Life Sciences & Biotechnology
Title : | Targeting CDC-like kinase 1 to overcome drug resistance in Castration Resistant Prostate Cancer |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Ashish Misra, Indian Institute Of Technology (IIT) Hyderabad, Telangana |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | ashishmisra@iith.ac.in |
Equipments : | Ultra low-temp Freezer (-80C)
Syringe Pump
PCR Machine
SDS-PAGE Gel Electrophoresis and western blotting apparatus
Pipettes
LineUp FlowEZ pressure based flow module with controller |
Details
Executive Summary : | Castration-resistant prostate cancer (CRPC) is a highly aggressive and incurable form of prostate cancer with a high mortality rate. Despite improvements in patient survival rates with androgen-receptor signalling inhibitors, almost all patients develop drug resistance and eventually die from the disease. To understand the mechanisms of drug resistance and develop new approaches, an innovative genome-wide human RNA interference (RNAi) screen was performed to identify factors that promote resistance to anti-androgen therapy (enzalutamide) in CRPC. One factor identified was CDC-like kinase 1 (CLK1), a dual-specificity protein kinase that phosphorylates serine/arginine-rich proteins involved in pre-mRNA splicing. Preliminary experiments revealed that Clk1 is aberrantly upregulated in CRPC patients, and its inhibition re-sensitizes enzalutamide-resistant cells to enzalutamide and blocks cell growth. Clk1 knockdown leads to the loss of expression of prostate cancer serological marker PSA and other marker genes. Pharmacological inhibition of Clk1 or its protein-protein interaction network could directly inhibit tumor growth by blocking Clk1-driven oncogenic signaling that promotes enzalutamide-resistance. To test these predictions, the researchers will determine whether the highly specific CLK1 small molecule inhibitors KH-CB19 and TG003 can effectively inhibit tumor signaling and growth using a complementary series of 3D spheroid and mouse models of CRPC. The results of these experiments will elucidate a novel druggable pathway that promotes CRPC development and evaluate a new approach for treating drug-resistant CRPC. |
Co-PI: | Dr. Suhanya Duraiswamy, Indian Institute Of Technology (IIT) Hyderabad, Telangana-502284 |
Total Budget (INR): | 66,33,000 |
Organizations involved