a) Immunotoxins
Targeted therapy of cancer has shown considerable promise in treating cancer with the increased understanding of their molecular mechanisms. Immunotoxins are chimeric fusion proteins that selectively targets and destroys cancer cells.
It is well established that cancer cells over-express several tumor associated antigens, membrane receptors and carbohydrate antigens. Ligands for surface receptors or monoclonal antibodies or single chain variable fragments (scFv) targeted against these antigens are fused with bacterial, fungal or plant toxins to construct immunotoxins. Immunotoxins target the surface of cancer cells with considerable potency and use protein toxins capable of killing a cell with a single molecule.
We have developed many such chimeric immunotoxins using bacterial/fungal toxins like Diphtheria toxin (DT), Pseudomonas Exotoxin (PE) and Restrictocin (RT) or humanized pro-apoptotic proteins like DNA fragmentation factor (DFF) and Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). These killing moiety were fused to targeting molecules like cytokines, monoclonal antibodies, immunoglobulins and growth factors (IL2, GM-CSF, SCF, CD47). We have proved the tremendous potential of these toxins targeted against various types of solid tumors and leukemia using cell lines as well as patient samples.
Human cancers have been recently proved to originate from tissue stem or progenitor cells known as cancer stem cells (CSCs) that have tumor initiating potential and have self-renewal capability like normal stem cells. CSC’s evade apoptosis and form the chemotherapy resistant side population, which result in the recurrence of disease. Targeting CSC’s would be the ideal therapeutic strategy to eliminate resistant population and to prevent recurrence. We are also working on isolating the leukemic stem cells from cell lines or patient samples and are developing immunotoxins to target these CSC’s.
The following are the list of immunotoxins that has been constructed and many of them have been proved to be effective in our laboratory.
Bacterial toxins: DT –IL2 targeting IL2Rα receptor for leukemia, DT-HN-1 for Head and Neck Squamous cell carcinoma, DT-SCF targeting c-kit receptor for leukemia, cervical carcinoma and pancreatic carcinoma, PE-SCF and RT-SCF for neuroendocrine carcinomas like, neuroblastomas and poorly differentiated human colon carcinoma cells (CRCs).
Humanized toxins: GM-CSF-DFF40 targeting GM-CSFR receptor for leukemia, IL-2-TRAIL for leukemia, SDF-TRAIL targeting CXCR4 receptor for breast cancer and anti-CD47-TRAIL targeting CD47 expressing cells.
b) Cancer Chemopreventive activity of Herbal extracts
New agents with novel mechanisms of action to prevent cancer are perhaps the most urgent need in the entire field of chemoprevention. The management of cancer is still not up to the mark and there is urgent need to search new drugs with low toxicity and high efficacy. Essential oils are natural, complex systems composed mainly of terpenes and some other non-terpene components. The proposed study on chemopreventive activity of EOs from medicinal plants is expected to provide valuable insights into the molecular mechanism of action involved in inducing apoptosis in cancer cells.
Intuitions