We seek to use a novel cell-internalization SELEX (Systemic Evolution of Ligands by Exponential enrichment) to isolate thioaptamer-conjugated liposomal nanoparticles (TA-NP) that internalize and deliver its siRNA into the cytosol of tumor initiating cells (TIC) of oral squamous cell carcinoma, minimizing off-target delivery. In vivo delivery and release of siRNA from the endosomes to cytosol remain the two biggest obstacles for translating anticancer siRNA drugs to the clinic. Oral squamous cell carcinoma commonly known as oral cancer (OC) is the most common malignancy of head and neck with high global public health impact. Fanconi anemia (FA) is a hereditary cancer syndrome that predisposes one to OC. Evidence points to TIC as the key driver of field cancerization, resistance to therapy and disease relapse. A therapeutic vehicle that selectively targets and delivers anticancer drugs to TIC offers great promise for OC treatment. Our data and published studies show: (1).TIC is more enriched in FA-OC than sporadic OC; (2) Chk1 and CD147 promote TIC survival and chemoresistance and its overexpression contribute to poor prognosis in OC. The main goal of this application is to use FA- OC-TIC as target cells to develop TA- NP for the cytosolic delivery of siRNA. We hypothesize that isolated TA-NP will facilitate targeted delivery of siRNA to OC-TIC cytosol, and silence CD-147/Chk1 in OC-TIC's, disrupting their niche and rendering them chemosensitive and susceptible to elimination by chemotherapy with gemcitabine.
Aims :(1): Elucidate the effect of RNAi mediated silencing of CD147/Chk1 in FA-OC-TIC; (2A): Select a list of TA-Liposomal NP (TA-NP) specific for TIC fraction of FA-OC cells, while avoiding hepatocyte uptake, using a positive and negative cell-uptake based SELEX; (2B): Determine the selected TA-NP's targeting specificity and therapeutic efficacy in in vitro and in murine OC xenografts. We will isolate ALDH+ TIC in FA-OC cell lines and examine the effects of siRNA-mediated silencing of CD147 and Chk1. (2) We will use a modified conjugate SELEX with positive and negative selections to identify OC-TIC-specific internalizing TA-NP. (3) We will validate TIC-targeting specificity and silencing efficacy of isolated TA-NP-sRNA in vitro and in murine orthotopic FA-OC xenografts. RNAi mediated inhibition of CD147 and Chk1 in OC-TIC will yield valuable insight into their potential role in the tumor propagating and chemoresistant properties of OC-TIC. The proposed TA-NP will have important clinical potentials for in vivo delivery of therapeutic and imaging agents targeting the OC-TIC.

Public Health Relevance

Oral cancer is the most common malignancy of the head and neck region and is associated with a poor prognosis due frequent local and distant tumor relapse after treatment. Tumor relapse is caused by the persistence of cancer stem cells also known as tumor initiating cells. These tumor initiating cells are inherently chemoradiation therapy resistant and hence are not eliminated with the current treatments. Our project is aimed at developing a therapeutic modality that can selectively target the tumor initiating cells and deliver siRNA drugs to overcome their therapeutic resistance in order to improve disease free survival and cure rate in patients with oral cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE024392-04
Application #
9283244
Study Section
Special Emphasis Panel (ZDE1-RK (24))
Program Officer
Wang, Chiayeng
Project Start
2014-07-25
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
$383,932
Indirect Cost
$91,422
Name
University of Texas Health Science Center Houston
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Yang, Eric C; Schwarz, Richard A; Lang, Alexander K et al. (2018) In Vivo Multimodal Optical Imaging: Improved Detection of Oral Dysplasia in Low-Risk Oral Mucosal Lesions. Cancer Prev Res (Phila) 11:465-476
Yang, Eric C; Tan, Melody T; Schwarz, Richard A et al. (2018) Noninvasive diagnostic adjuncts for the evaluation of potentially premalignant oral epithelial lesions: current limitations and future directions. Oral Surg Oral Med Oral Pathol Oral Radiol 125:670-681
Mu, Qingshan; Annapragada, Akshaya; Srivastava, Mayank et al. (2016) Conjugate-SELEX: A High-throughput Screening of Thioaptamer-liposomal Nanoparticle Conjugates for Targeted Intracellular Delivery of Anticancer Drugs. Mol Ther Nucleic Acids 5:e382
Mu, Qingshan; Annapragada, Akshaya; Srivastava, Mayank et al. (2016) Conjugate-SELEX: A High-throughput Screening of Thioaptamer-liposomal Nanoparticle Conjugates for Targeted Intracellular Delivery of Anticancer Drugs. Mol Ther Nucleic Acids 5:e382
Hoch, K; Volk, D E (2016) Structures of Thymosin Proteins. Vitam Horm 102:1-24
Rowan, Stephanie D; Hu, Shirley L; Brotzman, Jacob S et al. (2015) Knowledge Assessment of the Dental Community in Texas on the Role of Human Papilloma Virus in Oropharyngeal Cancer. Tex Dent J 132:528-36
Yu, Yau-Hua; Morales, Jose; Feng, Lei et al. (2015) CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: a tissue microarray study. Oral Surg Oral Med Oral Pathol Oral Radiol 119:553-65
Floriano, P N; Abram, T; Taylor, L et al. (2015) Programmable bio-nanochip-based cytologic testing of oral potentially malignant disorders in Fanconi anemia. Oral Dis 21:593-601
Vigneswaran, Nadarajah; Williams, Michelle D (2014) Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral Maxillofac Surg Clin North Am 26:123-41
Tackett, Bryan C; Sun, Hongdan; Mei, Yu et al. (2014) P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 307:G1073-87

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