T1

 New therapeutic targets to treat cardiovascular diseases

Cardiovascular (CV) diseases are a major health concern in industrialized countries. Heart failure (HF) is the only disease that is increasing in prevalence in Europe and the USA, currently with 2% of health costs in developed countries. HF is generally defined as inability of the heart to supply sufficient blood flow to meet the body needs. Despite modern efficient therapies, the annual mortality rate of heart failure is still ~10%. Most cases of HF are caused by diseases of heart muscle consecutive to a stress (hypertension, infarct, aortic regurgitation, toxicity, etc.) that results, when prolonged or excessive, in pathologic remodeling of the ventricular chamber, contractile dysfunction, depressed energy production transfer and utilization, and increased apoptosis. HF may also occur as a side-effect of cancer therapy. While left ventricular failure is the most common cause of HF, failure of the right heart is observed in pulmonary hypertension (PAH), secondary to remodeling of small pulmonary vessels. Thus identification of new targets and design of innovative treatments is of crucial importance in terms of quality of life, health of the population and health costs.

This project is divided in three sub-projects: T1-1; T1-2 and T1-3

T1-1

New therapeutic targets to treat heart failure

Coordinators: R. Fischmeister (Partner 2) and Y. Ambroise (Partner 12)
Starting date: January 2012

The general scope of the TREAT-HF project is to design new therapeutic drugs to treat HF. More specifically, our project targets two proteins involved in the beta-AR/cAMP signalling cascade, PDE4B and Epac1. First, we want to develop a PDE4B activator in order to lower cAMP concentration in the vicinity of cardiac Ca2+ channels, to avoid Ca2+ overload, pathological hypertrophy and arrhythmias.  Second, we want to develop an Epac1 inhibitor in order to prevent or treat maladaptive hypertrophy and HF. For both targets, we have original and protected advanced hit molecules and our goal is to deliver, by the end of 2017, a drug candidate ready to enter preclinical development.

T1-2

New therapeutic targets to treat Pulmonary Arterial Hypertension

Coordinators: S. Cohen-Kaminsky (Partner 6) and M. Alami (Partner 15)
Starting date: January 2012

Pulmonary arterial hypertension (PAH) describes a group of non-infectious rare (50/million) and lethal pulmonary vascular diseases due to subsequent right HF. There is unfortunately no cure of PAH. In spite of treatments that are now available to improve quality of life and survival, median survival of PAH remains <5 years and refractory cases are candidates for heart-lung transplantation. Right HF in PAH is secondary to remodeling of small pulmonary vessels, a complex and multifactor process in which inflammation plays a determinant role. Partner 6 has demonstrated that inflammation influences vessel remodeling and that immune dysfunction and autoimmunity contribute to the pathophysiology of PAH. On the basis of a unique biobank with pulmonary tissues collected during transplantation, he has identified an ion channel as a novel therapeutic target in PAH. This ion channel is involved in the 3 tissues interacting to cause PAH: the heart, the pulmonary circulation, and the immune system, and seems to play a major role in accumulation of perivascular inflammatory cells and vascular and cardiac remodeling.
Thus, new compounds targeting this ion channel in the 3 systems (cardiac, pulmonary, immune) concerned in PAH without central effects would be of great value to treat PAH. To date, most antagonists that reached clinical development cannot be used in the periphery without major secondary effects.

Objectives
1. Search for dysfunction of this ion channel in PAH pathophysiology at the vascular and cardiac cell levels and the contribution of immune/inflammatory cells to its activation (partner 6)
2. Design of new molecule hybrids to serve as potent allosteric effectors of this channel and thus modulate its function (partner 15)
3. Conception of pH-dependent antagonists that do not cross the blood-brain barrier, in order to target pulmonary inflammatory sites without central effects (partner 15)
4. Evaluate the new molecules in the classical and newly developed models of PAH (partner 6)
5. Understand how this channel is involved in PAH pathophysiology to propose a mechanism of action for these compounds in treating PAH, integrating data obtained from the 3 systems (immune, heart and lung) (partner 6)
6. Provide structural modeling for the interaction of the new compounds with the channel. The conformational changes of its subunits in presence/absence of the activation co-factors/modulators will be characterized through molecular dynamics approaches and potentially new therapeutic agents able to disturb such interactions will be designed or determined by in silico screening (partner 10)
7. Any opportunity of patenting will be examined with attention by the two arms of this project Pathophysiology/Biology-Chemistry (partners 6, 10, 15)

T1-3

Prevent adverse cardiotoxicity induced by anti-cancer therapy

Coordinators: M.C. Vozenin (Partner 8) and E. Morel (Partner 2)
Financial support from January 2012 until December 2014

Cardiotoxicity is among the chronic toxicities that alter quality of life and survival of patients under anti-cancer treatment. HF is a significant delayed side effect of both chemo- and radiotherapy and will become a major concern within the next years. The most adverse cardiac events are those related to radiotherapy, anthracyclines and their combination specially in pediatric patients, and in patients treated with targeted therapies including herceptin associated or not with radiation therapy. Despite the increasing occurrence of these chronic toxicities, this field of research remains underserved. Partner 8 is one of the rare French laboratories studying the biological basis of the radiotherapy and its consequences on tumors and normal tissues. A proof of concept has emerged recently linking anti-cancer treatments-induced cardiac toxicity and small G proteins. As shown above, Partner 2 has emphasized the role of Epac1 and the small G protein signaling cascade in the context of maladaptive cardiac hypertrophy and HF. Of interest, Epac1 activates common targets of the doxorubicin-induced pathway such as the small G protein Rac and mTOR.
Deliverables:
1. Identification of predictive biomarkers of cardiac disease from blood samples collected in breast and pediatric patients. Genetic polymorphism at the whole genome level (SNPs) will be performed as data reported in breast cancer patients support the relevance of SNPs to predict individual radiation sensitivity and show that possession of multiple SNPs associated with radiosensitivity correlates with an increased probability for developing severe radiation-induced sequels39.
2. Investigation of the alteration of cardiac physiological parameters using appropriate imaging on a cohort of 101 patients treated by radiotherapy for breast cancer. Preliminary results show early presence of cardiac hypertrophy without occurrence of any cardiac symptomatology reported so far, suggesting that radiation-induced cardiac remodeling is a progressive process initiated far before occurrence of any symptoms. Combined with predictive markers and imaging, this opens a new early therapeutic window and would help to improve long term follow up of patients.
3. The aim is to understanding the molecular and physiopathological basis of the radio- and anthracyclines- induced cardiac signaling response leading to the classical pattern of hypertrophy and heart failure and specially the small G-proteins.
4. Patenting and valorization will be undertaken at each step when applicable with the appropriate partners.