New Target for Cancer Therapy Discovered by IACS Scientists
- September 1, 2024
- Posted by: OptimizeIAS Team
- Category: DPN Topics
New Target for Cancer Therapy Discovered by IACS Scientists
Sub: Sci
Sec: Health
Why in News
Scientists from the Indian Association for the Cultivation of Science (IACS), Kolkata, have identified a novel target for cancer treatment that could pave the way for new therapeutic approaches. Their findings, published in The EMBO Journal, reveal critical insights into how cancer cells repair DNA during cell division, offering potential for precision medicine in cancer therapy.
Key Discoveries
Identification of a New Target
- IACS scientists discovered a crucial target in cancer cells that plays a role in DNA repair during cell division. This target could be exploited to develop new cancer therapies.
Role of Topoisomerase 1 in Cancer
- The enzyme topoisomerase 1 (Top1) is essential for DNA replication and transcription during cell division. Cancer drugs like camptothecin, topotecan, and irinotecan target Top1, leading to cancer cell death. However, cancer cells can develop resistance by utilizing DNA repair mechanisms involving the TDP1 protein.
What is Topoisomerase 1 (Top1): It is an enzyme that helps unwind and rewind DNA, which is vital for higher eukaryotes:
Function: TOP1 relaxes DNA supercoiling that’s created by transcription, replication, and chromatin remodeling. It does this by cutting one strand of DNA, relaxing it, and then reannealing it.
Structure: TOP1 is a type I topoisomerase, which means it’s further divided into two structurally and mechanistically distinct types: type IA and type IB.
Location: TOP1 is found in the nucleus and nucleolus.
Side effects: TOP1 poison-based chemotherapies can cause dysarthria, a neurotoxic side effect.
Targeting DNA Repair Mechanisms
- The study highlights that cancer cells use TDP1 to counteract the effects of Top1 inhibitors.
- Researchers found that targeting both CDK1 and TDP1 proteins simultaneously could enhance the effectiveness of cancer treatments.
What is CDK1 (Cyclin-Dependent Kinase 1): CDK1 is a crucial protein kinase that regulates the cell cycle, particularly the transition from the G2 phase (second phase) to the M phase (mitosis). It ensures proper cell division by interacting with cyclins and phosphorylating target proteins.
Role in Cancer: CDK1 is often overexpressed in cancer cells, leading to uncontrolled cell proliferation. Inhibiting CDK1 can disrupt the cell cycle, induce apoptosis (cell death), and enhance the effectiveness of cancer therapies.
Regulation: CDK1 activity is tightly regulated by binding to cyclins (especially cyclin B) and by phosphorylation events. Proper regulation is critical for the accurate division of cells.
Clinical Trials: Several CDK1 inhibitors, such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib, are currently in various stages of clinical trials. These inhibitors show potential in treating cancers by targeting the cell cycle.
Combination Therapy: Combining CDK1 inhibitors with other drugs, like Top1 inhibitors, has shown promise in preclinical studies by preventing cancer cells from repairing DNA damage, leading to increased cell death.
What is TDP1 (Tyrosyl-DNA Phosphodiesterase 1): TDP1 is an enzyme that plays a key role in the DNA repair process by resolving DNA lesions, particularly those caused by Top1 inhibitors. It removes covalent DNA-protein complexes, thus repairing DNA breaks.
Role in Cancer: Cancer cells often exploit TDP1 to repair the DNA damage caused by chemotherapy drugs, leading to drug resistance. Targeting TDP1 can potentially prevent cancer cells from repairing their DNA, making them more susceptible to treatment.
DNA Repair Mechanism: TDP1 specifically repairs DNA damage resulting from Top1 inhibitors, which are commonly used in chemotherapy. Its activity is crucial for the survival of cancer cells under treatment.
Phosphorylation: Phosphorylation of TDP1 during the cell cycle, particularly in the presence of Top1 inhibitors like camptothecin, is critical for its function. This modification helps remove TDP1 from chromosomes, a process necessary for accurate cell division.
Potential Target: The inhibition of TDP1, particularly when combined with other therapies like CDK1 inhibitors, could lead to enhanced treatment outcomes by preventing cancer cells from repairing chemotherapy-induced DNA damage.
| Phosphorylation: It is a biochemical process in which a phosphate group is added to a protein or other organic molecules, typically by an enzyme called a kinase. This modification often occurs on specific amino acids, such as serine, threonine, or tyrosine, within a protein. Importance in Cancer: Abnormal phosphorylation can lead to uncontrolled cell growth and cancer. For example, overactive kinases may continuously phosphorylate proteins that drive cell proliferation, contributing to tumorigenesis. Therapeutic Target: Phosphorylation pathways are often targeted in cancer therapy. Drugs that inhibit specific kinases can prevent the phosphorylation of proteins that promote cancer cell survival and proliferation, leading to cell death. |
Advanced Treatment Strategies
- Cancer cells often develop resistance to single-agent therapies by enhancing their DNA repair pathways or altering cell cycle regulation. The combination of Top1 and CDK1 inhibitors may overcome this resistance and improve treatment outcomes.
- The study suggests that personalized combinatorial chemotherapy, which targets different aspects of the cell cycle and DNA replication, could effectively kill cancer cells and reduce the chances of treatment resistance.
Chemotherapy: It is a cancer treatment that uses drugs to kill rapidly dividing cells by targeting specific phases of the cell cycle.
Top1 inhibitors like camptothecin disrupt DNA replication in cancer cells, leading to cell death.
Resistance to chemotherapy occurs when cancer cells activate DNA repair mechanisms to survive drug-induced damage.
Combination therapy using multiple drugs can prevent cancer cells from repairing DNA, increasing the treatment’s effectiveness.
What is Personalized Chemotherapy?
It refers to a tailored cancer treatment approach that targets the specific genetic and molecular characteristics of a patient’s tumour, using a combination of drugs to maximize efficacy and minimize resistance.
This approach considers individual variations in DNA repair mechanisms, drug metabolism, and tumour biology to optimize treatment outcomes.