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Validation of an « immune signature » predicting a therapeutic response to anthracyclines in breast cancer. – AP’ONCALYPSE

Validation of an « immune signature » predicting a therapeutic response to anthracyclines in breast cancer.

Chemotherapy applied to localized or advanced breast cancer can treat a variable percentage of patients. This healing appears to be inseparable from the development of an antitumor immune response generated by cell death post-chemotherapy. The question raised by this project is to decline the molecular mechanisms subtending the antitumor vaccination post-treatment with anthracyclines (immunogenic) to make a diagnostic test predictor of response.

Define immune predictors of response to adjuvant and neoadjuvant chemotherapy in breast cancers.

This grant application aims at validating a series of novel immune biomarkers of response to anthracyclines predicting the capacity of the host to get immunized (and cured) against his tumor with the hindsight to compensate the defects in immune signaling by specific targeted therapies in « predicted » non-responders. <br />The program project will be performed by the coordinated action of two INSERM teams worldwide recognized in the field of cell death biology and immunotherapy of cancer (U1015 and U848 INSERM closed to the Center of Clinical Investigations CICBT507), one bioinformatician/biomathematician from Ecole des Mines, and the IGR&D tech transfer Department of IGR. <br />The immune biomarkers of response to anthracyclines are composed of 3 nucleic acid probes (CRT map of the ER stress response, derived from tumor RNA) and of 3-6 nucleic acid probes (SNPs in host genes, derived from tumor or leukocyte DNA), for the latter depending whether the setting is adjuvant or neoadjuvant. Objective number 1 will be the validation of these immune signatures in two retrospective cohorts of 680 neoadjuvant treated BC and a 400 adjuvant treated BC. Objective number 2 will be to set up a reliable GLP chip array of prevalidated nucleic acid probes for routine usage. This tool will be patented, the rationale to start up a Biotec. Cie that should set up and validate the manufacturing and predictive value of the device in a prospective trial in two years in case of success of this ANR Emergence grant application (transition for research use only to IVDMIA Handling). The business model that we anticipate should be able to function in a decentralized model (type Agendia) where a diagnostic kit and the interpretation of its results should be provided by the Cie.

task 1. Validate the predictive value of the gene signature of the CRT pathway and host single nucleotide polymorphisms (SNPs) on a large retrospective cohort of >650 breast cancers (bc) treated with neoadjuvant anthracyclines.
Task 2.validate the predictive value of the gene signature of the CRT pathway and host SNPs on a large retrospective cohort of >400 bc treated with adjuvant anthracyclines
task 3. Establish the calculation of a formula from the algorithm of aligned parameters for each patient by appropriate bioinformatic and mathematical softwares.
Task 4. set up the GLP methods to go from the extraction of the cDNA and the gDNA from the tumor to their hybridization onto several fluorescent labelled specific nucleic acid probes (designed in specific aim 1) to support a reliable run of quantitative (CRT map) or qualitative (host SNPs) PCR.
Task 5. Set up an abaque or internal standard of all >300 specimen (obtained from all our retrospective studies containing >300 patients) which have determined the mean+/-sem of expression of each parameter to assess the “relative abundance “and positive and negative controls for the cDNA exploring the CRT map.
Task 6. Benchmarking and search for potential partners to outsource the manufacturing of the final device (diagnosis kit).

Based on test cohorts of breast cancers (BC) that responded or not to neoadjuvant chemotherapy, a list of 20 SNPs has been found to be predictive of response to anthracyclines in BC. These SNPs encode dysfunctions at the level of the immune system that could lead to compensatory treatment targeting the immune defect.

The major endpoint and prospect is to adapt the neoadjuvant chemotherapy to the patient (so called « personalized treatment ») so that her immune defects- predicted based on our model- be compensated by targeted immunomodulatory compounds (such as TLR agonists or calreticuline etc…).

One patent has been filed describing a list of 20 SNPs residing in immune functions that appear to predict non responders in neoadjuvant breast cancers (April 2012, IGR&D).
Our results have not yet been published because a confirmatory study based on a second independent BC cohort (in Germany, Dr DENKERT) will be analysed soon.

Current cancer management aims at integrating molecular signatures in the design of personalized therapies. Recent advances in “omics” have led to the identification of predictive factors pinpointing “drugable” signaling pathways, which can be interrupted by targeted therapies. Those molecular signatures (such as Oncotype DX or Mammaprint° in breast cancers (BC)) only rely on tumor cell profiling, overlooking the host reactivity to the tumor and practically allow to identify those patients that may not need adjuvant high dose chemotherapy, failing to propose a more personalized therapy for bad prognosis patients. However, accumulating evidence underscores a bidirectional tumor-host interaction during therapeutic intervention, indicating that molecular signatures should integrate host-intrinsic parameters. We showed that some cytotoxic compounds (i.e anthracyclines) are capable of triggering an “immunogenic” cell death, thereby eliciting an anticancer immune response that “vaccinate” the host against his cancer contributing to his definitive cure. Our data indicate that failure to activate an antitumor immune response compromises the success of conventional anticancer chemotherapies and can be predicted by specific molecular signatures. We have generated and patented an immunity-based predictor (“Immunpredictor”) in BC that allows us to estimate the probability of the patient to relapse despite anthracyclines (+/-taxanes). This predictive high performance signature consists in a small series of loss of function single nucleotide polymorphisms and candidate gene products involved in ER stress response and autophagy, derived from tumor DNA or RNA at diagnosis respectively. This immune signature is independent from and adds accuracy to the three known clinical factors (grade, HER2 and hormone receptor status) for breast cancer treated by adjuvant or neoadjuvant anthracycline-based chemotherapy. The project will be led by three complementary teams (cell death biology in INSERM U848, immunology in CICBT507 and bioinformatics in Ecole des Mines/Curie) as well as IGR&D technology transfer Department of IGR. The coordinated programm has two aims: 1/ validate these signatures in a two large retrospective cohorts of 680 patients in neoadjuvant and 800 patients in adjuvant, 2/ set up a multiplex chip array containing the validated set of nucleic acid probes for future exploitation and large scale prospective validation in anthracyclines-based therapies in BC. This urgent need for predictive tests that detect functional defects in anticancer immune responses in BC is prompted by the hindsight of designing appropriate compensatory therapies targeting these immune defects.

Project coordinator

Madame Laurence ZITVOGEL (INSTITUT GUSTAVE ROUSSY) – laurence.zitvogel@igr.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IGR&D INSTITUT GUSTAVE ROUSSY - IGR&D (valo)
ARMINES CBIO ASSOCIATION POUR LA RECHERCHE ET LE DEVELOPPEMENT DES METHODES ET PROCESSUS INDUSTRIELS (ARMINES)
IGR INSTITUT GUSTAVE ROUSSY
INSERM U848 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PARIS XI

Help of the ANR 271,671 euros
Beginning and duration of the scientific project: December 2011 - 18 Months

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