Pancreatic cancer is one of the most aggressive malignancies. In order to change its devastating prognosis, a novel therapeutic approach must be developed. The conditionally replicative adenovirus (CRAd) is one such promising therapeutic modality for pancreatic cancer. CRAd clinical trials to date have established the safety of these agents and identified their current limitations, and our laboratory is developing safer and more potent CRAds for therapeutic use. In this proposal, we plan to develop of a new generation pancreatic cancer CRAds with superior therapeutic potency and disease selectivity by exploiting the specific molecular features of this disease itself. We have developed new generation vector modifications which can provide a different level of transduction efficiency, and recent advancements in pancreatic cancer molecular biology have identified several target-worthy molecular features. The CRAds engineered for better potency and target specificity will be outfitted with anti-tumor effectors modifying pancreatic cancer tumor environment. New vectors will be tested not only with mouse subcutaneous and orthotopic xenograft models but also with models showing close relevance to human clinical situations. A hamster syngeneic pancreatic cancer model which allows human adenoviral replication will provide deeper insight into CRAd biology. The CRAd function analysis based on tissue slice technology permits us to evaluate CRAds in patient materials. These assessments will be further strengthened by the non-invasive viral replication monitoring capability we have developed. The development and analysis of next-generation CRAds will precede a clinically meaningful and novel therapy for pancreatic cancer.
The poor prognosis for pancreatic cancer drives our effort to develop new therapeutic modalities. More potent and safer CRAds can be fashioned into a clinically effective therapeutics. Also, detailed analyses of CRAd functionality in clinically relevant models will provide the crucial information required to advance vector design. The outcome of this project will lead to a clinically usable therapeutics for pancreatic cancer.
|LaRocca, Christopher J; Han, Joohee; Gavrikova, Tatyana et al. (2015) Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer. Surgery 157:888-98|
|Kosaka, Takashi; Davydova, Julia; Ono, Hidetaka A et al. (2015) Imaging and Antitumoral Effect of a Cyclo-oxygenase 2-specific Replicative Adenovirus for Small Metastatic Gastric Cancer Lesions. Anticancer Res 35:5201-10|
|Yamamoto, Yuki; Goto, Naoko; Miura, Kazuki et al. (2014) Development of a novel efficient method to construct an adenovirus library displaying random peptides on the fiber knob. Mol Pharm 11:1069-74|
|Miura, Yoshiaki; Yamasaki, Satoshi; Davydova, Julia et al. (2013) Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library. Mol Ther 21:139-48|
|Yamasaki, Satoshi; Miura, Yoshiaki; Davydova, Julia et al. (2013) A single intraduodenal administration of human adenovirus 40 vaccine effectively prevents anaphylactic shock. Clin Vaccine Immunol 20:1508-16|
|Oneal, M J; Trujillo, M A; Davydova, J et al. (2013) Effect of increased viral replication and infectivity enhancement on radioiodide uptake and oncolytic activity of adenovirus vectors expressing the sodium iodide symporter. Cancer Gene Ther 20:195-200|
|Oneal, Michael J; Trujillo, Miguel A; Davydova, Julia et al. (2012) Characterization of infectivity-enhanced conditionally replicating adenovectors for prostate cancer radiovirotherapy. Hum Gene Ther 23:951-9|
|Armstrong, Leonard; Arrington, Amanda; Han, Joohee et al. (2012) Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy. Am J Surg 204:741-50|
|Armstrong, Leonard; Davydova, Julia; Brown, Eric et al. (2012) Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy. Surgery 152:114-22|
|Pham, Lan; Beyer, Kayla; Jensen, Eric D et al. (2011) Bone morphogenetic protein 2 signaling in osteoclasts is negatively regulated by the BMP antagonist, twisted gastrulation. J Cell Biochem 112:793-803|
Showing the most recent 10 out of 61 publications