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Rational Therapy for Breast Cancer: Individualized Treatment for Difficult-to-Treat Breast Cancer Subtypes

Objective

Cancer genotyping has identified a number of correlations between mutations in specific genes and responses to targeted anti-cancer drugs, with many mutations occurring in kinases or downstream signaling components. While there are several ongoing large-scale genome re-sequencing studies for the major cancer types, there is no systematic effort to investigate kinase mutations in distinct biological subtypes of these cancers. Here, we will explore the rate of activation of all kinases (the “kinome”) in two poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available, namely “triple negative” (TN) breast tumors lacking the estrogen-, progesterone- and HER2 receptors, constituting 15% of breast cancers, and invasive lobular carcinomas (ILC) of the breast, which represent 10% of breast tumors. Thus, we lack effective targeted therapies for one quarter of all breast cancer patients. In this project, we will identify and validate novel kinase targets for therapy for these TN and ILC subtypes. Kinase targets will be identified via a 5-pronged approach: i) direct re-sequencing of the kinome of 150 TN and 150 ILC tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein array and tissue microarray technologies, iii) determination of copy number variation by SNP arrays, and iv) mRNA quantitation of the kinome using DNA microarrays and v) RNA sequencing to provide complementary information such as evidence of alternative splicing, translocations and RNA editing within the expressed kinome. Potential kinase targets for therapy will be validated in preclinical models using RNA interference. Finally, we will perform a phase I/II clinical trial to test the efficacy of a selective PI3K inhibitor in breast cancer. The project will deliver proof-of-concept for novel therapeutic interventions, together with matched molecular diagnostic approaches for patient stratification, for up to 25% of breast cancer patients.

Call for proposal

FP7-HEALTH-2010-two-stage
See other projects for this call

Coordinator

UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Address
Belfield
4 Dublin
Ireland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 921 505,59
Administrative Contact
Donal Doolan (Mr.)

Participants (7)

STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Netherlands
EU contribution
€ 1 858 088,42
Address
Plesmanlaan 121
1066 CX Amsterdam
Activity type
Research Organisations
Administrative Contact
Henri Van Luenen (Dr.)
INSTITUT CURIE
France
EU contribution
€ 346 000
Address
Rue D'ulm 26
75231 Paris
Activity type
Research Organisations
Administrative Contact
Corinne Cumin (Ms.)
MAX IV Laboratory, Lund University
Sweden
EU contribution
€ 140 000
Address
Paradisgatan 5C
22100 Lund
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Karin Jirström (Dr.)
FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON (VHIO)
Spain
EU contribution
€ 296 472
Address
Calle Nazaret 115-117
08035 Barcelona
Activity type
Research Organisations
Administrative Contact
Alejandro Piris Gimenez (Dr.)
THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom
EU contribution
€ 651 900
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Keith Cann (Mr.)
AGENDIA NV
Netherlands
EU contribution
€ 786 300
Address
Radarweg 60
1043 NT Amsterdam
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Iris Simon (Dr.)
ONCOMARK LIMITED
Ireland
EU contribution
€ 995 519,99
Address
172 Rathgar Road Rathgar
Dublin 6 Dublin
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Mairin Rafferty (Dr.)