Projects in the Altomare lab center around the following paradigm: 1) characterize genetically defined mouse models for their ability to mimic the molecular pathology of human tumors, 2) define common signaling pathways that are aberrant in both the mouse and human tumors, 3) perform preclinical testing of therapeutics or small molecule inhibitors in mouse models to determine efficacy in inhibiting tumor progression, 4) use in vitro and in vivo preclinical models to improve upon the functionality of small molecule inhibitors, 5) delineate biomarkers that may be helpful in determining responders vs. non-responders.  Current research projects focus predominantly on understanding tumor progression and targeting in pancreatic and ovarian tumors.  Special emphasis is placed on AKT signaling as a hallmark pathway important for tumor growth, progression and therapeutic resistance.    

AKT Function in Ovarian Tumor Cell Invasiveness and In Vivo Pathogenesis                

 High morbidity of ovarian cancer is largely attributed to rapid proliferation of tumor cells and spread or dissemination to multiple abdominal organs.   The molecular and signaling events that are important in this process are still largely unknown.  Amplification and overexpression of AKT2 was found in ovarian carcinomas.  We and others showed that all three AKT kinases, designated AKT1, AKT2 and AKT3, are hyperactivated in at least 40% of ovarian tumors.  In order to fully capitalize on the benefits of therapeutically targeting components of the AKT pathway, many questions remain regarding the essential role of AKT to specific stages of tumor progression, or whether AKT1 or AKT2 isoforms might differentially regulate particular stages of tumor pathogenesis.  For example, in breast cancer cells AKT1 may have a dual role in acting pro-oncogenically by suppressing apoptosis and anti-oncogenically by suppressing invasion and metastasis, while AKT2 may facilitate invasion. These novel findings highlight the need for a better understanding of substrate specificity and protein interactors since non-isoform specific inhibitors of AKT activity and/or tumor cell dependence on a particular isoform may adversely promote tumor metastasis.   The overall hypothesis is that an improved understanding of how different AKT isoforms cooperate with other molecular perturbations to facilitate tumor cell proliferation, survival and/or metastasis may lead to a more precise suppression of tumor dissemination through the targeting of AKT signaling without affecting other peripheral functions.  The objective is to use both ovarian cancer cells and genetically defined mouse models to provide mechanistic rationale for the role of AKT activation in ovarian tumor progression, underscore the role of specific AKT isoforms in the pathogenesis of ovarian cancer, and define molecular targets for improved ovarian cancer therapy.   

AKT Function in Pancreatic Tumor Cell Invasiveness and In Vivo Pathogenesis     

 Like ovarian cancer, pancreatic ductal adenocarcinoma is a highly aggressive, deadly disease characterized by invasive, metastatic progression and profound resistance to conventional therapies.  Delineation of the histological and genetic perturbations associated with this disease has improved its classification, but many aspects of pancreatic cancer biology remain unresolved. The central hypothesis of this proposal is that AKT cooperates with other genetic perturbations mapped within the classical pancreatic tumor progression cascade to facilitate tumor cell proliferation and survival.  The objective of these studies is to use genetically defined mouse models to provide mechanistic insights regarding the role of AKT activation in pancreatic tumorigenesis and to determine if AKT cooperates with Kras to drive pancreatic tumor progression.  Specifically, we propose to determine whether molecular alterations found in pancreatic tumors from mice expressing MyrAkt1 (active Akt1) or MyrAkt1;KrasG12D recapitulate molecular events recognized as being important for human pancreatic tumorigenesis. Translational significance is to directly test the function of active AKT in the pathogenesis of pancreatic cancer, and to define better molecular targets for pancreatic cancer prevention and therapy.  

Recent Publications 

1.       Altomare, D.A., Tanno, S., De Rienzo, A., Klein-Szanto, A.J., Tanno, S., Skele, K.L., Hoffman, J.P. and Testa, J.R. (2002) Frequent activation of AKT2 kinase in human pancreatic carcinomas.  J. Cell. Biochem. 87:470-476.  PMID: 14735903

2.       Altomare, D.A., Wang, H.Q., Skele, K.L., De Rienzo, A., Klein-Szanto, A.J., Godwin, A.K. and Testa, J.R. (2004) AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23:5853-5857.  PMID: 15208673

