IRP1 : UNDERSTANDING CELL PLASTICITY TO IDENTIFY INNOVATIVE CANCER CELL AND IMMUNE CELLS TARGETS
The IRP1 is Co-led by : 
Alexandra TRAVERSE-GLEHEN
Christophe CAUX
Nathalie BENDRISS-VERMARE
The IRP1 is divided into 4 axis, as follows :
AXIS 1. Genetic drivers and epigenetic reprogramming in cancer cell plasticity – Identifying genomic alterations and epigenetic modifiers (“epidrivers”) AXIS 2. Targeting EMT-driven cancer cell plasticity AXIS 3. Cell plasticity and immune responses AXIS 4. Patient trajectories, networks and accessibility to innovative treatments Intra-tumoral heterogeneity is a real challenge for precision medicine. To address this question, different approaches are being developped in order to identify new genetic or epigenetic targets involved in cancer cell plasticity. GENETIC TARGETS: ProFILER, the first molecular profiling clinical trial set up and supported by the first SIRIC has yielded a large amount of data available to perform datamining. Indeed, 3210 patients could benefit from the molecular characterization of their tumor (using a panel of 74 genes), among which 757 patients could have a recommandation of treatment. This first step led to ProFILER02, with the support of Roche Pharma France, which is dedicated to assess the benefit of a larger panel (Panel FOne FoundationOne®, 315 gènes) versus the acedemic panel used in ProFILER (74 genes). The identification of new genetic or epigenetic should should lead to drug developpement. Indeed, the C3D laboratory (CENTER FOR DRUG DISCOVERY AND DEVELOPMENT) is a dedicated structure able to perform the screening of a large number of drugs. The pre-clinical evaluation is also possible on site, giving the best environment conditions for innovation. The well-know and described plasticity mechanism is the epithelial-to-mesenchymal transition, aslo called EMT. The laboratory of Alain Puisieux (CRCL) has published key findings on the role of embryonic transcription factors in this process, as well as the capacity of stemness induced by those transcription factors can protect cells from chromosomal instability increasing stem cells’ intrinsic susceptibility to malignant transformation. Based on this strong expertise and well characterized cellular models, EMT associated biomarkers will be studies to generate EMT-targeting drugs. Cell plasticity and consequent escape mechanisms are not only true for cancer cells but also for immune cells. Antibodies against immune check points (PD1 or CTLA4) demonstrate remarkable efficiency in several major types of advanced cancers such as melanoma, lung, kidney, bladder and head and neck carcinomas. Response rates range from 15% to 40%. However, these promising immunotherapies have limitations: i) only 15% to 50% of patients respond to treatment in susceptible diseases, ii) certain cancer types are poorly sensitive to ICP immunotherapies, iii) responder patients often relapse because their tumor acquires resistance mechanisms, iv) toxicities are frequent, vi) the cost of these treatments is very high. Response to treatment is also known to be dependant on the infiltration of immune cells, such as T-Cells. The objectives are to decipher the consequences of tumor cell plasticity on immune recognition and immune escape and to characterize immune cell plasticity during tumor progression and identify targets to restore anti-tumor immunity. The program will, in first place, focus on breast, gynecological, and lung cancers, melanomas, lymphomas mesothelioma and sarcoma.
Integrated social sciences and humanities projects
Due to the emergence of various new targeted therapies, a number of sociological questions arise regarding their accessibility to the general population. Therefore, three axis will allow to investigate: – the access, – the impact on patient trajectories, – the difference in France and in Europe. Unique active networks, such as the sarcoma network or the European Reference Network (EURACAN), will be used to assess the various questions of this IRP1 regarding access to innovation.
