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Nano Curcumin for Breast Cancer Prevention
Banu Arun, M.D.
Professor, Breast Medical Oncology
Co-Director Clinical Cancer Genetics
Background
• Selective estrogen receptor modulators (SERMs): Tamoxifen and Raloxifene decrease breast cancer risk by ~50%; the only FDA approved drugs
• Tamoxifen more effective than raloxifene in reducing risk of invasive cancer
Background
• Side effects of SERMS: Risk of thromboembolic events, endometrial cancer, menopausal symptoms
• Only 30% high risk women and 50% patients with DCIS opt to take tamoxifen
• Raloxifene not indicated in postemenopausal women
Background
• SERMs: No effect on ER negative (ER-) breast cancer risk reduction
• ⇒ Need for ER- breast cancer risk reduction agents
for pre-and postmenopausal women
• Curcumin (turmeric) potential agent
Background• Curcumin is derived from the plant Curcuma longa• Is commonly used as a spice and flavoring agent • Suppress proliferation, induce apoptosis, anti-inflammatory
properties• Clinical phase I studies: MTD 8000mg (no toxicity)
- Reversal of oral leukoplakia (Sharma et.al 2001, Cheng et al. 2001)
• Phase I study at MDACC pancreatic cancer at 8 g/d: 2/25 had clinical benefit, COX-2 and NFkB expression was downregulated
• To date no prospective prevention study in breast cancer
Background-Nano curcumin
• Despite no toxicity, concern about oral bioavailability• Recently drug delivery systems created using
nanoparticle technology• Preclinical studies 60x higher bioavailability• Phase I study in patients with heart failure ongoing• Phase I study for solid tumors at MDACC at 500
mg/d ongoing
Preliminary Studies
Curcumin Inhibits Proliferation of Human Breast Cancer
Cell Lines
Cell
Pro
life
rati
on
(
MT
T,
A5
70
nm
)
76543210
0.0
0.2
0.4
0.6
0.8
MDA-MB-436
Days
0 M
10 M
50 M
MDA MB 468
765432100.0
1.0
2.0
0 M
10 M
50 M
Days
Aggarwal
Curcumin prevents mammary tumor formation
DMBA induced mammary tumor
Singletary, K. et al. , 1996
Preliminary Studies
Specific Aims
• Specific Aim #1
To evaluate curcumin induced changes in cytology and proliferation pathways (NFkB, IGFBP, Ki-67, EGFR, PI3K) in breast tissue and serum of women at increased risk for breast cancer
• Specific Aim #2
To evaluate changes in breast density before and after curcumin measured with mammogram and breast MRI
0 0.5 1 2 4 8 t (h)
NF-B
Curcumin inhibits constitutive nuclear NF-kB in MDA-MB-436 cells
Cyclin D1
COX-2
actin
Bcl-2
0 2 4 8 12 24 Curcumin (h)
Curcumin downregulates the NF-kB regulated gene products in MDA-MB-436 cells
Curcumin inhibits Nuclear NF-kB and NF-kB Regulated Genes
Aggarwal et.al, 2003
Preliminary Studies
Preliminary Studies
Selected markers inhibited by Curcumin:
• NF-kB• Ki-67• COX-2• EGFR, Her-2/Neu• AP-1
Aggarwal et al. 2003
Preliminary Studies
Predominantly cytoplasmic staining by immunohistochemistry with focal nuclear positivity (using the anti-phospho-NFB p65 (Ser536)
antibody (Cell Signaling Technology (Beverly, MA)).
NFkB p65 expression in breast cancer
Conduct of Study
Nano curcumin 12 mo
MTD from phase I
Endpoints:
1) Modulation of cytology (FNA) and proliferation pathway
2) Change in mammographic density and change in MRI
3) (Evaluation of curcumin metabolites in serum and urine)
FNA FNA
Serum, urine Serum, urine
Eligibility
• Patients with ER negative breast cancer, stage I-III, NED for at least 3 months and intact opposite breast
• No current endocrine, targeted therapy• Adequate organ function• Willing to undergo FNA x2• Sign consent
Accrual: Preliminary data
Phase II Celecoxib and Anastrozole study:
86 patients underwent FNA and DL at baseline• FNA:
Samples obtained from 100%96% adequate cells (>10 epithelial cells/slide)Total adequacy: 96%
None of the patients dropped from the study! Procedure was very acceptable.
Arun et al CCR 2007
Cytologic analysis
FNA: Benign ductal epitheliumArun et al CCR 2007
Cytology Findings
Cytology Findings
• Hyperplasia: 26%• Atypical hyperplasia: 24.4 %
Arun et al ASCO 2007
Modulation of IGFBP-1 with Celecoxib
7.03
9.78
0
2
4
6
8
10
12
1 2
IGFB
P-1
(ng/
mL)
Pre Post
No change was observed in IGF-1 and IGFBP-3
p=0.04 (Wilcoxon
signed rank test)
Arun et al ASCO 2007
0
4
8
12
16
20
24
28
32
pre post
seru
m IG
FB
P-1
(n
g/m
L)
Modulation of IGFBP-1 with Celecoxib
Arun et al ASCO 2007
Biomarker changes
• Increase of IGFBP-1 also shown in our Anastrozole phase II study (Arun ASCO 2009)
• Also shown with Tamoxifen by D Euhus (UTSW)
(Euhus et al AACR-Epidemiology and Prevention, 2007. Manuscript submitted)
⇒ Changes in cytology and IGFBP-1 will be used in
Aim #1 as primary endpoint
Importance of this study
• First! Phase II breast cancer prevention study that can be carried out in the community. Community MDs and their patients will be able to participate without needing to travel to major academic centers
• Interest in NCAMs: My patients want this and they are taking it anyway: Curcumin, fish oil, palm tree oil
• Information gained from this study will help to plan:– In patient with breast cancer: Secondary prevention– In high risk (including BRCA mutation carriers): Primary
prevention
THANK YOU !