PROJECT 3b (replaced Project 3a in 2013)
Safety and pharmacokinetics studies after repeated intravenous JO injection (alone and in combination with PLD) in Macaca fascicularis.
André Lieber. PhD - University of Washington
Charles Drescher, MD - Fred Hutchinson Cancer Research Center
Our goal is to evaluate a novel approach to improving therapeutic response in epithelial ovarian cancer. One of the key features of epithelial tumors is tight junctions, which link tumor cells to one another and pose physical barriers to intratumoral penetration and dissemination of cancer therapeutics. A recombinant therapeutic protein, JO-1, opens up the intercellular junctions between tumor cells to increase penetration of cancer therapeutics into tumors. Markedly enhanced therapeutic effects have been demonstrated when JO-1 is combined with a variety of chemotherapy drugs as well as monoclonal antibodies in a range of cancers in over 25 mouse models. Toxicology studies carried out in mice and monkeys have shown that JO-1 is safe and well-tolerated. Additional in vivo studies have demonstrated that JO-1 has minimal immunogenicity, and antibodies, when purposely generated against JO-1, do not affect its activity. We are now focused on the clinical translation of JO-1 in combination with PEGylated liposomal doxorubicin (PLD)/Doxil® for ovarian cancer therapy. PLD is a standard treatment for patients with ovarian cancer that has progressed or recurred after platinum-based chemotherapy. Although commonly used, response rates to PLD are low, the response duration is short, and toxicity is significant. In preclinical studies in mouse models of ovarian cancer, we have shown that co-administration of JO-1 increases the efficacy and reduces the toxicity of PLD.
The Specific Aim of this proposal is to generate preclinical safety and pharmacokinetics data for repeated intravenous JO-1 injection (alone and in combination with PLD) in Macaca fascicularis.
We have finished safety and efficacy studies with JO-1 and PLD in huDSG2 transgenic mice. However, it is unclear whether the huDSG2-mouse system completely models a homologous system with human DSG2 in human cells. A better model is therefore non-human primates. DSG2 biodistribution in the tested NHP species, Macaca fascicularis, is similar to that in humans and JO-1 binds to monkey DSG2.
This project lays the groundwork for a clinical trial that is proposed for the next SPORE funding cycle.
Project 3a Publications (Tewari)
1. Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK, Hindson BJ, Vessella RL, and Tewari M. Absolute quantification by droplet digital PCRversus analog real-time PCR. Nat Methods. 2013 Oct;10(10):1003-5. doi: 10.1038/nmeth.2633. Epub 2013 Sep 1. PMID:23995387. PubMed Link ↗
2. Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK, Hindson BJ, Vessella RL, and Tewari M. Absolute quantification by droplet digital PCRversus analog real-time PCR. Nat Methods. 2013 Oct;10(10):1003-5. doi: 10.1038/nmeth.2633. Epub 2013 Sep 1. PMID:23995387. PubMed Link ↗
3. Knouf E, Garg K, Arroyo J, Correa Y, Sarkar D, Parkin R, Wurz K, O'Briant K, Godwin A, Urban N, Ruzzo W, Gentleman R, Drescher C, Swisher E, Tewari M. An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription. Nucleic Acids Res. 2012 Jan 1;40(2):499-510. PMCID: PMC3258134. PubMed Link ↗
4. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nature reviews Genetics. 2012 May;13(5):358-69. Invited Review. PubMed Link ↗
5. Pritchard CC1, Kroh E, Wood B, Arroyo JD, Dougherty KJ, Miyaji MM, Tait JF, Tewari M. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res (Phila). 2012 Mar;5(3):492-7. doi: 10.1158/1940-6207.CAPR-11-0370. Epub 2011 Dec 12. NIHMS344003. PubMed Link ↗
6. Bendoraite A, Knouf EC, Garg KS, Parkin RK, Kroh EM, O'Briant KC, Ventura AP, Godwin AK, Karlan BY, Drescher CW, Urban N, Knudsen B, Tewari M. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: Evidence supporting a mesothelial-to-epithelial transition. Gyn Onc. 2010 Jan;116(1):117-25. PMCID: PMC2867670. PubMed Link ↗
7. Kroh EM, Parkin RK, Mitchell PS, Tewari M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods. 2010 Apr;50(4):298-301. NIHMID: NIHMS177877. PubMed Link ↗
8. Wilson BK, Mentele T, Bachar S, Knouf E, Bendoraite A, Tewari M, Pun SH, Lin LY. Nanostructure-enhanced laser tweezers for efficient trapping and alignment of particles. Optics express. 2010 Jul 19;18(15):16005-13. PMC3387742. PubMed Link ↗
9. Wurz K, Garcia RL, Goff BA, Mitchell PS, Lee JH, Tewari M, Swisher EM. miR-221 and miR-222 alterations in sporadic ovarian carcinoma: Relationship to CDKN1B, CDKNIC and overall survival. Genes Chromosomes Cancer. 2010 Jul;49(7):577-84. PMCID: PMC2869465. PubMed Link ↗
Project 3b Publications (Lieber)
1. Strauss R, Bartek J, Lieber A. Analysis of EMT by flow cytometry and immunohistochemistry. Methods Mol Biol. 2013;1049:355-68. doi: 10.1007/978-1-62703-547-7_27. PMID: 23913230. PubMed Link ↗
2. Wang H, Yumul R, Cao H, Ran L, Fan X, Richter M, Epstein F, Gralow J, Zubieta C, Fender P, Lieber A. Structural and functional studies on the interaction of adenovirus fiber knob domains and desmoglein 2. J Virol. 2013. Nov;87(21):11346-62. doi: 10.1128/JVI.01825-13. Epub 2013 Aug 14. PMCID:PMC3807342. PubMed Link ↗
3. Beyer I, Cao H, Persson J, Song H, Richter M, Feng Q, Yumul R, van Rensburg R, Li ZY, Berenson R, Carter D, Roffler S, Drescher C, Lieber A. Co-administration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs. Clin Cancer Res. 2012 Jun 15;18(12):3340-51. PMCID: PMC3547677. PubMed Link ↗
4. Beyer I, van Rensburg R, Strauss R, Li Z, Wang H, Persson J, Yumul R, Feng Q, Song H, Bartek J, Fender P, Lieber A. Epithelial Junction Opener JO-1 Improves Monoclonal Antibody Therapy of Cancer. Cancer Res. 2011 Nov 15;71(22):7080-90. PMCID: PMC3217128. PubMed Link ↗
5. Liu Y, Tuve S, Persson J, Beyer I, Yumul R, Li Z, Tragoolpua K, Hellström KE, Roffler S, Lieber A. Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models. Cancer Gene Therapy. 2011 Jun;18(6):407-18. PMCID: PMC3096725. PubMed Link ↗
6. Wang H, Li ZY, Liu Y, Persson J, Beyer I, Möller T, Koyuncu D, Drescher MR, Strauss R, Zhang XB, Wahl JK, Urban N, Drescher C, Hemminki A, Fender P, Lieber A. Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11, and 14. Nature Medicine. 2011 Jan; 17(1):96-104. PMCID: PMC3074512. PubMed Link ↗
7. Wang H, Li Z, Yumul R, Lara S, Hemminki A, Fender P, Lieber A. Multimerization of adenovirus serotype 3 fiber knob domains is required for efficient binding of virus to desmoglein 2 and subsequent opening of epithelial junctions. Journal of Virology, 2011 85(13):6390-402. PMCID: PMC3112237. PubMed Link ↗