Regulation of Pancreatic Tumorigenesis by Necroptosis
Final Report Abstract
The present results indicate a potential therapeutic efficacy of a novel experimental drug for use in pancreatic cancer. The immune system, which attacks foreign organisms like pathogens uses sensors to turn off in order to prevent aberrant and detrimental activation. Tumors have been shown to inappropriately use this “turn off” mechanism to avert immune attack. The current results show the effectiveness in blocking the RIP1 signaling pathway in pancreatic ductal adenocarcinoma. Previous attempts at harnessing the immune system to enhance cytotoxic T cell function have failed – however, the results from this study indicate that blocking RIP1 with GSK547 helps prime T cells to identify cancer cells and evade them for attack. . An upcoming Phase I Clinical trial on the study drug GSK095 will measure the side effects of the drug candidate along with its ability to treat pancreatic cancer. The study is listed on the National Institutes of Health’s website at https://clinicaltrials.gov/ct2/show/NCT03681951. Additionally to this project, I have investigated the question of whether simple perturbations in mechanical forces transform into cellular signals that lead to T-lymphocyte reprogramming. This type of conversion of biophysical forces into cellular programs is known to occur in plants, where mechanotransduction affects morphogenesis. I therefore addressed the question of whether increased interstitial pressure can induce T-cell exhaustion via activation of the mechanosensitive channel Piezo1. The results from this investigation have led to a patent application.
Publications
- Dectin-1 Signaling drives pancreatic oncogenesis by promoting adaptive immune suppression. Nature Medicine. 2017, 23(5):556-567
D Daley, VR Mani, N Mohan, N Akkad, A Ochi, KB Lee, DW Heindel, CP Zambirinis, G Werba, RM Barilla, A Torres-Hernandez, S Nayak, D Wang, M Hundeyin, B Diskin, B Aykut, R Rodriguez, S Chang, L Gardner, LK Mahal, B Ueberheide, G Miller
(See online at https://doi.org/10.1158/2326-6074.TUMIMM16-A08) - NLRP3 Signaling Drives Macrophage Induced Adaptive Immune Suppression in Pancreatic Carcinoma. Journal of Experimental Medicine. 2017, 214(6):1711-1724
D Daley, VR Mani, N Mohan, N Akkad, KB Lee, A Torres-Hernandez, B Aykut, B Diskin, K Ismail, A Mahmud, G Werba, E Morales, S Lall, M Farooq, B Wadowski, A Rubin, M Berman, R Narayanan, M Hundeyin, G Miller
(See online at https://doi.org/10.1084/jem.20161707) - Cancer Cell. 2018, 12;34(5):757-774
W Wang, JM Marinis, AM Beal, S Savadkar, Y Wu, M Khan, PS Taunk, N Wu, W Su, J Wu, A Ahsan, E Kurz, T Chen, I Yaboh, F Li, J Gutierrez, B Diskin, M Hundeyin, M Reilly, JD Lich, PA Harris, MK Mahajan, JH Thorpe, P Nassau, JE Mosley, J Leinwand, JA Kochen- Rossi, A Mishra, B Aykut, M Glacken, A Ochi, N Verma, JI Kim, V Vasudevaraja, D Adeegbe, C Almonte, E Bagdatlioglu, DJ Cohen, K Wong, J Bertin, G Miller
(See online at https://doi.org/10.1016/j.ccell.2018.10.006) - Cancer Discovery. 2018, 8(4): 403-16
S Pushalkar, M Hundeyin, D Daley, CP Zambrinis, E Kurz, A Mishra, N Mohan, B Aykut, M Usyk, LE Torres, G Werba, K Zhang, Y Guo, Q Li, N Akkad, S Lall, B Wadowski, J Gutierrez, JA Kochen Rossi, JW Herzog, B Diskin, A Torres-Hernandez, J Leinwand, W Wang, P Taunk, S Savadkar, M Janal, A Saxena, X Li, D Cohen, R Balfour Sartor, D Saxena, G Miller
(See online at https://doi.org/10.1158/2159-8290.CD-17-1134)
