HonCode

Go Back   HER2 Support Group Forums > Inflammatory Breast Cancer
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 11-27-2011, 11:39 AM   #1
Lani
Senior Member
 
Join Date: Mar 2006
Posts: 4,717
ALK signalling pathway linked to IBC, may drive metastasis

from recent AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in SF

Signaling pathway linked to inflammatory breast cancer may drive disease metastasis
[European Society for Medical Oncology]
Amplification of anaplastic lymphoma kinase (ALK), which has been reported in other cancers such as non-small cell lung cancers, may be a primary driver of the rapid metastasis that patients with inflammatory breast cancer experience. If validated, the use of ALK inhibitors may be a new treatment approach for patients with this lethal form of breast cancer.

These data were presented at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held in San Francisco, November 12-16, 2011.

Only a few molecules identified and matched

A diagnosis of inflammatory breast cancer carries a very low five-year survival rate of about 40%, clearly indicating the critical need for an understanding of the molecular basis of the disease. According to Fredika Robertson, PhD, professor in the department of experimental therapeutics at The University of Texas MD Anderson Cancer Center and a member of the Morgan Welch Inflammatory Breast Cancer Research Program, currently there are few molecules that have been identified and matched with available targeted therapies of clinical benefit in patients with inflammatory breast cancer.

ALK amplification in 13 of 15 tumor samples

Dr Robertson and colleagues used patient-derived tumors, tumor cell lines and animal models to evaluate protein-signaling pathways and genetic abnormalities with the goal of identifying molecules that may be associated with the increased metastases of inflammatory breast cancer. They discovered ALK amplification in 13 of 15 tumor samples taken from patients with this lethal variant of breast cancer. They then validated the presence of this abnormality in tumor cell lines and newly developed xenograft models.

Gene amplification of ALK is only found in about 2% of the overall breast cancer population, according to Robertson. However, results from this analyzis indicate that in inflammatory breast cancer, it could be occurring in up to 86% of patients.

The observation that ALK is amplified in inflammatory breast cancer suggests that ALK may serve as a good target for treatment. To test this, the researchers evaluated the effects of a drug that inhibits ALK using tumor cells isolated from patients with metastatic inflammatory breast cancer and in two animal models that recapitulate the disease. Results: indicated that the use of this drug resulted in tumor cell death.

Patients are now being evaluated for a phase I clinical trial

Patients with inflammatory breast cancer are now being evaluated for ALK genetic abnormalities, and if found eligible, may be enrolled in a phase I, dose-escalation clinical trial of a small-molecule ALK/cMet inhibitor. Dr Massimo Cristofanilli, chair of medical oncology at Fox Chase Cancer Center in Philadelphia has implemented this trial at the center's Inflammatory Breast Cancer Clinic.

Moving forward, researchers emphasized the importance of collaborating with a research team with expertise in using both proteomic and genomic approaches to define molecular biology of tumors, to identify therapeutic targets and, once validated, to rapidly translate these findings to the clinic.

The funding for these studies came from an American Airlines/Komen Race for the Cure Promise Grant KGO81287; Robertson and Cristofanilli are co-principal investigators on this grant. The proteomics studies were performed in collaboration with Emanuel Petricoin III, PhD, and Lance Liotta, MD, PhD, at the George Mason Center for Applied Proteomics and Molecular Medicine in Manassas, USA.
^^^^^^^^^^^^^^^^^^

AACR-NCI-EORTC 2011: ABSTRACT #PR-4: Gene amplification of Anaplastic Lymphoma Kinase in Inflammatory Breast Cancer
[American Association for Cancer Research]

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer associated with a 40% 5-year survival in spite of appropriate multidisciplinary care, suggesting resistance to current therapies. IBC serves as a paradigm for tumors that have a program of accelerated metastasis and exhibit characteristics of an mesenchymal-epithelial transition, with robust expression of E-cadherin, and a lack of expression of ZEB1 and TFG beta. Although a few genes such as RHO-C GTPase have been shown to be expressed in IBC, to date, there has been no primary genetic alteration linked to the metastasis observed in IBC patients.

