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Thapa Lab: Cell Death Signaling

Principal Investigator: Roshan Thapa, MD, Molecular Pathogenesis

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and have high mortality rate. HCC high mortality is most likely due to its resistance to existing chemotherapeutic agents along with concomitant complications of end-stage liver disease and frequent diagnosis at late stages when limited treatment options are available. Current HCC treatment modalities include sorafenib and regarofenib, which are widely used despite their limited survival advantages. Other treatment strategies encountered multiple failures. Thus, there is an urgent need for developing novel therapeutic approaches for the cure of HCC and it is of utmost importance to understand the causes of HCC development. To find a novel therapeutic strategy for HCC treatment, the Thapa lab is applying following research approaches:

 

A. Selective killing of HCC cells by exploiting HBV surface antigen expressed on HCC cells

We are using multiple pro-apoptotic and pro-necroptotic sensitizers to activate hepatocellular death in the context of HBV infection or stable overexpression of HBV antigens. One such sensitizer we used is Smac mimetics which sensitized HCC cells to programmed cell death. We have also identified a novel compound, KPD10, through our cell-based high-throughput compound screening, which selectively kills the HCC cells expressing HBV surface antigen. In addition, we have started another high-throughput compound screening for selective killing of HCC-derived cells expressing whole genome of HBV or surface antigen of HBV only. These studies will help in developing novel therapeutic avenues for HBV-induced hepatocellular carcinoma.

 

B. Selective killing of HCC cells by using interferon-necroptosis synergy model and aminothiazoles

 We are utilizing interferon-mediated regulated cell death approach to sensitize refractory HCC cells. Both type I and type II classes of interferons (IFN) are being used to activate regulated cell death in the presence of commonly used chemotherapeutic agents like 5-Fluorouracil, Cisplatin, and Trabectedin. Our lab is also examining the compounds, HBF-0079 and its derivatives, we identified in our earlier compound screening. These compounds selectively kill hepatocellular carcinoma cells without succumbing normal hepatocytes. We are currently outlining the molecular target and exploring mechanism of death induced by these drugs. After successful completion of in-vitro studies, exact mechanism of action of the compounds will be identified and drugs can be advanced for further studies in animal model and clinical trials. In addition to above projects, we are currently conducting cell-based high-throughput compound screening for identifying selective death inducers of HCC-derived cells.

 

C.  Induction of death in hepatocellular carcinoma cells by prolong activation of STING

We are using novel STING agonists to activate death in HCC-derived cells. We have found that prolong activation of STING, an innate immune sensor, triggers death in hepatocellular carcinoma cell lines. The detailed molecular mechanism is being studied and will be reported soon. This report will facilitate novel insight in HCC immunotherapy.

 

Additional Information:

  1. Nogusa, S.; Thapa, R. J.; Dillon, C. P.; Liedmann, S.; Oguin, T. H., 3rd; Ingram, J. P.; Rodriguez, D. A.; Kosoff, R.; Sharma, S.; Sturm, O.; Verbist, K.; Gough, P. J.; Bertin, J.; Hartmann, B. M.; Sealfon, S. C.; Kaiser, W. J.; Mocarski, E. S.; Lopez, C. B.; Thomas, P. G.; Oberst, A.; Green, D. R.; Balachandran, S., RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus. Cell Host Microbe 2016, 20 (1), 13-24.
  2. Thapa, R. J.; Basagoudanavar, S. H.; Nogusa, S.; Irrinki, K.; Mallilankaraman, K.; Slifker, M. J.; Beg, A. A.; Madesh, M.; Balachandran, S., NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis. Mol Cell Biol 2011, 31 (14), 2934-46.
  3. Thapa, R. J.; Chen, P.; Cheung, M.; Nogusa, S.; Pei, J.; Peri, S.; Testa, J. R.; Balachandran, S., NF-kappaB inhibition by bortezomib permits IFN-gamma-activated RIP1 kinase-dependent necrosis in renal cell carcinoma. Mol Cancer Ther 2013, 12 (8), 1568-78.
  4. Thapa, R. J.; Ingram, J. P.; Ragan, K. B.; Nogusa, S.; Boyd, D. F.; Benitez, A. A.; Sridharan, H.; Kosoff, R.; Shubina, M.; Landsteiner, V. J.; Andrake, M.; Vogel, P.; Sigal, L. J.; tenOever, B. R.; Thomas, P. G.; Upton, J. W.; Balachandran, S., DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death. Cell Host Microbe 2016, 20 (5), 674-681.
  5. Thapa, R. J.; Nogusa, S.; Chen, P.; Maki, J. L.; Lerro, A.; Andrake, M.; Rall, G. F.; Degterev, A.; Balachandran, S., Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc Natl Acad Sci U S A 2013, 110 (33), E3109-18.