2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one and Triple-Negative-Breast-Neoplasms

TP53 (p53) is the most frequently mutated gene in cancer, being altered in approximately 50% of human malignancies. In most, if not all, cancers lacking mutation, wild-type (WT) p53 is inactivated by interaction with cellular (MDM2/MDM4) or viral proteins, leading to its degradation. Because of its near universal alteration in cancer, p53 is an attractive target for the development of new targeted therapies for this disease. However, until recently, p53 was widely regarded as ‘‘undruggable’’. This situation has now changed, as several compounds have become available that can restore wild-type properties to mutant p53 (e.g., PRIMA-1 and PRIMA-1MET). Other compounds are available that prevent the binding of MDM2/MDM4 to WT p53, thereby blocking its degradation (e.g., nutlins). Anti-mutant p53 compounds are potentially most useful in cancers with a high prevalence of p53 mutations. These include difficult-totreat tumors such as high grade serous ovarian cancer, triple-negative breast cancer and squamous lung cancer. MDM2/4 antagonists, on the other hand, are likely to be efficacious in malignancies in which MDM2 or MDM4 is overexpressed such as sarcomas, neuroblastomas and specific childhood leukemias. Presently, early clinical trials are ongoing evaluating the anti-mutant p53 agent, PRIMA-1MET, and specific MDM2–p53 nutlin antagonists.

Topics: Antineoplastic Agents; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Proteins; Female; Genes, p53; Genetic Therapy; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Nuclear Proteins; Peptides; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53

The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1

Topics: Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Mutation; Quinuclidines; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53