Insmed Inc (INSM)

[Christiaan F]

NVA to announce deal with INSM as well?

Results with combination of RhIGFBP-3 & Letrozole (NVA) is very convincing!

L.Shiry (INSM)
Leyland Jones ( http://www.medicine.mcgill.ca/oncology/pubs/Leyland-Jones/Leyland-Jones_2005_02_EssentialRoles.pdf#s... )

http://www.eurcancen.org/GenetoCure06/abstracts/0.17.pdf

O.17
Recombinant Human Insulin-like Growth Factor-Binding Protein 3 (rhIGFBP-3) has Single Agent Anti- Tumor Activity and Enhances Letrozole Effects in Postmenopausal Breast Cancer Model.

A.N. Alami1, K. Banerjee, V. Page, Z. Li, R. Audet, L. Macedo, L. Shiry, A. Brodie, B. Leyland-Jones
1McGill University,Oncology, 3655 Sir William Osler, # 717 MONTREAL, Canada

Estrogen and insulin-like growth factors (IGFs) stimulate the proliferation of human breast cancer (BC). Both
hormones have been shown to act through an interactive cross-talk between estrogen and IGF signaling
pathways, resulting in subsequent activation of the downstream signaling cascades, such as the PI3-kinase and
ERK pathways. IGF-binding proteins (IGFBPs), predominately, IGFBP-3, bind to IGFs regulating their
bioavailability and preventing their interaction with the IGF-IR, thereby inducing growth inhibition/apoptotic
effects. Studies have shown that increased levels of IGF-I and/or reduced levels of IGFBP-3 are associated with
increased risk of BC.
Despite substantial improvements in the efficacy of endocrine therapy in estrogen-receptor positive (ER+) post
menopausal BC patients following the introduction of aromatase inhibitors, de novo or subsequent resistance
remains a major limitation. In the present study, we used a postmenopausal breast cancer model developed by
Brodie et al to investigate the effectiveness of targeting both estrogen and IGF by combining the non-steroidal
aromatase inhibitor, letrozole, and rhIGFBP-3.
Ovariectomized, athymic mice bearing subcutaneous tumors of ER+ estrogen-receptor positive human breast
cancer cells stably transfected with the aromatase gene (MCF-7 Ca) were used. All mice received ∆-4-
androstenedione (100 µg/day) subcutaneously (s.c.) from days 1 through 28, along with one of the following
treatments: rhIGFBP-3 at 10 or 30 mg/kg, s.c., twice daily, letrozole (2 or 5 µg/ day), s.c., or their combination at
the lowest doses.
All treatments were effective in suppressing tumor growth as compared with the control (P < 0.001). Both
rhIGFBP-3 and letrozole, as single courses, showed dose-dependent tumor growth inhibition. rhIGFBP-3
showed significant antitumor activity at both 10 & 30 mg/kg and induced a tumor growth inhibition (TGI) of 43
and 55% at day 28, respectively. Letrozole caused a TGI of 63 and 71 %, at 2 and 5 µg/day, respectively. The
treatment with rhIGFBP-3 (10 mg/kg) and letrozole (2 µg/ day) elicited an enhancement of letrozole anti-tumor
activity (TGI = 78%) and was more effective than letrozole alone even at the highest dose tested. Moreover, this
combination regimen resulted in tumor regression to the initial level at day 18. Tumor regression continued
throughout the treatment period, with no apparent toxicity, whereas tumors in the letrozole treated groups (2 & 5
µg/day) were not reduced to the initial level up to day 28.
Western blots analysis of representative tumors are undertaken to explore the effect of the cross-talk between
ER and IGF-IR signaling and the downstream cascades on tumor growth inhibition.
Our results demonstrate, for the first time, the antitumor activity of rhIGFBP-3 against established MCF-7 Ca
post-menopausal human breast cancer model and that its combination with letrozole at sub-optimal doses is
proved superior to treatment with letrozole as first line treatment.

CF