Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor

Abstract

In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.

Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

“…Of the 31 evaluable patients, one patient (3%) had a confirmed partial response, 16 patients (52%) had stable disease for at least 6 weeks, and seven patients (23%), including one patient with prostate cancer, remained on study for 8 months (Bendell et al 2012). Neuropsychiatric adverse events, including reversible and generally mild-to-moderate mood alterations and depression were seen with BKM120 treatment and are thought to reflect the ability of BKM120 to cross the blood-brain barrier and inhibit the PI3K/Akt/mTOR pathway in the brain (Maira et al 2012a, Nanni et al 2012. In support of this, low/dysfunctional PI3K/Akt/mTOR signaling has been shown to reduce the concentration of the neurotransmitters GABA and serotonin in anxiety-related brain regions such as the amygdala and has been linked to anxiety and depression (Ackermann et al 2008).…”

Blood-brain Barrier Remodeling during Brain Metastasis Formation

“…In addition, increased activity of the PI3K-Akt pathway, a crucial regulator of cell survival and proliferation, has been reported in several tumor cell types, including melanoma and breast cancer cells metastasizing to the brain (51)(52)(53). Recent studies demonstrated that inhibition of PI3K effectively controls metastatic growth of HER2-positive breast cancer cells in the brain (52).…”

Targeted Therapies Overcoming Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

“…The number of adverse-event-related on-treatment deaths is particularly evident in patients above 65 years [20], therefore the FDA recommends strict indications especially for elderly patients. Moreover, for PI3K inhibitors mood changes have been described as a further serious side effect, which can be connected to a possible crossing of the blood-brain barrier [33][34][35]. The major toxicity of palbociclib is neutropenia [31].…”