Abstract IA020: Improving treatment of primary and metastatic brain tumors: Emerging insights and novel strategies

Abstract Approximately 200,000 patients develop metastasis each year in US alone. This incidence is approximately 20 times higher than glioblastoma – a uniformly fatal disease where all Phase III immune-checkpoint trials have failed to date. Patients diagnosed with metastatic breast cancer have a median survival of two years and account for approximately 40,000 deaths annually in the US alone. About 1/3rd of women with advanced breast cancer are at risk of developing brain metastases (BMs). A notable example is human epidermal growth factor receptor 2 (HER2)-positive breast cancer, where BMs from this disease are refractory to drugs that otherwise control disease in extracranial sites, for two reasons: i) the blood-brain/blood-tumor barrier (BBB/BTB) hinders the delivery of drugs to BMs, and ii) the brain tumor microenvironment (TME) reduces the efficacy of these therapies even when they accrue in BMs (Arvanitis et al, Nature Reviews Cancer 2020). By employing clinically relevant murine models, we demonstrated that theanti-HER2 antibody trastuzumab can upregulate VEGF in the microenvironment of BM (Izumi et al, Nature 2002), and thus, adding anti-VEGF/R agents can improve the efficacy of anti-HER2 therapies (Kodack et al, PNAS 2012). We further showed that HER3 is overexpressed in BMs and confers de novo resistance to anti-HER2 therapies. Blocking HER3 enhanced the efficacy of FDA-approved targeted therapies including trastuzumab and neratinib - a finding supported by independent clinical trials (Kodack et al, Science Translational Medicine 2017). In our attempt to improve survival further, we discovered that breast cancer cells implanted in the brain exhibit increased de novo lipid synthesis compared to breast cancer cells implanted in the breast or liver. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reducesHER2+ breast tumor growth in the brain – unlike those grown in the breast or liver, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies (Ferraro et al, Nature Cancer 2021). In parallel, we have employed focused ultrasound to improve delivery of various therapeutics to BMs by transiently disrupting BBB/BTB (Arvanitis et al, PNAS 2018). Finally, by recognizing the similarities between the TME of BM and glioblastoma, we have developed 3 new strategies to reprogram the immunosuppressive microenvironment of glioblastoma to improve the efficacy of immune-check point blockers against these uniformly fatal tumors (Amoozgar et al, Nature Communications 2021, Amoozgar et al, bioarxiv 2022, Datta et al. bioarxiv 2022). These strategies are likely to also benefit patients with brain metastases that have now become a leading cause of morbidity and mortality with improved detection and extracranial treatments. Citation Format: Rakesh K. Jain. Improving treatment of primary and metastatic brain tumors: Emerging insights and novel strategies [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA020.