CNS) cancers include a group of heterogeneous dis-eases characterized by a relative resistance to treatments and distinguished as either primary tumors arising in the CNS or secondary tumors that spread from other organs into the brain. Despite therapeutic efforts, they often cause significant mortality and morbidity across all ages. Radiotherapy (RT) remains the main treatment for brain cancers, improving associated symptoms, improving tumor control, and inducing a cure in some. However, the ultimate goal of cancer treatment, to improve a patient’s survival, remains elusive for many CNS cancers, especially primary tumors. Over the years, there have thus been many preclinical studies and clinical trials designed to identify and overcome mechanisms of resistance to improve outcomes after RT and other therapies. For example, immunotherapy delivered concurrent with RT, especially hypo-fractionated stereotactic RT, is synergistic and has revolutionized the clinical management and outcome of some brain tumors, in particular brain metastases (secondary brain tumors). However, its impact on gliomas, the most common primary malignant CNS tumors, remains limited. In this review, we provide an overview of radioresistance mechanisms, the emerging strategies to overcome radioresistance, the role of the tumor microenviroment (TME), and the selection of the most significant results of radiation–immuno–oncological investigations. We also identify novel therapeutic opportunities in primary and secondary brain tumors with the purpose of elucidating current knowledge and stimulating further research to improve tumor control and patients’ survival.

“…Treating glioma stem cells with cerulenin resulted in the inhibition of migration and proliferation of the cells [69]. In a clinical study on patients of first-relapse GBM, co-administration of the FASN inhibitor TVB-2640 and bevacizumab significantly improved the progression-free survival at 6 months compared with bevacizumab treatment alone [70]. A further clinical trial is ongoing to investigate the effect of the oral, selective small-molecule inhibitor of FASN, ASC40 and bevacizumab (Table 1).…”

Section: De Novo Lipogenesismentioning

confidence: 99%

Emerging Lipid Targets in Glioblastoma

Darwish,

Pammer,

Gallyas

et al. 2024

GBM accounts for most of the fatal brain cancer cases, making it one of the deadliest tumor types. GBM is characterized by severe progression and poor prognosis with a short survival upon conventional chemo- and radiotherapy. In order to improve therapeutic efficiency, considerable efforts have been made to target various features of GBM. One of the targetable features of GBM is the rewired lipid metabolism that contributes to the tumor’s aggressive growth and penetration into the surrounding brain tissue. Lipid reprogramming allows GBM to acquire survival, proliferation, and invasion benefits as well as supportive modulation of the tumor microenvironment. Several attempts have been made to find novel therapeutic approaches by exploiting the lipid metabolic reprogramming in GBM. In recent studies, various components of de novo lipogenesis, fatty acid oxidation, lipid uptake, and prostaglandin synthesis have been considered promising targets in GBM. Emerging data also suggest a significant role hence therapeutic potential of the endocannabinoid metabolic pathway in GBM. Here we review the lipid-related GBM characteristics in detail and highlight specific targets with their potential therapeutic use in novel antitumor approaches.