ID: P_37_783
MySMIS Code: 103557
Contract Number: 41/02/09/2016
POC 2014-2020
Priority Axis 1- Research, Innovation and Technological Development support for Economic Competitiveness and Business Development
Action-1.1.4 Research&Development support by involving specialized personnel from abroad
Project Director: Daniel Irimia, Massachusetts General Hospital, Harvard medical School, Boston, MA, USA
Extent of the project: 48 months (02.09.2016-01.09.2020)
Grant Budget: 1915000 Euros
Motivation for executing the project

The implementation of this project can be justified by several major aspects:

1. Developing a microfluidic platform can serve both cancer research and personalized medicine. It can be used for a more accurate characterization of tumor cells evolution with an impact over cancer prognostic.
2. Project implementation would help to create a high-end research facility with specialized personnel in cancer research.
3. The project would create partnership opportunities between the private and public domains for developing specific microfluidic devices to be used in the research work.
4. Being able to manufacture microfluidic devices within the institute would provide a support for personalized medicine.

High-end cancer research facility able to manufacture microfluidic devices

Specialized team trained in advanced cancer research techniques

Partnerships between public and private domains to identify potential microfluidic designs to be used in clinical applications

Improvements in personalized medicine and cancer therapy response and prognosis

Our drive to develop a microfluidic platform comes to meet the need of a more accurate characterization of tumor phenotypes, including the interactions between cellular subpopulations contained in the tumor microenvironment. The goal would be to enhance the accuracy of cancer diagnostic and prognostic as well as to increase the therapy response. Due to the fact that breast cancer has the highest incidence and mortality levels among women’s cancer in Romania and worldwide, we chose this pathology as the central point of our research. During the last 5 years, 8000 patients have been diagnosed and treated for breast cancer within our projects’ host institution, The Oncology Institute “prof. Dr. I. Chiricuta” in Cluj-Napoca.
Breast cancer is a highly heterogeneous disease both at a molecular level as well as among the patients and this diversity is a key factor in determining the risk of metastasis, therapy resistance and relapse.
Actual therapy fails to address the high molecular variability of breast cancers because it is based on general histological characteristics of the tumors. The presence of progesterone and estrogen receptors (PR, ER) and epidermal growth factor receptors (ERB2/HER2) defines four major breast cancer subtypes: Luminal A (ER+, PR+, HER2-); Luminal B (ER+, PR+, HER2+); HER2+ (ER-, PR-, HER2+); Triple Negative (ER-, PR-, HER2-) that represent the targets of the current therapy schemes.
In spite of using some targeted therapeutic compounds (ex: Tamoxifen, Herceptin) combined with classical therapy approaches including surgery, chemotherapy/ radiotherapy, there still remains a high number of patients with an incomplete response and a high risk of developing metastases and relapse over time. Although tumor biology and resistance mechanisms have gained more understanding in the last few years, an accurate characterization of tumor phenotype and tumor cells subpopulations still represents a challenge for worldwide medical research.
The development of multidisciplinary research has brought microfluidic technology to the front because it is able to provide an important support for obtaining new information regarding tumor phenotype characteristics. Microfluidic technology, due to its nanoscale dimensions, gives the user the ability to analyze cells behavior in conditions that resemble the metastasis process at single-cell resolution. Moreover, using microfluidic devices, it is possible to simulate real life conditions in which cells can interact with the tumor microenvironment. This can provide useful information that can lead to a better understanding of the evolution of tumor phenotype correlated with cellular subpopulations contained. Last but not least, there are still unanswered questions regarding the mechanisms underlying the intrinsic or developed therapy resistance, a common occurrence in oncological pathology. Having that in mind, the possibility to develop microfluidic devices that could be used to evaluate patient’s cancer cells response to therapy by treating them with different drugs ex vivo and then applying a personalized therapy scheme to the patients, would mean an important breakthrough in shifting the traditional approach of treating cancer towards a more personalized option.
For all the reasons listed above, we think that the development of a microfluidics research platform at the Oncology Institute “Prof. Dr. Ion Chiricuta” in Cluj-Napoca, would represent an important evolution in the field of translational research and personalized medicine in breast cancer. This new approach of Romanian research is consistent with the high standards of cancer research centers worldwide.

The development and implementation of a microfluidic platform for cancer research within IOCN’s Department of Functional Genomics, Proteomics and Experimental Pathology represents a novel initiative in Romania, for being the first integrated platform for microfluidic research in the whole country. Developing this platform would represent a major advantage both for cancer research as well as for creating collaboration networks inside and outside the country.
By coordinating this project, Prof. Dr. Daniel Irimia, Harvard Medical School, Boston, MA, USA opens a door for the know-how transfer and medium-to-long term collaborations involving oncological and microfluidics research leaders from Europe and USA. Building relationships would also grow the numbers of specialized personnel for developing and exploiting the microfluidic platform to serve the interest of cancer patients. This is the reason why our department aspires to build international collaboration and research networks for fighting cancer at an international level (Horizon 2020).
Building the microfluidics platform for making devices would also mean developing partnerships within the public and private domains, with an important accent on working with the IT industry for bringing the building process of microfluidic devices and data analysis to a more automatic state.

