During the previous funding period, we defined multiple antitumor activities associated with E1A gene expression and established an appropriate animal model to evaluate the anti-ovarian cancer activity of an E1Aliposome complex. A phase I study using ElA-liposome complex targeting of breast and ovarian cancers was completed and reported during the previous funding period (Appendix 1-J. Clin. Oncol. 19:3422-3433, 2001). Based on this experience, we initiated a phase II trial of intraperitoneal single-agent E1A gene therapy in patients with recurrent ovarian cancer in 2001. Because of the small number of patients who met the eligibility requirements, we terminated the phase II trial and initiated a new phase l/ll trial that combines chemotherapy with E1A gene therapy and that has more appropriate eligibility requirements. This phase l/ll trial has been opened and has begun to accrue patients. In the competitive renewal, we will continue both preclinical studies and clinical trials to ensure the development of an effective therapeutic approach for ovarian cancer that utilizes gene therapy. To achieve this goal, we propose the following three Specific Aims:
Specific Aim 1 : To complete the phase l/ll trial of E1A gene therapy combined with chemotherapy. Using a novel trial design, we will perform a randomized phase l/ll trial in which one arm receives weekly i.v. paclitaxel (to establish a concurrent control group for a heterogeneous group of patients) and the other arm receives weekly i.v. paclitaxel with i.p. liposomal E1A gene therapy at different does levels. This study will define the toxicity, maximum tolerated dose (MTD), clinical response rate, and progression-free survival of weekly paclitaxel plus E1A- p d complex treatment. Biopsies will be obtained to monitor therapy at the cellular level.
Specific Aim 2 : To develop an ovarian cancer-specific gene delivery system and expression vector. Two approaches will be used to improve systemic i.v. targeting of E1A gene therapy to treat ovarian cancer xenografts: 1) development of ovarian cancer-specific promoter elements and 2) conjugation of liposomes with targeting peptides, folate ligand, and anti?folate receptor antibodies.
Specific Aim 3 : To develop an effective combination of E1A gene therapy with other agents in a preclinical ovarian cancer model. Using ovarian cancer xenografts, we will test the efficacy and toxicity of E1A gene therapy in combination with cytotoxic drugs used to treat ovarian cancer patients as well as novel biologic agents (TNFa and TRAIL). Preliminary data suggest that these agents may exert synergistic antitumor activity at subtoxic doses. The clinical data from Aim 1 and preclinical insights from Aims 2 and 3 can be combined in the future to design novel and potentially even more effective therapeutic strategies.
| Jung, Youn-Sang; Wang, Wenqi; Jun, Sohee et al. (2018) Deregulation of CRAD-controlled cytoskeleton initiates mucinous colorectal cancer via ?-catenin. Nat Cell Biol 20:1303-1314 |
| Jung, Youn-Sang; Jun, Sohee; Kim, Moon Jong et al. (2018) TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/?-catenin signalling. Nat Cell Biol 20:1421-1433 |
| Nagaraja, Archana S; Dood, Robert L; Armaiz-Pena, Guillermo et al. (2018) Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 3: |
| Seo, Hyeonglim; Choi, Ikjang; Whiting, Nicholas et al. (2018) Hyperpolarized Porous Silicon Nanoparticles: Potential Theragnostic Material for 29 Si Magnetic Resonance Imaging. Chemphyschem 19:2143-2147 |
| Mitamura, T; Pradeep, S; McGuire, M et al. (2018) Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene 37:722-731 |
| Yuan, Jiao; Hu, Zhongyi; Mahal, Brandon A et al. (2018) Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell 34:549-560.e9 |
| Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2018) Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations. Cancer Chemother Pharmacol 81:255-267 |
| Haemmerle, Monika; Stone, Rebecca L; Menter, David G et al. (2018) The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell 33:965-983 |
| Allen, Julie K; Armaiz-Pena, Guillermo N; Nagaraja, Archana S et al. (2018) Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res 78:3233-3242 |
| Umamaheswaran, Sujanitha; Dasari, Santosh K; Yang, Peiying et al. (2018) Stress, inflammation, and eicosanoids: an emerging perspective. Cancer Metastasis Rev 37:203-211 |
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