S100P antibody-mediated therapy as a new promising strategy for the treatment of pancreatic cancer

Abstract

Despite progresses in diagnosis and treatment, pancreatic cancer continues to have the worst prognosis of all solid malignant tumors. Recent evidences suggest that the metastasis-promoting protein S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression through extracellular functions. Moreover, its expression is strongly correlated with poor prognosis in patients with several types of cancer although the entire molecular mechanism responsible for the diverse biological functions is not fully understood. We showed that extracellular S100P stimulates pancreatic carcinoma BxPC3 cell line by promoting cell proliferation. We also demonstrated that S100P induces, in this cell line, the phosphorylation of IκBα and the secretion of matrix metalloproteinase 9 (MMP-9). In addition, treatment with S100P protected cells from injuries induced by the cytotoxic agent Gemcitabine. On the basis of these results, we developed function-blocking anti-S100P monoclonal antibodies (mAbs) that abolished all of its in vitro activities. Furthermore, in vivo treatment with the candidate 2H8 antibody decreased tumor growth and liver metastasis formation in a subcutaneous and orthotopic BxPC3 tumor model. We conclude here that a therapeutic strategy blocking the extracellular activity of S100P by means of specific mAbs could be an attractive therapeutic approach as a single agent or in combination with target-directed or chemotherapeutic drugs to treat pancreatic cancer.

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

“…High plasma S100P levels have also been correlated with poor prognosis in metastatic breast cancer patients, with levels decreasing following treatment, suggesting a role of S100P in dynamic monitoring of response [43]. In the present study, S100P gene expression and protein levels were significantly higher in resistant tumours after long-term treatment, as well as being differentially expressed before treatment supporting its potential role as a therapeutic target [44] and a predictive marker.…”

S100 proteins in cancer

“…Although gene therapy has not been used to modulate the expression of S100 family members in patients with cancer, it has been used in preclinical animal models, in which it beneficially upregulates S100A1 expression in heart disease 142 . Other approaches to modulate S100 protein activity include S100A4- and S100P–neutralizing antibodies 93,94,143 , and peptibodies (peptide–Fc fusion proteins) directed against S100A8 and S100A9 (REF. 144); both approaches reduce tumour growth in murine cancer models.…”

The role of S100 proteins and their receptor RAGE in pancreatic cancer

“…As a result, several RAGE/S100P inhibitors were developed and used to block RAGE-dependent, pancreatic-cancer cell or tumor growth [7, 30, 34-37]. A S100P-derived peptide, which blocks the RAGE/S100P interaction, inhibited pancreatic-tumor growth and metastasis formation in a pancreatic ductal adenocarcinoma mouse model [30, 34].…”

“…Different forms of cromolyn, 5-methyl cromolyn and cromolyn encapsulated into liposomes [35], were shown to reduce pancreatic-tumor growth in mice [7, 36]. Recently, Dakhel et al showed that monoclonal antibodies against S100P could also reduce pancreatic-cancer cell growth and metastasis formation in a xenograft mouse model [37]. …”

“…Another therapeutic approach consists of targeting S100 proteins with monoclonal antibodies. Recent studies have shown that treatment with anti-S100P or anti-S100A4 antibodies could effectively reduce the tumor’s growth and the formation of metastases in mouse models of pancreatic cancer [37]. In conclusion, blocking the RAGE/S100 ligand axis appears to be a promising, new therapeutic approach to treat pancreatic ductal adenocarcinoma.…”