Executive Summary : | Prostate cancer (PCa) is the 2nd leading cause of cancer deaths and primary diagnosed caner in males with 1 in 6 men diagnosed with PCa. Projection of burden states that by 2030, 499,000 deaths worldwide will occur due to PCa. By 2021 there will be about 51,979 cases of PCa in India and is expected to rise by 140% in few years. Androgen receptor is an important ligand dependent transcription factor (TF) involved in PCa progression, that controls the expression of androgen-responsive genes. In order to access its target genes, a TF requires localization to the nucleus, restricting this transcription factor in the cytoplasm prevents its activity. Therefore, a crucial regulatory step involved in the action of AR is its nuclear translocation. There is no defined therapy effectively targeting Androgen Receptor (AR) nuclear localization in PCa. Most of the small molecules discovered against PCa so far cease to act and salvage their survival through PI3K pathway after a defined time and eventually PCa transforms into castration-resistant PCa (CRPC). So, lack of potency and selectivity, off-target effects as well as poor metabolic stability, are hallmarks of early small molecules developed to target PCa and have not shown long-term effects in curing PCa. There is no therapy specifically designed for and capable of effectively targeting AR nuclear localization in CRPC cells. The identification and characterization of novel bioactive molecules inhibiting AR could lead to more effective and new treatment options for patients with CRPC, including those which relapse after treatment. In light of the limitations of the current anticancer drugs, our lab started a drug discovery program in 2016, funded by SERB-ECRA, which led to the discovery of 16 new small molecules against PCa from medicinal plants. Two novel small molecules, SKCIDDL-1 and SKCIDDL-2, were successfully evaluated in nude mice, demonstrating PSA reduction, significant tumor shrinkage, and doubled survival rates. These findings led to the filing of three patent applications (details provided in the final progress report submitted to SERB-ECRA-2016-2019).
Building on these promising results, the current proposal aims to evaluate the toxicity, biodistribution, and pharmacokinetics of these molecules in a mouse model. Comparative transcriptomics via RNAseq will be employed to identify dysregulated pathways and elucidate the underlying mechanisms of action. Additionally, the discovery of differentially expressed proteins may pave the way for new approaches in treating and diagnosing metastatic prostate cancer (PCa).
These efforts focus on developing small molecules capable of effectively targeting androgen receptor (AR) nuclear localization and function in castration-resistant prostate cancer (CRPC) cells, advancing the molecules toward clinical trials and commercialization. |