Malignant melanoma is the most deadly of all skin cancers. Despite its lethality, no targeted topical chemopreventive agents exist to inhibit this cancer in its earliest forms or when cells are present in the lymphatic system in the proximity of the early primary lesion. Among possible chemopreventive targets is Akt3 whose activity increases in ~70% of tumors to promote melanoma development. Targeting early melanocytic lesion cells using siRNA-based agents to inhibit Akt3 and other key kinases could be important for targeted melanoma chemoprevention, but delivery of siRNA remains a challenge. Currently, no technology or approach utilizes siRNA as a chemopreventive agent to inhibit early melanoma development. This application focuses on melanoma chemoprevention by targeting early melanocytic lesions using siRNA-based agents to inhibit Akt3 and mutant V600EB-Raf, GSK31 or Wee1 kinases, which are shown to synergistically inhibit melanocytic lesion cells. Thus, the central hypothesis for the proposed research is that siRNA targeting Akt3 and mutant V600EB-Raf, GSK31 or Wee1 kinases can be delivered via novel ultrasound-nanoliposomal technology into skin containing early melanocytic lesions to prevent melanoma development and invasion of these cells into or through the lymphatic system. The rationale is that siRNA targeting these genes would serve as pathway specific targeted chemopreventive agents to prevent melanoma development. We formulated this hypothesis based on proof-of-principal preliminary discoveries identifying kinases to target that can synergise with Akt3 inhibition. Furthermore, we show that siRNA against Akt3 and V600EB-Raf can be loaded into nanoliposomes and placed on skin containing melanocytic lesions following ultrasound treatment, effectively inhibiting melanoma cell survival, and if delivered together it can cooperatively prevent disease development. Thus, the objectives of this application are to first, evaluate the chemopreventive efficacy of novel nanoliposomes containing siRNA-targeting Akt3 and mutant V600EB-Raf, GSK31 or Wee1 kinases in a transgenic animal model of the disease in which both Akt3 and V600EB-Raf are deregulated to promote spontaneous melanocytic lesion development. This will be accomplished by loading siRNA targeting Akt3 and V600EB-Raf, GSK31 or Wee1 into antibody-targeted nanoliposomes and following ultrasound treatment, effectively deliver agents into spontaneously developing early melanocytic lesions in skin of animals. Second, we will determine whether these agents can prevent or decrease lymph node invasion by early melanocytic cells to decreased disease development and aid survival. This will be accomplished by treating mice with nanoliposomal siRNA prior to or following invasion of the lymph node basin by melanocytic lesion cells to establish whether it will prevent disease progression. Delivery of siRNA against key kinases using an antibody-targeted nanoliposomal formulation following ultrasound-mediated skin permeabalization is a novel approach critically needed for more effective chemoprevention of melanoma and inhibition of its spread into and through the lymphatic system.

Public Health Relevance

Over the long-term, discovery of targeted chemopreventive agents that inhibit kinases involved in melanocytic lesion development are predicted to significantly decrease melanoma incidence rates. Specifically, development of this nanoscale antibody-targeted chemopreventive agent would have significant potential to impact human health by decreasing the number of people developing this disease, thereby directly decreasing mortality rates from melanoma. Therefore, the positive impact of this study for preventing melanoma would be significant.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136667-02
Application #
8044192
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2010-03-12
Project End
2014-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$432,123
Indirect Cost
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Kuzu, Omer F; Gowda, Raghavendra; Sharma, Arati et al. (2018) Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. Cancer Biol Ther 19:53-62
Gowda, Raghavendra; Dinavahi, Saketh S; Iyer, Soumya et al. (2018) Nanoliposomal delivery of cytosolic phospholipase A2 inhibitor arachidonyl trimethyl ketone for melanoma treatment. Nanomedicine 14:863-873
Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra et al. (2018) Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations. Mol Pharmacol 93:190-196
Kuzu, Omer F; Gowda, Raghavendra; Noory, Mohammad A et al. (2017) Modulating cancer cell survival by targeting intracellular cholesterol transport. Br J Cancer 117:513-524
Gowda, Raghavendra; Kardos, Gregory; Sharma, Arati et al. (2017) Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma. Mol Cancer Ther 16:440-452
Gowda, Raghavendra; Inamdar, Gajanan S; Kuzu, Omer et al. (2017) Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport. Oncotarget 8:28260-28277
Gowda, Raghavendra; Sharma, Arati; Robertson, Gavin P (2017) Synergistic inhibitory effects of Celecoxib and Plumbagin on melanoma tumor growth. Cancer Lett 385:243-250
Kuzu, Omer F; Noory, Mohammad A; Robertson, Gavin P (2016) The Role of Cholesterol in Cancer. Cancer Res 76:2063-70
Kardos, Gregory R; Wastyk, Hannah C; Robertson, Gavin P (2015) Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway. Mol Cancer Res 13:1408-20
Song, Chunhua; Gowda, Chandrika; Pan, Xiaokang et al. (2015) Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood 126:1813-22

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