Kidney cancer comprises approximately 3% of all adult malignancies, and account for over 30,000 cases and 12,000 deaths per year. Unfortunately, efficient intervention of this deadly disease is currently lacking, and effective therapy for this deadly disease is urgently needed. Numerous epidemiological studies have strongly demonstrated the importance of dietary vitamin D in preventing various cancers. In addition, therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D and its analogs in cancer is well-documented. However, inherent calcemic toxicity of this hormone, particularly at therapeutic doses, has prevented its general use as an anticancer agent, opening the door for the development of vitamin D analogs with potent antiproliferative activity with reduced systemic toxicity. Recently we developed a novel derivative of 1,25(OH)2D3 [11,25- dihydroxyvitamin D3-3-bromoacetate, 1,25(OH)2D3-3-BE] that covalently attaches 1,25(OH)2D3 inside the ligand-binding pocket of VDR. We demonstrated that 1,25(OH)2D3-3-BE strongly inhibits the growth of several human cancer cells, including a set of kidney cancer cells. We also demonstrated that 1,25(OH)2D3-3-BE reduces hormone-insensitive prostate tumor at 0.1-0.5 5g/kg dose level in a mouse xenograft model without significant toxicity. Collectively, these results demonstrate potential therapeutic utility of this compound in kidney cancer. The goal of this R21 proposal is to appraise the potential therapeutic value of 1,25(OH)2D3-3-BE in kidney cancer, and evaluate the molecular mechanism of this novel VDR-cross-linking derivative of 1,25(OH)2D3. These goals will be met by two specific aims:
Specific Aim 1 : Determine the efficacy of 1,25(OH)2D3-3-BE on human renal cell carcinoma in a mouse xenograft model;
and Specific Aim 2 : Evaluate the molecular mechanism of growth-inhibition and apoptosis by 1,25(OH)2D3-3-BE in kidney cancer cells. Successful completion of this pilot project will be crucial for the development of 1,25(OH)2D3-3-BE and similar VDR-alkylating analogs of vitamin D hormone for kidney cancer.

Public Health Relevance

Inherent calcemic toxicity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D has prevented its general use as an anticancer agent. Recently we developed a novel derivative of 1,25(OH)2D3 that strongly inhibits the growth of several human kidney cancer cells, and induces programmed cell death in these cells. The goal of this project is to evaluate the therapeutic potential of this compound in kidney cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA127629-01A2
Application #
7471169
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2008-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$182,813
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118