Lung cancer is one of the leading causes of cancer deaths in the US with 5 year survival rate of ~15% due to the lack of specificity, poor efficacy, and side effects associated with current therapies. The lung cancer incidences are highest in African Americans, American Indians/Alaska Natives, and Pacific Islanders. The non- small cell lung cancer (NSCLC) is most prevalent (~80% occurrence) among lung cancer patient. NSCLC has wide molecular heterogeneity, which mandates simultaneous targeting of multiple pathways. Vascular endothelial growth factor (VEGF) gene over-expression (in ~90% of NSCLC's) is associated with growth, survival, and angiogenesis. The use of VEGF antibodies to block VEGF has been limited due to their non- specificity, poor efficacy and adverse effects. In this line, silencing VEGF using VEGF-siRNA (siRNA-V) will be an effective option, however, the clinical utility of siRNA has been hampered due to non-specific effect, poor cell permeation and rapid in vivo elimination. The use of nanocarriers for siRNA-V delivery will help to overcome these issues. Furthermore, PI3K/mTOR was found to be predominantly activated in NSCLC, additionally, mTOR inhibition results in compensatory activation of Akt (a promoter of cell survival and proliferation). Hence, simultaneous targeting of mTOR and Akt along with VEGF silencing will pave the way for more effective NSCLC therapy. PF-04691502 (PF0) is a potent PI3K/mTOR/AKT inhibitor. Targeting mTOR/AKT pathway using PF0 along with VEGF silencing will complement the clinical potential of these bioactives against NSCLC. LHRH receptors are over-expressed on NSCLC cells with restricted expression on normal tissues. For the first time, we are herewith proposing the development of biodegradable, LHRH receptor-targeted PEGylated hybrid nanocarrier (HNC) for the simultaneous targeted delivery of siRNA-V and PF0 (HNC-VP-L) to NSCLC. We hypothesize that the development of stable, LHRH receptor-guided PEGylated albumin-chitosan based hybrid nanocarriers will deliver the synergistically-acting siRNA-V and PF0 in a targeted fashion to NSCLC tumors and will result in a significant improvement of anticancer activity, at lower doses, while overcoming adverse effects. We plan to test our hypothesis by following specific aims:
Aim 1 : To evaluate the combination effect of siRNA-V and PF0;development and evaluation of HNC-VP-L;
Aim 2 : To evaluate the in vivo efficacy of HNC-VP-L in nude mice;
and Aim 3 : To elucidate mechanism, evaluate metastasis and toxicological parameters. We plan to utilize LHRH receptor positive and LHRH receptor negative tumor cell based in vitro as well as in vivo models (xenograft and orthotropic) to investigate the targeting potential of developed nan carriers. Our approach aims at developing a more effective treatment modality for the treatment of NSCLC to reduce the burden of lung cancer disparity. The long term goal is to advance this novel delivery concept to the clinic level. We will be able to establish the first nan carrier based extramural cancer program in the state of Hawaii and train the unrepresented students through this project.

Public Health Relevance

Lung cancer is one of the leading causes of cancer deaths and has poor survival rates compared to other types of cancers. The lung cancer incidence is highest in African Americans, underserved Whites, American Indians/Alaska Natives, and Pacific Islanders thereby the disparities in treatment outcomes exists. The non- small cell lung cancer (NSCLC) is prevalent (~80% occurrence) among lung cancer patient. The site specific delivery of therapeutic agents to tumors is still a major challenge in cancer research. NSCLC has wide molecular heterogeneity and therefore, warrants targeting of multiple pathways for improving the outcome among lung cancer patients. The tumor specific delivery of therapeutic agents targeting multiple pathways involved in NSCLC progression represents a potential approach to treat the NSCLC owing to its advantages over existing treatment modalities. In this regard, some attempts have been made to deliver chemotherapeutic agents using Nan carriers, however, our proposed combination therapy of PF-04691502 (PF0), an ATP- competitive PI3K/mTOR/AKT dual inhibitor and siRNA-V using targeted hybrid nan carriers of natural biopolymers (albumin and chitosan) for the treatment of NSCLC is novel and has not been studies so far. Stable, biodegradable, and tumor-specific LHRH receptor-guided hybrid nan carriers loaded with synergistically acting PF0 and siRNA-V will selectively deliver PF0 and siRNA-V to NSCLC and exert significant antitumor activity while sparing normal tissues. This is the first time targeted hybrid Nan carriers are being explored for the simultaneous co-delivery of PF0 and siRNA-V for the treatment of NSCLC. This project combines a highly innovative and collaborative approach with advanced nanotechnologies and in vivo cancer cell biology including LHRH receptor positive and LHRH receptor negative tumor cell based models to evaluate developed targeted delivery system. Our proposed studies are aimed at developing a more effective and reliable treatment modality that can be safely used for the treatment of NSCLC and also help to reduce the burden of lung cancer disparity. We will be able to establish the first Nan carrier based cancer program in the state of Hawaii, obtain extramural NIH/DOD funding, and train the unrepresented students through this project. The results will also provide the proof-of-concept for similar targeted Nan carrier therapies against other forms of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
1SC3GM109873-01
Application #
8667358
Study Section
Special Emphasis Panel (ZGM1-TWD-6 (SC))
Program Officer
Okita, Richard T
Project Start
2014-05-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$89,291
Indirect Cost
$14,291
Name
University of Hawaii at Hilo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
195738039
City
Hilo
State
HI
Country
United States
Zip Code
96720