Extended Par-4 protein to treat cancer
A tumor suppressor protein, Par-4 (Prostate apoptosis response-4), was first identified in 1994. This protein induces apoptosis in cancer cells but not in normal cells, by functioning intracellularly and extracellularly. Par-4 can cause apoptosis by binding to cell surface GRP78, which is found in various types of tumor cells.
University of Kentucky researchers developed a Par-4 protein with an extended sequence, called Par-4Ex, in order to increase the half life and improve the in-vivo performance of the original Par-4 protein. In early stage mice studies the Par-4Ex increased the half life by approximately 7-fold, which then demonstrated to be more potent in suppressing metastatic tumor growth.
As further substantiation of this pathway, previously, the team had identified two safe, anti-malarial drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) as potent secretagogues of Par-4. Positive results of preclinical studies in mouse models with CQ and HCQ led to clinical trials at the Markey Cancer Center in a broad range of cancer patients. Two clinical trials showed positive results in cancer patients. Two other clinical trials with HCQ in combination with chemotherapy, radiation or surgery have been written up for approval by various committees at the College of Medicine.
- Rangnekar, Vivek, et. al., “Chloroquine-Inducible Par-4 Secretion is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis”, Cell Reports, 2017, 18, pg. 508 – 519.
- Rangnekar, Vivek, et. al., “Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma Par-4 levels and apoptosis in diverse tumors”, Genes and Cancer, 2018, Volume 9 (5-6), pg. 190 – 197.
- Rangnekar, Vivek, et. al., “Arylquins Target Vimentin to Trigger Par-4 Secretion for Tumor Cell Apoptosis”, Nat Chem Biol., 2014, Volume 10, Issue 11, pg. 924 – 926.