Novel secreted peptides from TCApF precursor for cancer treatment

human mouse tcapf sequence comparison

The aim of the present phase I first-in-human study was to investigate the safety/efficacy of dTCApFs (a novel hormone peptide that enters cells through the T1/ST2 receptor), in advanced/metastatic solid tumors. The primary objective of this open-label dose-escalation study was to determine the safety profile of dTCApFs. The study enrolled patients (aged ?18 years) with pathologically confirmed locally advanced/metastatic solid malignancies, who experienced treatment failure or were unable to tolerate previous standard therapy. The study included 17 patients (64% male; median age, 65 years; 47% colorectal cancer, 29% pancreatic cancer). The patients received 1-3 cycles of escalating dTCApFs doses (6-96 mg/m2). The mean number ± standard deviation of treatment cycles/patient was 3.2±1.4; no dose-limiting toxicities were observed up to a dose of 96 mg/m2, and the maximum tolerated dose was not reached. Half-life, maximal plasma concentration, and dTCApFs exposure were found to be linearly correlated with dose. Five patients were treated for ?3 months (12, 24, 48 mg/m2) and experienced stable disease throughout the treatment period, and 1 experienced pathological complete response. Analysis of serum biomarkers revealed decreased levels of angiogenic factors at dTCApFs concentrations of 12-48 mg/m2, increased levels of anticancer cytokines, and induction of the endoplasmic reticulum (ER) stress biomarker GRP78/BiP. Efficacy and biomarker data suggest that patients whose tumors were T1/ST2-positive exhibited a better response to dTCApFs. In conclusion, dTCApFs was found to be safe/well-tolerated, and potentially efficacious, with linear pharmacokinetics. Consistent with preclinical studies, the mechanism through which dTCApFs exerts anticancer effects appears to involve induction of ER stress, suppression of angiogenesis, and activation of the innate immune response. However, further studies are warranted.

Stemmer SM, Benjaminov O, Silverman MH, et al. Mol Clin Oncol. 2018;8(1):22-29.

We report the isolation of a novel Tumor-Cells Apoptosis Factor (Nerofe). We found that cDNA of this protein is expressed mainly in the human thymus and partially in the colon and in the frontal lobe of brain. Immunohistochemical studies localize Tumor-Cells Apoptosis Factor (TCApF) to the medulla and Hassal's corpuscles of the thymus gland, which are responsible for negative pick. Treatment of mice with induced AML terminates the cancer development and completely eliminates metastatic cell colonies from the bone marrow and the spleen that reduces probability of the cancer return. We find that TCApF binds to the T1/ST2 receptor and activates caspases 8, 9 and 3 mediated apoptosis, together with activation of JNKinase and p38 MAPKinase. Application of TCApF to cells induced apoptosis in acute myeloid leukemia proliferating cells (U937 premeyloid cells), in human breast carcinoma (MCF7), human glioblastoma, human neuroblastoma, human prostate cancer and human lung cancer proliferating cells. In contrast, TCApF was unable to induce apoptosis in non-proliferating cells. The selectivity of TCApF-induced apoptosis is related to the level of T1/ST2 receptor expression. This is the first report linking the T1/ST2 receptor to apoptosis.

Sandler U, Devary O, Braitbard O, et al. J Exp Ther Oncol. 2010;8(4):327-39.

dTCApFs (Nerofe™) is a 14-amino acid derivative of a longer hormone peptide, tumor-cells apoptosis factor (TCApF), which enters the cells through the T1/ST2 receptor. In the present study, the mechanism of action (MOA) of dTCApFs as an anticancer agent was investigated. Experiments were performed in pancreatic cancer cell lines, and immunofluorescent staining demonstrated that dTCApFs is located in the Golgi apparatus of treated cells. It was also demonstrated in pancreatic, breast and ovarian cell lines that dTCApFs treatment led to Golgi structural changes, loss of Golgi function, and molecular effects associated with endoplasmic reticulum (ER) stress, such as increased levels of C/EBP homologous protein, binding immunoglobulin protein (BiP), phosphorylated inositol-requiring enzyme 1 (pIRE1), and increased phosphorylation of eukaryotic translation initiation factor 2α, and to the generation of reactive oxygen species, which was attenuated by ER stress inhibitors. Moreover, in these cell lines, long-term exposure to dTCApFs led to downregulation of spliced X-box-binding protein 1, which is an ER stress repair mechanism gene, downregulation of the Golgi anti-apoptotic protein, and reduced cell viability. In vivo studies using murine xenograft models of human pancreatic cancer verified the cell culture findings by demonstrating structural changes in the ER/Golgi and increased levels of pIRE1and BiP in dTCApFs-treated mice vs. the controls. Finally, human tissue samples from a patient who received dTCApFs for 11 months in a clinical trial were analyzed, and an increase was observed in the number of cells expressing pIRE1 and BiP post-treatment. In conclusion, we herein report a novel MOA for an anticancer agent involving triggering of apoptosis through induction of opposite effects: ER stress and downregulation of the ER stress repair mechanism. These findings provide the framework for the clinical evaluation of dTCApFs.

Ohana J, Sandler U, Kass G, Stemmer SM, Devary Y. Mol Clin Oncol. 2017;7(6):991-999.

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