Methods: Using reverse phase proteomics, whole transcriptome analysis, fluorescence in situ hybridization, real time PCR and western blotting, we designed a discovery strategy to identify the signaling pathways that are activated in IBC, using tissue samples from primary IBC patients (core and skin punch biopsy samples), established IBC cell lines and newly developed new IBC cell lines and xenograft models, designated as FC-IBC-01, and FC-IBC-02, that were established from tumor cells isolated from IBC patients who had developed pleural effusion under an IRB-approved protocol.

Results:Activation of phospho-ALK-tyrosine 1586 as a common occurrence in IBC cell lines at a level similar to that found in non-small cell lung cancer (NSCLC) patients with ALK genetic abnormalities. Our studies revealed first time evidence for amplification (3-7 fold) of the receptor tyrosine kinase ALK in 13/15 IBC patient tumor specimens thus far examined by fluorescence in situ hybridization (FISH) and in 66% of IBC cell lines, including Mary-X, and the newly developed FC-IBC01, and FC-IBC02 xenograft models. Interestingly, ALK amplification is not detected in SUM149, SUM190 and KPL-4 cell lines which are the most commonly studied IBC cell lines. Tumor cells isolated from IBC patients with pleural effusion whose tumor was ALK amplified were very sensitive to the anti-proliferative effects of the small molecule cMet/ALK inhibitor crizotinib [PF-02341066] at submicromolar levels (IC50=0.88 nM) but were completely resistant to paclitaxel. Thus far we have not found EML4-ALK or NPM-ALK translocation in IBC cell lines nor have we identified ALK mutations at sites reported to be present large cell anaplastic lymphoma, NSCLC, or neuroblastoma. Analysis of signaling pathway maps reveal that ALK is a central regulator of tumor growth, survival and metastatic progression through its association to multiple downstream effectors including PI3K/AKT, mTOR, and JAK/STAT3. In contrast, cMet is not differentially expressed or phosphorylated in pre-clinical models of IBC. We are currently assessing the activities of the combination of PI3K/mTOR inhibitors and small molecule ALK inhibitors to determine synergistic effects.

Discussion: These studies are the first to suggest that ALK may be a primary molecular driver in the rapid metastasis exhibited in IBC and also suggests that proteomics based approaches are critically important to incorporate into studies to identify targets for development of effective treatments for IBC patients. Furthermore, these studies provide a critical path to clinical evaluation of ALK inhibitors in IBC patients with disease progression for whom there are few therapeutic options.
Lani is offline   Reply With Quote
Old 12-06-2011, 01:59 PM   #2
Midwest Alice
Senior Member
 
Midwest Alice's Avatar
 
Join Date: Dec 2008
Location: Southern Indiana
Posts: 452
Re: ALK signalling pathway linked to IBC, may drive metastasis

Thanks Lani,
__________________
Alice
04/08 age 50 III IBC Her2+++ ER/PR-8cm 14/14 Double M, Body and Brain CT/PET clear, ? on spine,Muga 53
06/08, 4 A/C, Neulasta
08/08, Herceptin/tax 12 every week
10/08, CT/PET clear, ? on pelvis, hips, MUGA 43, started Enalaprial for heart, Herceptin every 3 weeks
11/08 33Rads; 12/08 MUGA 48
2/09 MRI spine and bone scan, old mets to spine, Chest x-ray, blood work, IV NED,regular CPAP use,Zometa x6, first -flue like symptoms 2 days;Herceptin x3; stage 2 lymphoedema..sleeve and glove
4/09 Brain MRI - CLEAR; MUGA 54
7/09 chest ultrasound,
10/09 PET, brain and spin MRI NED Herceptin only. MUGA 59!!!
1/11 Hip replacement 7/11 Hip 2 replacement
4/12 4 years!! Herceptin
6/12 start reconstruction finish in 12/12
2/14 Herception - 6 years!!!

1 Corinthians 10:13 "No temptation has seized you except what is common to man. And God is faithful; he will not let you be tempted beyond what you can bear. But when you are tempted, he will also provide a way out so that you
can stand up under it."

Midwest Alice is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On

Forum Jump


All times are GMT -7. The time now is 02:44 AM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2018, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007
free webpage hit counter