Cancer Vaccines, Treatment of the Future: With Emphasis on HER2-Positive Breast Cancer.

Breast cancer is one of the leading causes of death in women. With improvements in early-stage diagnosis and targeted therapies, there has been an improvement in the overall survival rate in breast cancer over the past decade. Despite the development of targeted therapies, tyrosine kinase inhibitors, as well as monoclonal antibodies and their toxin conjugates, all metastatic tumors develop resistance, and nearly one-third of HER2+ breast cancer patients develop resistance to all these therapies. Although antibody therapy has shown promising results in breast cancer patients, passive immunotherapy approaches have limitations and need continuous administration over a long period. Vaccine therapy introduces antigens that act on cancer cells causing prolonged activation of the immune system. In particular, cancer relapse could be avoided due to the presence of a longer period of immunological memory with an effective vaccine that can protect against various tumor antigens. Cancer vaccines are broadly classified as preventive and therapeutic. Preventive vaccines are used to ward off any future infections and therapeutic vaccines are used to treat a person with active disease. In this article, we provided details about the tumor environment, different types of vaccines, their advantages and disadvantages, and the current status of various vaccine candidates with a focus on vaccines for breast cancer. Current data indicate that therapeutic vaccines themselves have limitations in terms of efficacy and are used in combination with other chemotherapeutic or targeting agents. The majority of breast cancer vaccines are undergoing clinical trials and the next decade will see the fruitfulness of breast cancer vaccine therapy.

The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of ß-catenin, a GSK3 substrate, in human glioblastoma cells.

Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhanced phosphorylation of Ser9 of GSK3ß via a positive feedback mechanism, and both salts elicited this enhancement. Another GSK3 substrate is ß-catenin, which has a central role in Wnt signaling. In A172 human glioblastoma cells, lithium treatment caused a surprising increase in phospho-Ser33/Ser37-ß-catenin, which was quantified using an antibody-coupled capillary electrophoresis method. The ß-catenin hyperphosphorylation was unaffected by p53 RNAi knockdown, indicating that p53 is not involved in the mechanism of this response. Lithium caused a decrease in the abundance of axin, a component of the ß-catenin destruction complex that has a role in coordinating ß-catenin ubiquitination and protein turnover. The axin and phospho-ß-catenin results were reproduced in U251 and U87MG glioblastoma cell lines. These observations run contrary to the conventional view of the canonical Wnt signaling pathway, in which a GSK3 inhibitor would be expected to decrease, not increase, phospho-ß-catenin levels.This article has an associated First Person interview with the first author of the paper.