Our project aims to evaluate the tumor phenotype of breast cancer by using genomic and microfluidic approaches. This way, the research will provide new prediction markers for invasion and metastasis as well as makers for evaluating the intrinsic and acquired resistance to anticancer drugs. We are confident that by achieving our goals within this project we will be able to bring new insights regarding the tumor phenotype, invasion and metastasis capability of cancer cells and mechanisms of therapy resistance and our data will have an important impact in developing personalized therapies and cancer management, improving patients’ outcome.

Specific Objective 1. The characterization of molecular mechanisms involved in cancer cells’ migration and the correlation between these mechanisms and the clinic-pathological data of breast cancer patients. For pursuing this objective, we will use microfluidic devices in order to assess the migration speed of different types of cancer cells and their behavior during migration. We will analyze the genomic profile of the migrating cells, especially tumor stem cells and circulating tumor cells and correlate the data with migration speed.

Specific Objective 2. Modulating specific mechanisms involved in cancer invasion in vitro. We will study the activation and inhibition mechanisms of signaling pathways involved in cellular migration. We will use microfluidic devices to measure the effects of our interventions on cells and to optimize these interventions in order to achieve a complete blockage of migration.

Specific Objective 3. To validate the data obtained by modulating the mechanisms of tumor invasion on breast cancer cells obtained from patients. We will analyze patients’ tumor cells migration in microfluidic devices that will simulate the molecular interactions from tumor microenvironment that are responsible for the evolution, invasion and metastasis of breast cancer cells. We will assess the aggressiveness, invasiveness and metastasis potential of these cells as well as the effect of our interventions on their behavior. Moreover, we will develop pharmaco-genomic studies correlating cells migration in microfluidic devices with drugs cytotoxicity. The results will be usable in clinical research to evaluate the effects of drugs over cells from breast cancer patients.

The research team
This project will be carried through by a multidisciplinary team, including researchers and personnel from different fields such as clinicians, anatomopathologists, as well as students (master, phd, post-doc). The team will be coordinated by Prof. Dr. Daniel Irimia from Harvard Medical School, Boston, MA, USA. By participating in this study, the staff involved will have the opportunity to learn new techniques and gain experience, hence increasing their competitivity at an international level. The project manager has a vast experience in designing and pursuing experiments in translational medicine which he gained while working at the Massachusetts General Hospital, one of the most important hospitals in USA. Moreover, while working on this project, the researchers will have the opportunity to use a cutting edge microfluidic technology that will help them expand their research competence and to build strong interdisciplinary connections.

The research team is composed by the following members:
Prof. Dr. Daniel Irimia- Project Manager
Dr. Oana Tudoran- Specialist
Dr. Ovidiu Balacescu-Specialist
Dr. Olga Soritau-Specialist
Prof. Dr. Ioana Neagoe- Specialist
Dr. Alexandru Eniu- Specialist
Dr. Loredana Balacescu- Specialist
Dr Claudia gherman- Specialist
Dr. Bogdan Fetica- Pathological Anatomy MD
Dr. Carmen Lisencu- Tumor Imaging MD
Dr. Claudia Burz- MD
Dr. Mihaela Aldea- MD
Valentina Pilecki- PhD student
Oana Baldasici- Master student
Daniel Cruceriu- PhD student
Roman Andrei- PhD student
Dr. Laura Pop- Post-doc
Dr. Pall Emoke- Post-doc
Dr. Diana Cenariu- Post-doc
Ana Maria Fit- PhD student
Flaviu Drigla- Technician
Laura Maja- Technician
Simona Visan- Statistician
Sorina Florea- Nurse

From a scientific point of view, the results of this project will bring new information at a molecular level that will bring clarifications upon some aspects of the breast cancer invasiveness and metastasis potential related to tumor phenotype.
By modulating the molecular mechanisms underpinning the migration and invasion of cancer cells, we could gain new data that can be used for improving cancer management in breast cancer patients by blocking cancer cells invasion. Last but not least, pharmacogenomics and microfluidics studies will help to investigate the mechanisms of intrinsic and acquired therapy resistance in order to identify specific prognostic markers to be used for alternative treatment options in less responsive patients. Our aim is to publish the results of this study in highly ISI rated journals.
Considering the high potential of developing a high end microfluidic platform that assemblies microfluidic devices for medical research we are aiming to build partnership networks both in the public and private domain in order to encourage production and scientific research. The microfluidic platform will provide a strong basis for our next research and collaborations with public and private domains with an intention to apply for founding especially from the EU. Another important result of our study will be the know-how transfer and the development of a group of scientists and specialists in microfluidics that will grow into a bio-medical research excellence spot inside the country.