nano curcumin for breast cancer prevention banu arun, m.d. professor, breast medical oncology...

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 !