Mechanism and treatment of pancreatic tumor progression
The 5-year survival rate of patients diagnosed with advanced pancreatic tumor is a dismal 6% and effective therapeutic treatment strategies are needed. The etiology leading to early stages of the disease is still unclear, although inflammation is thought to play a role. During the lag time for tumor development, there is a series of genetic alterations that is known to occur prior to rapid growth and metastasis. Our research uses genetic mouse models that have a susceptibility to develop pancreatic cancer to understand relevance to the human disease so that we can better elucidate pancreatic tumor biology, and propose preventive or therapeutic strategies for patients. Our group also has expertise in implanting human or mouse pancreatic tumor cells in the mouse pancreas so that we can test the tolerability and effectiveness of novel drug strategies to block tumor growth or metastasis.
Preclinical response of human cancer to immune cell therapy
Approximately 80% of ovarian cancer patients will respond to surgery and first-line chemotherapy. However, patients frequently relapse with chemotherapy resistant disease. The challenge is to develop novel therapeutic strategies that can be effective in these patients to extend progression-free and overall survival. Different from traditional drug treatments, immune-therapeutic approaches are being investigated as a new research direction. Our group is assessing the ability of innate immune cells, namely natural killer cells, to facilitate ovarian tumor killing. The studies use mice implanted with human ovarian tumor cells followed by injection of human blood cells and we track response of the tumors, expansion of the immune cells, as well as persistence and homing characteristics of the immune cells in order to understand the biology and effectiveness of adoptive cell transfer as a therapy for ovarian and other cancers.
- Muth, A., Pandey, V., Kaur, N., Wason, M., Baker, C., Han, X., Johnson, T. R., Altomare, D.A., Phanstiel, O. IV. (2014) Synthesis and biological evaluation of antimetastatic agents predicated upon dihydromotuporamine C and its carbocyclic derivatives. J. Med. Chem. 57(10): 4023-4034.
- Menges, C.W., Kadariya, Y., Altomare, D.A., Talarchek, J., Neumann-Domer, E., Wu, Y., Xiao, G.-H., Shapiro, I., Kolev, V.N., Pachter, J.A., Klein-Szanto, A.J., Testa, J.R. (2014) Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis. Cancer Res. 74(4): 1261-1271.
- Altomare, D.A., Khaled, A.R. (2012) Homeostasis and the importance for a balance between Akt/mTOR activity and intracellular signaling. Curr. Med. Chem. 19(22): 3748-3762.
- Altomare, D.A., Menges, C.W., Xu, J., Pei, J., Zhang, L., Tadevosyan, A., Neumann-Domer, E., Liu, Z., Carbone, M., Chudoba, I., Klein-Szanto, A.J., Testa, J.R. (2011) Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. PLoS One. 6(4): e18828.
- Mabuchi, S., Kawase, C., Altomare, D. A., Morishige, K., Hayashi, M., Sawada, K., Ito, K., Terai, Y., Nishio, Y., Klein-Szanto, A. J., Burger, R. A., Ohmichi, M., Testa, J. R., Kimura, T. (2010) Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol. Cancer Ther. 9(8): 2411-2422.
- Altomare, D.A., Rybak, S.M, Pei, P., Maizel. J.V., Cheung, M., Testa, J.R., Shogen, K. (2010) Onconase responsive genes in human mesothelioma cells: implications for an RNA damaging therapeutic agent. BMC Cancer. 10: 34. http://www.biomedcentral.com/1471-2407/10/34
- Tan, Y., You, H., Wu, C., Altomare, D.A., Testa, J.R. (2010) Appl1 is dispensable for mouse development, and loss of Appl1 has growth factor- selective effects on Akt signaling in murine embryonic fibroblasts. J. Biol. Chem. 285(9): 6377-6389.
- Altomare, D.A., Zhang, L., Deng, J., Di Cristofano, A., Klein-Szanto, A.J., Kumar, R., Testa, J.R. (2010) GSK690693 delays tumor onset and progression in genetically-defined mouse models expressing activated Akt. Clin. Cancer Res. 16(2): 486-496.
- Mabuchi, S., Kawase, C., Altomare, D.A., Morishige, K., Sawada, K., Tsujimoto, M., Yamoto, M., Klein-Szanto, A.J., Schilder, R.J., Ohmichi, M., Testa, J.R., Kimura, T. (2009) mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary. Clin. Cancer Res. 15(17): 5404-5413.
- Menges, C.W., Altomare, D.A., Testa, J.R. (2009) FAS-Associated Factor 1 (FAF1): diverse functions and implications for oncogenesis. Cell Cycle (Invited Perspective) 8(16): 2528-2534.
- Timakhov, R.A., Tan, Y., Rao, M., Lui, Z., Altomare, D.A., Xu, J., Wiest, D.L., Favorava, O.O., Knepper, J.E., Testa, J.R. (2009) Recurrent chromosomal rearrangements implicate oncogenes contributing to T-cell lymphomagenesis in Lck-MyrAkt2 transgenic mice. Genes Chromosomes Cancer, 48(9): 786-794.
- Altomare, D.A., Menges, C.W., Pei, J., Zhang, L., Skele-Stump, K.L., Carbone, M., Kane, A.B., Testa, J.R. (2009) Activated TNFα/NFĸB pro-survival signaling via down regulation of Fas-associated factor-1 in asbestos-induced mesotheliomas from Arf knock-out mice. Proc. Natl. Acad. Sci., USA, 106(9): 3420-3425.