ABSTRACT
Prognosis of HPV negative head and neck squamous cell carcinoma (HNSCC) patients remains poor despite surgical and medical advances and inadequacy of predictive and prognostic biomarkers in this type of cancer highlights one of the challenges to successful therapy. Statins, widely used for the treatment of hyperlipidaemia, have been shown to possess anti-tumour effects which were partly attributed to their ability to interfere with metabolic pathways essential in the survival of cancer cells. Here, we have investigated the effect of statins on the metabolic modulation of HNSCC cancers with a vision to predict a personalised anticancer therapy. Although, treatment of tumour-bearing mice with simvastatin did not affect tumour growth, pre-treatment for 2 weeks prior to tumour injection, inhibited tumour growth resulting in strongly increased survival. This was associated with increased expression of the monocarboxylate transporter 1 (MCT1) and a significant reduction in tumour lactate content, suggesting a possible reliance of these tumours on oxidative phosphorylation for survival. Since MCT1 is responsible for the uptake of mitochondrial fuels into the cells, we reasoned that inhibiting it would be beneficial. Interestingly, combination of simvastatin with AZD3965 (MCT1 inhibitor) led to further tumour growth delay as compared to monotherapies, without signs of toxicity. In clinical biopsies, prediagnostic statin therapy was associated with a significantly higher MCT1 expression and was not of prognostic value following conventional chemo-radiotherapy. These findings provide a rationale to investigate the clinical effectiveness of MCT1 inhibition in patients with HNSCC who have been taking lipophilic statins prior to diagnosis.
Subject(s)
Head and Neck Neoplasms/diagnosis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Monocarboxylic Acid Transporters/antagonists & inhibitors , Animals , Biomarkers/metabolism , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lactic Acid/metabolism , Mice , Oxidative Phosphorylation , Precision Medicine , Prognosis , Pyrimidinones/pharmacology , Thiophenes/pharmacologyABSTRACT
OBJECTIVE: This study examined the effect of a cognitive-behavioral stress management (CBSM) intervention on emotional well-being and immune function among women in the months following surgery for early-stage breast cancer. METHOD: Twenty-nine women were randomly assigned to receive either a 10-week CBSM intervention (n=18) or a comparison experience (n=11). The primary psychological outcome measure was benefit finding. The primary immune function outcome measure was in vitro lymphocyte proliferative response to anti CD3. RESULTS: Women in the CBSM intervention reported greater perceptions of benefit from having breast cancer compared to the women in the comparison group. At 3-month follow-up, women in the CBSM group also had improved lymphocyte proliferation. Finally, increases in benefit finding after the 10-week intervention predicted increases in lymphocyte proliferation at the 3-month follow-up. CONCLUSION: A CBSM intervention for women with early-stage breast cancer facilitated positive emotional responses to their breast cancer experience in parallel with later improvement in cellular immune function.
