Early stage melanoma can usually be cured by surgical removal;however, melanoma in advanced stages is invariably resistant to existing chemotherapeutic agents. Despite decades of extensive research, dacarbazine (DTIC) remains the gold standard for treating malignant melanoma, yet it provides complete remission in fewer than 5% of patients. With the rapidly rising incidence of melanoma in the United States, there is an urgent need to develop novel treatment options that will be more effective for this disease. Our goal is to address this significant problem by testing our overall hypothesis that our recently discovered potent tubulin inhibitors can effectively circumvent multidrug resistance (MDR), and by combining with innovative biodegradable nanoparticle-based drug delivery/targeting strategies, they can become an effective agent for improved treatment of malignant melanoma. Our rationale is that these compounds have IC50 values in the low nanomolar range and can inhibit melanoma tumor growth in vivo significantly better than high-dose DTIC. They work by disrupting microtubule formation and inducing cancer cell apoptosis, similar to that of Taxol. But unlike Taxol, they effectively overcome P- glycoprotein (Pgp) mediated multidrug resistance (MDR) and are very amenable to structural modification for further clinical development. Compared with similar compounds currently in clinical trials (e.g., CA-4 and ABT-751), these compounds have some distinct advantages. Our objectives are to (1) synthesize a focused set of thiazole analogs aided by computer modeling;and (2) develop an optimal nanoparticle based drug delivery approach and selectively target melanoma tumors via over-expressed receptors on melanoma cell surface to substantially reduce the dose and minimize potential side effects associated with systematic administration. We will meet our goal and objective by accomplishing the following specific aims: (1) Optimize molecular structures for improved potency and aqueous solubility while maintaining effectiveness against MDR;(2) Screen synthesized compounds against MDR melanoma in vitro and define their mechanism of action;and (3) Develop nanoparticle based drug delivery and targeting strategies for efficient in vivo activity of selected analogs. Our outcome will be the development of several highly efficacious thiazole analogs against MDR melanoma and the associated nanoparticle based drug delivery/targeting strategies for a more effective treatment of malignant melanoma, either as a single agent or in combination with existing drugs.

Public Health Relevance

Currently there is no curative therapy for malignant melanoma;available treatments are aimed at slowing the spread of the disease and relieving the symptoms. We proposed in this grant to develop novel classes of tubulin inhibitors that we recently discovered as potential more selective and curative therapy to treat malignant melanoma. Studies proposed herein are designed to test our hypothesis that these compounds can effectively circumvent multidrug resistance (MDR) problems, and by developing suitable nanoparticle-based drug delivery/targeting strategies, they can provide the groundwork for further clinical development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148706-04
Application #
8589375
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$276,390
Indirect Cost
$89,640
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Arnst, Kinsie E; Wang, Yuxi; Hwang, Dong-Jin et al. (2018) A Potent, Metabolically Stable Tubulin Inhibitor Targets the Colchicine Binding Site and Overcomes Taxane Resistance. Cancer Res 78:265-277
Chen, Guan; Li, Wei (2018) Editorial Preface for Targeted Cancer Therapy. Acta Pharm Sin B 8:501-502
Bumbaca, Brandon; Li, Wei (2018) Taxane resistance in castration-resistant prostate cancer: mechanisms and therapeutic strategies. Acta Pharm Sin B 8:518-529
Banerjee, Souvik; Arnst, Kinsie E; Wang, Yuxi et al. (2018) Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy. J Med Chem 61:1704-1718
Wang, Qinghui; Arnst, Kinsie E; Wang, Yuxi et al. (2018) Structural Modification of the 3,4,5-Trimethoxyphenyl Moiety in the Tubulin Inhibitor VERU-111 Leads to Improved Antiproliferative Activities. J Med Chem 61:7877-7891
Yang, Ruinan; Mondal, Goutam; Ness, Rachel A et al. (2017) Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma. J Control Release 249:32-41
Chen, Hao; Lin, Zongtao; Arnst, Kinsie E et al. (2017) Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy. Molecules 22:
Wang, B; Liu, Y; Huang, L et al. (2017) A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. Mol Psychiatry 22:990-1001
Patil, Shivaputra A; Addo, James K; Deokar, Hemantkumar et al. (2017) Synthesis, Biological Evaluation and Modeling Studies of New Pyrido[3,4-b]indole Derivatives as Broad-Spectrum Potent Anticancer Agents. Drug Des 6:
Wu, Xiaoxin; Wang, Qinghui; Li, Wei (2016) Recent Advances in Heterocyclic Tubulin Inhibitors Targeting the Colchicine Binding Site. Anticancer Agents Med Chem 16:1325-38

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