368MO Fatty acid synthase inhibitor TVB-2640 with bevacizumab in recurrent glioblastoma

Abstract

Background: Central nervous system (CNS) neoplasms are relatively uncommon and potentially debilitating. From 1984-2012, there were around 200 new cases of malignant primary brain tumours each year in Hong Kong, and the trend has been static. To improve epidemiological reporting of CNS tumours in Hong Kong, the Hong Kong Cancer Registry (HKCaR) has established the brain and CNS tumour registry (BCTR) to collect all incident cases of primary malignant and non-malignant CNS tumours since 2013.Methods: The HKCaR is a population-based cancer registry in Hong Kong. Clinical records and pathology reports were obtained from public and private care providers with high coverage of 95%. These records were entered, cleansed and validated. Incidence of pathologically or clinically diagnosed CNS tumours with malignant, benign or uncertain behaviours were reported over the period of 2013-2017. The incidence were age-standardized with the 2000 US standard population and compared with US data from CBTRUS.Results: The age-standardised incidence of malignant and non-malignant brain tumours pooled over the period of 2013 to 2017 were 3/100,000 population and 8.6/ 100,000 population respectively. The top three most common types of malignant neoplasms were glioblastoma, other glial tumours and embryonal tumours; and in non-malignant neoplasms being meningioma, pituitary tumours and nerve sheath tumours. The incidence of both malignant and non-malignant tumours were around half of that in the US (7.08 and 16.33 per 100,000 population in the period of [2012][2013][2014][2015][2016]. The incidence of non-malignant and malignant brain tumours both increases significantly with age, with steep increment for non-malignant tumours starting from age of 45-64 and for malignant after the year of 65. The incidence rate in the whole population and in each age group has remained static over the reported years.Conclusions: Significant geographical differences in incidence of CNS tumours was observed between Hong Kong and the US. Under-diagnosis of brain tumour is unlikely due to easy access to public healthcare service and cross sectional imaging. The difference may be due to ethnic and environmental factors, which include higher rate of allergic conditions in Hong Kong which may confer protection. Further investigations are warranted.Legal entity responsible for the study: The authors.

Formate Promotes Invasion and Metastasis by Activating Fatty Acid Synthesis and Matrix Metalloproteinases

“…Importantly, targeting fatty acid synthesis with the specific FASN inhibitor TVB-2640 was effective to inhibit formate-dependent invasiveness in ex vivo brain tissue slices. Notably, TVB-2640 is in clinical development for the treatment of CRC and very encouraging results with a 66.7% overall response rate have also been reported from a phase 1 trial of TVB-2640 in combination with bevacizumab in recurrent GBM (W. Kelly et al, 2020). Our results indicate fatty acid synthesis targeting as a mechanistic entry point to impede formate-dependent GBM invasion and to possibly also hinder metastatic progression of other tumor types.…”

“…In contrast, TVB-2640 treatment. The latter inhibitor is currently tested in phase 2 clinical trials for non-small cell lung carcinomas (Gerber, 2019) and GBM (W. Kelly et al, 2020). In contrast to C75, TVB-2640 did not cause a decrease of basal invasion rate.…”

Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

“…This agent has also been tested in a phase I clinical trial for patients with obesity in which it was found to reduce hepatic de novo lipogenesis as assessed by acetate isotope tracing and decrease intrahepatic triacylglycerols (113). Results from a phase II study of TVB-2640 in combination with the VEGF inhibitor bevacizumab for patients with glioblastoma has been reported in abstract form at the European Society for Medical Oncology (ESMO) virtual conference 2020 and suggested this regimen was well tolerated and improved progression-free and overall survival compared with historical controls (114). Clinical trials are ongoing testing safety and efficacy of this agent for patients with KRASmutated non-small cell lung cancer (NCT03808558), resectable colon cancer (NCT02980029), and HER2-positive advanced breast cancer (NCT03179904).…”