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Nano Curcumin for Breast Cancer Prevention

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Presentation on theme: "Nano Curcumin for Breast Cancer Prevention"— Presentation transcript:

1 Nano Curcumin for Breast Cancer Prevention
Banu Arun, M.D. Professor, Breast Medical Oncology Co-Director Clinical Cancer Genetics

2 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

3 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

4 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

5 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 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

6 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

7 Curcumin Inhibits Proliferation of Human Breast Cancer
Preliminary Studies Curcumin Inhibits Proliferation of Human Breast Cancer Cell Lines Cell Proliferation (MTT, A570nm) 7 6 5 4 3 2 1 0.0 0.2 0.4 0.6 0.8 MDA-MB-436 Days 0 M 10 M 50 M MDA MB 468 1.0 2.0 Curcumin inhibits cellular proliferation of Breast Cancer cells. MDA-MB-436 and MDA-MB-468 (2000/0.2ml) were incubated with either medium or different concentrations of curcumin for zero to six days of duration and then cell viability was determined for each duration by MTT method. Results are plotted as mean % viability (± s.d.) of triplicate cultures compared to the untreated control. Aggarwal

8 Curcumin prevents mammary tumor formation
Preliminary Studies Curcumin prevents mammary tumor formation DMBA induced mammary tumor Singletary, K. et al. , 1996

9 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

10 Curcumin inhibits Nuclear NF-kB and NF-kB Regulated Genes
Preliminary Studies Curcumin inhibits Nuclear NF-kB and NF-kB Regulated Genes t (h) NF-B Cyclin D1 COX-2  actin Bcl-2 Curcumin (h) In our preliminary studies we have demonstrated that curcumin suppresses constitutive NFkB activation and p65 phosphorylation in human MDA-MB-436 breast cancer cell lines. We were also interested in evaluating whether curcumin modulates the expression of NFkB regulated genes. In our preliminary studies we have found that curcumin downregulates the expression of COX-2 and bcl-2 in MDA-MB-436 breast cancer cell lines Curcumin downregulates the NF-B regulated gene products. One million MDA-MB-436 cells treated with 50M curcumin for the indicated hours and whole cell extracts were prepared. Sixty micrograms whole cell extracts were resolved on 10% SDS-PAGE gel, electrotransferred on a nitrocellulose membrane, and probed for CyclinD1, Bcl-2, and COX-2 by western blotting. The same blots were stripped and reprobed with anti--actin antibody to show equal protein loading. Curcumin inhibits constitutive nuclear NF-kB in MDA-MB-436 cells Curcumin downregulates the NF-kB regulated gene products in MDA-MB-436 cells Aggarwal, 2003

11 Preliminary Studies Selected markers inhibited by Curcumin:  NF-kB
 Ki-67  COX-2  EGFR, Her-2/Neu  AP-1 Extensive research in last several years has indicated the therapeutic potential of curcumin in the prevention and treatment of cancer based on its in vitro and in vivo anti-tumor activity [Aggarwal, 2003 #2552]. Eventhough, the exact mechanisms for its anti-tumor and anti-metastatic properties are not fully understood, Aggarwal et al. 2003

12 Preliminary Studies NFkB p65 expression in breast cancer
Predominantly cytoplasmic staining by immunohistochemistry with focal nuclear positivity (using the anti-phospho-NFB p65 (Ser536) antibody (Cell Signaling Technology (Beverly, MA)).

13 Conduct of Study FNA FNA Nano curcumin 12 mo MTD from phase I
Serum, urine Serum, urine Endpoints: Modulation of cytology (FNA) and proliferation pathway Change in mammographic density and change in MRI (Evaluation of curcumin metabolites in serum and urine)

14 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

15 Phase II Prevention Studies at MDACC
Celecoxib: Completed Anastrozole: Completed Atorvastatin (NCI): Ongoing Poly-E (NCI- Hershman): Completed Bexarotene (NCI-BCM): Completed Src inhibition: Pending activation (S Kome Promise) Metformin (endometrial & breast prevention): Pending activation

16 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

17 Cytologic analysis FNA: Benign ductal epithelium Arun et al CCR 2007

18 Cytology Findings Cytology Findings Hyperplasia: 26%
Atypical hyperplasia: % Arun et al ASCO 2007

19 Modulation of IGFBP-1 with Celecoxib
p=0.04 (Wilcoxon signed rank test) Pre Post No change was observed in IGF-1 and IGFBP-3 Arun et al ASCO 2007

20 Modulation of IGFBP-1 with Celecoxib
Arun et al ASCO 2007

21 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, Manuscript submitted) ⇒ Changes in cytology and IGFBP-1 will be used in Aim #1 as primary endpoint

22 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


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