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Objectives
The MAMMOTH project aims to meet the twin objectives of earlier detection of breast cancer and new
patient-tailored therapies to treat it. It will do so by developing innovative imaging techniques capable of
detecting alterations in cell biology that indicate the presence of breast cancer – for example, hypoxic
tissue, angiogenesis and changes in the expression of hormone and growth factor receptors.
The project team will identify ligands for these cell biology markers, labelling them either with fluorescent
tracers to allow the use of molecular optical imaging for breast cancer screening, or with radioactive
tracers to use PET/SPECT imaging for improving breast cancer staging and characterization. Optical
(fluorescent) molecular imaging is a promising modality for screening because it is patient-friendly, fast
and does not involve ionizing radiation. Being non-invasive, SPECT/PET molecular imaging is preferable
to obtaining tumour biopsies in order to determine detailed receptor activity in individual lesions.
Fluorescent and radioactive tracers will be validated in-vitro and in-vivo in rodent models, and will include
pharmacokinetic and safety studies. Thereafter, relevant tracers will be produced under GMP conditions
for use in clinical ‘proof-of-concept’ trials for screening and optimization of patient-tailored therapy, by
comparing the data obtained from fluorescence and SPECT/PET molecular imaging with
immunohistochemical results obtained from biopsy samples.
Mammary Carcinoma Molecular Imaging for Diagnosis and Therapeutics (MAMMOTH)
Principal Investigator Prof. Dr. E.G.E. de Vries (University Medical Center Groningen)
CTMM Program manager: Eric Caldenhoven
Breast cancer is the most common cause of cancer death among women. Every year, around 13,000
Dutch women get breast cancer and 3,500 die of the disease. For improved patient outcomes, earlier
detection and new patient-tailored therapies are crucial. The MAMMOTH project aims to meet both these
requirements by developing innovative imaging techniques to detect essential alterations in cell biology
that indicate breast cancer. These key alterations include lack of oxygen (hypoxia), outgrowth of new
vessels (angiogenesis), and changes in expression of hormone receptors (ER, PR) and growth factor
receptors such as HER2 and EGFR. Several types of ligand for these alterations can be developed.
Labeling suitable ligands with fluorescent tracers will allow molecular optical imaging to be used for breast
cancer screening, while labeling with radioactive tracers for PET/SPECT imaging will improve breast
cancer staging and characterization. To achieve this, the MAMMOTH consortium includes expertise on a
wide range of topics required to develop and implement novel breast imaging techniques.
Early detection is currently achieved by mammographic screening and enhances the success of breast
conserving treatment and patient survival. However, mammography detects only 30% of new patients
with breast cancer, and is less reliable for women with dense breasts. Optical (fluorescent) molecular
imaging is a promising modality for screening as it is patient-friendly, fast and does not involve ionizing
radiation. It therefore has the potential to overcome many of the limitations of existing modalities.
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In the treatment of metastases, optimal patient-tailored therapy is hampered by the fact that staging and
‘work-up’ of specific tumor characteristics (for example, immunohistochemically detected ER, PR and
HER2 status) that determine optimal treatment is variable and not perfectly accurate. In addition, these
characteristics can vary during the course of the disease and can even vary between different lesions in
the same patient. To ascertain the efficacy of treatments that target these receptors, information about
the actual receptor status of lesions is crucial. Obviously, non-invasive, highly sensitive, whole body
imaging technologies would be preferable to obtaining tumor biopsies in order to determine actual
receptor activity. Fortunately, innovative SPECT/PET radioactive tracers to visualize various tumor targets
are within reach.
In the MAMMOTH project, optical molecular imaging as a new method for screening, and molecular
PET/SPECT scanning for optimization of patient-tailored therapy, will be evaluated both in the laboratory
and in patients. For PET/SPECT molecular imaging, several types of ligand (for example, antibodies and
nanobodies) will be developed for relevant therapeutic targets (among others, angiogenesis targets,
HER2, EGFR and ER). These ligands will be linked to fluorescent or radioactive labels, depending on the
question to be answered. Because hypoxia is an early event in breast cancer development, fluorophore
linked hypoxia ligands will be developed and directed against known hypoxia-related molecular targets
that discriminate benign and (pre)invasive breast lesions. Hormone receptor tracer development will be
especially of value for investigating advanced breast cancer using PET/SPECT scanning. Fluorescent
and radioactive tracers will be validated in-vitro and in rodent models. This will include pharmacokinetics
and safety studies. Thereafter, relevant tracers will be produced under GMP conditions for clinical trials.
Proof-of-concept
To demonstrate proof-of-concept for early tumor detection, women with breast cancer lesions expressing
the molecular targets will undergo imaging using ‘dual’ (fluorescent/radioactive) tracers allowing
comparison of optical and highly sensitive PET images of a molecular breast tumor target. Optical images
will be 3-D reconstructed and integrated with MRI and PET. Imaging results will be correlated to
immunohistochemical expression of the targeted proteins in the resected tumor.
To demonstrate proof-of-concept for optimal patient-tailored therapy, patients with metastatic breast
cancer will be studied with the newly-developed molecular targeted PET/SPECT tracers directed against
therapeutic targets. Tracers will be validated and scans will be repeated in individual patients to study
changes in tumor characteristics. PET/SPECT imaging will be correlated to immunohistochemical
expression of targets in tumor lesions and conventional imaging. Accessible metastatic lesions will be rebiopsied and immunohistochemically assayed. The results of PET/SPECT imaging will be compared with
the level of the respective targets in the tissue obtained by these biopsies. In these extensively
characterized patients, repeated plasma analyses will also be performed to search for new tumor
(response) markers. New software will be developed for both imaging techniques. All these studies will
feed MTA research.
In summary, the MAMMOTH project will result in improved breast tumor detection and accurate staging
and selection of metastatic patients for targeted drugs. This will improve secondary prevention and avoid
the administration of drugs that are not effective or no longer effective, not only increasing the quality of
life for patients but also reducing health care costs and unwanted side effects.
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In addition, MAMMOTH has the clear potential to speed up drug development and generate patents. The
generated IP and technology will be valorized.
Budget, organization and partners
Project budget: 15 M€
9 Industrial partners
5 Academic partners
Start date: 01-04-2010
Biomade Technology Foundation
BiOrion Technologies
LinXis
MSD Oss
PepTx Inc
Philips Electronics Netherlands BV
QVQ
Roche Nederland BV
Westburg BV
Eindhoven University of Technology
University Medical Center Groningen
University Medical Center Utrecht
Utrecht University
VU University Medical Center Amsterdam
End date: 31-12-2014
Allocated at year-end-2011:
48 researchers (19.1 FTEs)
General
In response to the first call for project proposals in 2007, the Center for Translational Molecular Medicine
(CTMM) announced on April 1, 2008, that nine first-call projects would receive research funding
amounting to a total of 150 million Euro. On March 10, 2009, it announced that eight new project
proposals, submitted in the fall of 2008 in response to the second call for proposals, will receive funding
amounting to a total of almost another 100 million Euro.
All Dutch university medical centers, plus several universities, a broad spectrum of small and mediumsized enterprises, major industry leaders including Philips and DSM, and the Dutch Government are
involved.
The funding is provided by the Dutch government, industry and academia. The research is focused firmly
on the ‘translational’ aspects of molecular medicine so that results can be applied as quickly as possible
to actual patient care.
Mammoth is one of the projects from the second call.
3 January 2013
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