Dear Isehaq,

1-The following publication provides proof-of-concept that

a small-molecule inhibitor of nuclear β-catenin activity (called C3)

can inhibit both the AR and β-catenin–signaling pathways that are

often misregulated in prostate cancer.

Inhibition of androgen receptor and β-catenin activity

in prostate cancer

Eugine Leea,b, Aviv Madarc

, Gregory Davida

, Michael J. Garabediand

, Ramanuj DasGuptaa,b,e,1, and Susan K. Logana,b,e,f,1

Departments of a

Biochemistry and Molecular Pharmacology, b

Stem Cell Biology, d

Microbiology, f

Urology, and e

New York University Cancer Institute, New

York University School of Medicine, New York, NY 10016; and c

Department of Biology, Center for Genomics and Systems Biology, New York University,

New York, NY 10003

Edited by Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, NY, and approved August 13, 2013 (received for review October 18, 2012)

Androgen receptor (AR) is the major therapeutic target in aggressive

prostate cancer. However, targeting AR alone can result in drug

resistance and disease recurrence. Therefore, simultaneous targeting

of multiple pathways could in principle be an effective approach

to treating prostate cancer. Here we provide proof-of-concept that

a small-molecule inhibitor of nuclear β-catenin activity (called C3)

can inhibit both the AR and β-catenin–signaling pathways that are

often misregulated in prostate cancer. Treatment with C3 ablated

prostate cancer cell growth by disruption of both β-catenin/T-cell

factor and β-catenin/AR protein interaction, reflecting the fact that

T-cell factor and AR have overlapping binding sites on β-catenin.

Given that AR interacts with, and is transcriptionally regulated by

β-catenin, C3 treatment also resulted in decreased occupancy of

β-catenin on the AR promoter and diminished AR and AR/β-catenin

target gene expression. Interestingly, C3 treatment resulted in decreased

AR binding to target genes accompanied by decreased recruitment

of an AR and β-catenin cofactor, coactivator-associated

arginine methyltransferase 1 (CARM1), providing insight into the

unrecognized function of β-catenin in prostate cancer. Importantly,

C3 inhibited tumor growth in an in vivo xenograft model and

blocked renewal of bicalutamide-resistant sphere-forming cells, indicating

the therapeutic potential of this approach.

For more details, see attached paper.

2-A review article on the topic under discussion:

Pharmacological modulation of

beta-catenin and its applications in cancer therapy

Ravi Thakur a

, Durga Prasad Mishra a,

Beta-catenin (b-catenin) is a multifunction protein with a central role in physiological homeostasis. Its abnormal expression leads to various diseases

including cancer. In normal physiology, b-catenin either maintains integrity of epithelial tissues or controls transcription of various genes

on extracellular instigations. In epithelial tissues, b-catenin functions as a component of the cadherin protein complex and regulates epithelial

cell growth and intracellular adhesion. In Wnt signalling, b-catenin is a major transcriptional modulator and plays a crucial role in embryogenesis,

stem cell renewal and organ regeneration. Aberrant expression of b-catenin can induce malignant pathways in normal cells and its abnormal

activity is also exploited by existing malignant programmes. It acts as an oncogene and modulates transcription of genes to drive cancer initiation,

progression, survival and relapse. Abnormal expression and function of b-catenin in cancer makes it a putative drug target. In the past decade,

various attempts have been made to identify and characterize various pharmacological inhibitors of b-catenin. Many of these inhibitors are

currently being investigated for their anticancer activities in a variety of cancers. The first half of this review will focus on the role of b-catenin in

cancer initiation, maintenance, progression and relapse whereas the second half will briefly summarize the recent progress in development of

agents for the pharmacological modulation of b-catenin activity in cancer therapeutics.

For more details, see attached file.

Hoping this will be helpful,

Rafik

Thank you very much Dr. Rafik Karaman  for the suggestions and the good papers that you attached.

It was really useful.