Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

INVESTIGATION OF NOVEL THERAPIES AND DELIVERY SYSTEMS FOR TREATMENT OF HEPATOCELLULAR CARCINOMA

Badawi, Mohamed A
http://rave.ohiolink.edu/etdc/view?acc_num=osu1511888029983406

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths worldwide. While management options of early stage hepatocellular carcinoma are diverse and result in good clinical outcomes, the disease prognosis for advanced stage hepatocellular carcinoma remains poor. Sorafenib, a tyrosine kinase inhibitor, is FDA approved as the first line treatment for hepatocellular carcinoma. However sorafenib exhibits low response rates and minimal improvement in survival. This highlights the need to develop new therapies for treatment of advanced hepatocellular carcinoma. mTOR pathway is commonly activated in HCC making it an attractive target for therapy. However, the rapalogs, allosteric inhibitors of mTORC1, failed to show improved clinical outcomes. We investigated the potential use of the ATP-competitive mTOR inhibitor, INK128 for treatment of HCC. We evaluated INK128 in CD44low and CD44high HCC cell lines, and in those cell lines with acquired sorafenib resistance. CD44 was significantly increased in Huh7 HCC cells made resistant to sorafenib. Forced expression of CD44 enhanced cellular proliferation and migration, and rendered the cells more sensitive to the anti-proliferative effects of INK128. INK128 showed better anti-proliferative activity in CD44high and sorafenib resistant cells compared to CD44low cells. Moreover, a combination of INK128 and sorafenib showed improved anti-proliferative effects in CD44high HCC cells. INK128 was efficacious at reducing tumor growth in CD44high SK-Hep1 xenografts in mice when given as monotherapy or in combination with sorafenib. Our findings suggest that ATP-competitive mTOR inhibitors may be effective in treating advanced, CD44-expressing HCC patients who are insensitive or resistant to sorafenib. Next, we evaluated extracellular vesicles (EVs) as a delivery system for oligonucleotide therapy in HCC. We present a thorough analysis of the immunogenic potential of human-cell derived EVs in preclinical mouse models. We report a lack of toxicity or immune response in mice after repeated dosing of EVs (10 doses). We also evaluated the pharmacokinetic properties of antisense miR-221 (ASO-221) loaded EVs in plasma, liver and tumor of SK-Hep1 orthotopic xenograft mice. Therapeutic levels of ASO-221 were achieved in both plasma and liver. While ASO-221 concentrations in the tumor xenograft did not reach our target concentration relevant to clinical application, pharmacokinetic simulations predict that therapeutic concentrations could be achieved by adjusting the dosage regimen. In summary we report here the effectiveness of INK128 in treatment of CD44 positive and sorafenib resistant HCC. We also demonstrate the safety and pharmacokinetics of human-cell derived EVs as a vehicle for delivery of therapeutic cargo in preclinical mouse models. These findings have great potential for development of new therapies and delivery methods for treatment of advanced HCC.
Thomas Schmittgen, PhD (Advisor)
Mitch Phelps, PhD (Advisor)
Sharyn Baker, PhD (Committee Member)
Jack Yalowich, PhD (Committee Member)
132 p.
Pharmaceuticals
Hepatocellular carcinoma; miRNA; extracellular vesicles; exosomes; INK128; mTOR inhibitors; pharmacokinetics

Recommended Citations

Citations

  • Badawi, M. A. (2017). INVESTIGATION OF NOVEL THERAPIES AND DELIVERY SYSTEMS FOR TREATMENT OF HEPATOCELLULAR CARCINOMA [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1511888029983406

    APA Style (7th edition)

  • Badawi, Mohamed. INVESTIGATION OF NOVEL THERAPIES AND DELIVERY SYSTEMS FOR TREATMENT OF HEPATOCELLULAR CARCINOMA. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1511888029983406.

    MLA Style (8th edition)

  • Badawi, Mohamed. "INVESTIGATION OF NOVEL THERAPIES AND DELIVERY SYSTEMS FOR TREATMENT OF HEPATOCELLULAR CARCINOMA." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1511888029983406

    Chicago Manual of Style (17th edition)

osu1511888029983406
30
© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.