3.       Subhi, A.L, Tang, B., Balsara, B.R., Altomare, D.A., Testa, J.R., Cooper, H.S., Hoffman, J.P., Meropol, N.J. and Kruger, W.D.  (2004) Loss of methylthioadenosine phosphorylase and elevated ornithine decarboxylase is common in pancreatic cancer.  Clin. Cancer Res., 10: 7290-7296.  PMID: 15534104

4.       Xiao, G.-H., Gallagher, R., Shetler, J., Skele, K., Altomare, D.A., Pestell, R.G., Jharwar, S. and Testa, J.R. (2005) The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression. Molec. Cell. Biol., 25: 2384-2394.  PMID: 15743831

5.       Wang, H.Q., Altomare, D.A., Skele, K.L., Di Cristofano, A., Kuhajda, F.P. and Testa, J.R. (2005) Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene, 24: 3574-3582.  PMID: 15806173

6.       Cacciotti, P., Barbone, D., Porta, C., Altomare, D.A., Testa, J.R., Mutti, L., Gaudino, G. (2005) SV40-Dependent AKT activity drives mesothelial cell transformation after asbestos exposure. Cancer Res. 65: 5256-5262.  PMID: 15958571

7.       Altomare, D.A., You, H., Xiao, G.-H., Ramos-Nino, M.E., Skele, K.L., De Rienzo, A.,  Jhanwar, S.C., Mossman, B.T., Kane, A.B. and Testa, J.R. (2005) Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth.  Oncogene, 24: 6080-6089.  PMID: 15897870

8.       Altomare, D.A.,Vaslet, C.A., Skele, K.L, De Rienzo, A., Devarajan, K., Jhanwar, S.C., McClatchey, A.I., Kane, A.B. and Testa, (2005) J.R. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res. (Priority Report), 65: 1-5.  PMID: 16166281

9.       Altomare, D.A. and Testa, J.R. (2005) Perturbations of the AKT signaling pathway in human cancer.  Oncogene, 24: 7455-7464.  PMID: 16288292

10.     Ramos-Nino, M., Testa, J.R., Altomare, D.A., Pass, H.I., Carbone, M., Bocchetta, M. and Mossman, B.T. (2006) Cellular and molecular parameters of mesothelioma.  J. Cell. Biochem., 98:723-734.  PMID: 16795078

11.     Mabuchi, S., Altomare, D.A., Connolly, D.C., Klein-Szanto, A.J.P., Litwin, S., Hoelzle, M.K., Hensley, H.H., Hamilton, T.C. and Testa, J.R. (2007) RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer, Cancer Res. (Priority Report), 67:2408-2413. PMID: 17363557   

12.     Garland, L.L., Rankin, C.J., Gandara, D.R., Rivkin, S.E., Scott, K.M., Nagle, R.B., Altomare, D.A., Klein-Szanto, A.J.P., Testa, J.R. and Borden, E.C. (2007) A phase II study of oral EGFR tyrosine kinase inhibitor Erlotinib in patients with malignant pleural mesothelioma: A Southwest Oncology Group Study. J. Clin. Oncol., 25:2406-24

13.  PMID: 1755795413.     Mabuchi, S., Altomare, D.A., Cheung, M., Zhang, L., Poulikakos, P., Hensley, H.H., Schilder, R.J., Ozols, R.F. and Testa, J.R. (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin. Cancer Res., 13: 4261-4270.  PMID: 17634556

14.     Tan, Y.F., Timakhov, R.A.,  Rao, M., Altomare, D.A., Xu, J., Liu, Z., Gao, Q., Jhanwar, S.C., Di Cristofano, A., Wiest, D.L., Knepper, J.E., Testa, J.R. (2008) A novel recurrent chromosomal inversion implicates Dlx5 in T-cell lymphomas from Lck-Akt2 mice. Cancer Res., 68: 1296-1302.  PMID: 18316591

15.     Ramos-Nino, M.E., Blumen, S.R., Sabo-Attwood, T., Pass, H., Carbone, M., Testa, J.R., Altomare, D.A. and Mossman, B.T. (2008) HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. Amer J Resp Cell Mol Biol, 38: 209-217.  PMID: 17872495  PMCID: 2214675

16.     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: 3420-3425.  PMID: 19223589   PMCID:  2644256

17.     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, 48:786-794.  PMID: 19530243  PMCID: 2739734

18.     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: 2528-2534.  PMID: 19597341  PMCID: 2739729

19.     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: 5404-5413. PMID: 19690197 NIHMS: 125079  PMCID: Pending