IRP2 : COMBINING TREATMENTS TO PREVENT PRIMARY AND SECONDARY RESISTANCE THROUGH CANCER CELL PLASTICITY
The IRP1 is Co-led by : 
Pierre SAINTIGNY
Stéphane DALLE
Armelle DUFRESNE
The IRP1 is divided into 4 axis, as follows :
Axis 1. Mechanisms of resistance to targeted oncogenic therapies Axis 2. Understanding and overcoming intrinsic and acquired resistance to immunotherapies Axis 3. Innovative combinations with immunotherapy/ Innovative immunotherapy-containing combinations Axis 4. From experimentation to implementation of therapeutic innovations in the general public of cancer patients Resistance mechanisms occur through aquisition of new genetic alteration, generating resistant subclones. However, other mechanisms such as cell plasticity are also known to result in resistance by escaping treatment. As an example, Epithelial-to-Mesenchymal transition (EMT) is known to confer resistance to a variety of cancer therapies. The objective of the IRP2 is to decipher the mechanisms driving resistance through cell platicity in order to identify new actionable pathways to facilitate access to new drugs. This approach also involves developping algorithms and mathematical model of response to treatment, and identify strong driver(s). This work will rely on previous and forthcoming clinical trials, such as : first-in-human phase I (Frizzled10 Ab, NCT01469975, Netrin Ab NCT02977195), phase II (NiloPVNS NCT01261429), randomized phase II trials (IL-7 in lymphopenic patients NCT02029001, Pazopanib in GIST NCT01368107) and large scale longitudinal cohorts, including the ProfiLER trial (NCT01774409). They definitively provide unique opportunities to better explore the resistance mechanisms to Targeted Therapies and immunotherpaies. Innovative approaches or screening techniques will also allow to investigate genetic modifiers of response to targeted therapies, EMT-driven cancer cell plasticity in circulating tumor cells (CTCs) as well as ibrutinib-resistant malignant lymphoma. Comparing « cold » versus « hot » tumors, the role of the immune sytem will aslo be analyzed to propose new strategies to induce immunogenic response. The identification of new mechanisms of resistance will provide the rational for future innovative combination clinical trials proposed within the frame of LYriCAN.
Integrated social sciences and humanities projects
Rapid advances in the genomic characterization of tumors combined with the development of targeted therapies and immunotherapies are generating major changes in the landscape of clinical oncology. Precision medicine not only impacts on health professionals by redefining medical specialties, but also on hospital organization. The goal here is to investigate how this emerging data-driven medicine may transform medical practices in oncology. Moreover, the role of the patient is also evolving and is becoming, or is asked to become, more and more active. Benefits from self-reporting have been shown and this will be evaluated with patients treated by targeted- or immunotherapies.
IRP3 : PHYSICAL AND MATHEMATICAL METHODS TO ANALYSE AND OVERCOME TUMOR PLASTICITY AT THE MACROSCOPIC LEVEL FOR PERSONALISED TREATMENTS
The IRP1 is Co-led by : 
Anne-Laure GIRAUDET
David SARRUT
Aurélien DUPRE
This axis is devided into 4 axis, as follows:
Axis 1. Ultrasound guided focal treatment of tumors with High Intensity Focused Ultrasound (HIFU) Axis2.Image-based personalized dosimetry in radiotherapy Axis 3. Multiscale radiomic phenotype determination for personalized treatment Axe 4. Exploring the Volume Outcome Relationship in the framework of innovative radiation therapy This IRP3 is focusing on the development of image-based personalised treatments using physical agents to analyze tumor heterogeneity and plasticity in vivo. Physical destruction or removal of macroscopic tumor cell masses, in patients with localized inoperable disease, as well as in patients with metastatic disease, enables to treat in a single step a large number of tumor cells and cancer ecosystems. Tumors cells plasticity generates inter-patients as well as intra- and inter-lesions heterogeneity within a single patient, evolving spatially and over time. Personalized medicine must include an appraisal of this heterogenous behavior across tumor sites in a single patient. Imaging and computer simulations are keys elements to explore this heterogeneity and plasticity at the macroscopic level for this purpose. The first axis is devoted to the increasing development of High Intensity Focused Ultrasound (HIFU) as an image-guided tumor ablation technique alternative to surgical resection, with a specific program dedicated on the impact of this therapy on the immune system. The second axis focuses on image-based personalized dosimetry to customize radiation dose to be delivered according to imaging exams; the aim here is to boost targeting and personalized sparing of organs at risk, both for external and internal radiation therapy. The third axis is dedicated to multiscale radiomic phenotype determination based on mpMRI and nuclear imaging. Machine learning approaches (radiomic) will be used to link images and deformation characteristics to biological parameters. A fourth axis is devoted to the analysis of the volume outcome relationship (VOR) in a collaboration between Social and Human Sciences and economy researchers. The goal here is to demonstrate the impact of image-based adaptive methodologies on several treatments, but also provided insights through quantitative biomedical imaging for the others IRP.
Integrated social sciences and humanities projects
The volume outcome relationship (VOR) is a concept mainly investigated in health economics: higher volume hospitals provide better outcomes (e.g lower mortality rates). Studies can for example explain the VOR in the context of surgery, with surgical techniques linked to surgeons’ volume. The goal here is to explore the VOR in the field of personalized medicine by developing a theoretical framework of the VOR and go further to propose an innovative radiation therapy. The ultimate goal is to provide significant and qualitative data to impact on policy implication and improve patients’ care and health economy.