Person:

Patel, Shalin

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.

Recent advances in immunotherapy for cancer have led to increasing interest in the role of the immune system in the pathogenesis and treatment of various tumors. Tumor-infiltrating lymphocytes have been associated with more favorable prognoses in a number of malignancies, though the mechanism of such outcomes remains unclear. This study, to our knowledge, is the first to describe lymphocytic infiltration in chordoma. Slides from 62 patients with chordoma were evaluated for lymphocyte infiltrates. Lymphocytic infiltration was found in 84% of tumors. Twenty-four tumors were selected for immunohistochemical (IHC) analysis. All of the tumors with lymphocytic infiltration that underwent IHC staining had CD4-positive lymphocytes present. CD8-positive lymphocytes were noted in 52% of tumors. HLA class I antigen defects were noted in 79% of chordoma tumors. These included negative membranous and/or cytoplasmic staining patterns, weakly positive staining, and heterogeneous combinations of these defects. Both heavy chain isoforms and beta-2-microglobulin components were affected. Our novel finding of intratumoral lymphocytes in chordoma tumors suggests that a patient’s immune system mounts a response against their tumor. The absence of HLA class I antigen components is compatible with the possibility that a patient’s immune response imposes selective pressure that facilitates the outgrowth of chordoma cell subpopulations that have developed escape mechanisms from host immune recognition. While the clinical significance requires further evaluation, these data have implications in optimally selecting patients for appropriate treatment regimens. We believe these data will spark further inquiry into the role of immunotherapy in the treatment of chordoma and other bone tumors.