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WO2008031910A2 - Modèles expérimentaux pour la métastase osseuse du cancer du poumon non microcytaires - Google Patents

Modèles expérimentaux pour la métastase osseuse du cancer du poumon non microcytaires Download PDF

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WO2008031910A2
WO2008031910A2 PCT/ES2007/000519 ES2007000519W WO2008031910A2 WO 2008031910 A2 WO2008031910 A2 WO 2008031910A2 ES 2007000519 W ES2007000519 W ES 2007000519W WO 2008031910 A2 WO2008031910 A2 WO 2008031910A2
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cell line
cells
lung cancer
genes
small cell
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WO2008031910A3 (fr
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Fernando Lecanda Cordero
Silvestre Vicent Cambra
Francisco Javier De Las Rivas Sanz
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Proyecto de Biomedicina CIMA SL
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0331—Animal model for proliferative diseases

Definitions

  • the present invention is encompassed within the study of cancer, in particular the development of experimental models of lung cancer.
  • STATE OF THE TECHNIQUE Lung cancer represents the leading cause of death in Western countries with more than 500,000 deaths annually in the United States and more than one million worldwide, with a 5-year survival rate around 10-15% More than 90% of lung cancers have been associated with tobacco use.
  • Most current efforts are aimed at improving both early diagnosis and therapy, but so far there are few studies devoted to metastasis, the most devastating complication of lung cancer, responsible for almost all deaths.
  • Adenocarcinoma a form of non-small cell lung cancer, accounts for approximately 80% of cases of non-small cell lung cancer.
  • stage I disease is associated with a favorable prognosis
  • 30-40% of patients diagnosed with stage I non-small cell lung cancer relapsed with metastasis after complete tumor removal.
  • lung cancer cells often escape the primary focus and tend to spread well locally in the cavity.
  • SUBSTITUTE SHEET (RULE 26) thoracic or even distant organs such as the brain, bone, adrenal gland, pericardium and liver.
  • the median survival of these patients is ⁇ 6 months, the lowest of all types of cancer that metastasize to bone, therefore it is by far the worst prognosis.
  • the metastasis of lung cancer to bone is clinically associated with pain, often refractory to conventional therapies, and with compression and fracture of the bone marrow, with fatal outcome in all cases.
  • This multi-stage process involves the coordinated action of multiple genes that allows invasion and intravasation, survival in the capillaries, arrest and growth or finally extravasation and multiplication in the target organ.
  • the metastatic capacity of tumor cells is greatly influenced by their interaction with the bone microenvironment. Heterotopic tumor-stromal interactions, cell-matrix interactions, and paracrine stimulation by soluble factors, can modulate tumor behavior.
  • the ability to metastasize to one or the other organ depends on the phenotypic characteristics of each cell type, that is, on the expression of a profile of promtastatic genes that confer the ability to form metastases in one or the other organs. So far it is not known which are the genes whose expression defines tropism and metastaticity towards one or the other organ.
  • the object of the present invention relates to a non-human animal model of bone metastasis of non-small cell lung cancer.
  • Non-small cell lung cancer is the most frequent and accounts for about 70-80% of the total of all cases of lung cancer.
  • bone metastases are obtained with an efficiency of at least 90%, and in a reproducible and extraordinarily fast manner with a latency time of 9-12 days, differing from the aforementioned US application in that additionally, metastases do not occur multiorganic, but almost exclusively with bone tropism.
  • tumor refers to a cancer or tumor (secondary tumor) that develops in an organ or part of the body by dissemination from tumor cells from a tumor initiated in another organ or part. of the body (primary tumor).
  • tumor cells that have spread to the bone from another organ are not a bone cancer, but bone metastases from a breast cancer. These tumor cells will remain breast tumor cells, regardless of their location in the bone.
  • Non-small cell lung cancer groups several histological lung subtypes that are characterized by they have a slow growth and dissemination and because they can be treated in the same way (surgical resection as a first option, radiotherapy and chemotherapy). Unlike microcytic lung cancer, which is characterized by being very aggressive and rapidly spreading, and because once it has metastasized, it is not a candidate for surgical resection and does not respond to conventional chemotherapy. From the epidemiological point of view, the most relevant non-small cell lung cancer subtypes are: mixed adenocarcinoma (mixed cell adenocarcinoma or mixed subtypes), squamous carcinoma and bronchoalveolar carcinoma (bronchioloalveolar carcinoma), the latter included among the adenocarcinomas.
  • mixed adenocarcinoma mixed cell adenocarcinoma or mixed subtypes
  • squamous carcinoma squamous carcinoma
  • bronchoalveolar carcinoma bronchioloalveolar carcinoma
  • Non-small cell lung cancer subtypes also include large cell carcinoma and other more rare histological subtypes.
  • Intracardiac injection refers to the injection into the left ventricle of the heart of the animal in question.
  • a cell line has the ability to metastasize to bone with an "efficiency of at least 90%" refers to the fact that in at least 9 out of 10 mice that have received an intracardiac injection of said cells, masses have formed Bone tissue tumors.
  • the term "overexpression" of a gene refers to its expression level being at least 1.5 times higher than the expression level of the cells used as a control.
  • the "antimetastatic activity" of a compound refers to its ability to reduce cell migration from the primary focus, or its accommodation in a secondary focus or its growth and development in that focus secondary. Within the context of the present invention the secondary focus is a bone.
  • the present invention relates firstly to a lung cancer cell line characterized in that it is a non-small cell lung cancer and has the ability to metastasize to bone with an efficiency of at least 90% with a latency time of between 9 12 days
  • a lung cancer cell line is characterized in that said cancer has been selected from a line derived from a large cell carcinoma (LCC), carcinoid and bronchoalveolar carcinoma.
  • LCC large cell carcinoma
  • the present invention relates to a non-small cell lung cancer cell line according to claims 1 or 2, characterized in that said cell line is selected from: NCI-H460 subpopulation M5 (ECACC 06091547): LCC, H727 subpopulation M5 / M2 (ECACC 06091545): carcinoid and A549 subpopulation Ml / Ml (ECACC 06091546): bronchoalveolar adenocarcinoma.
  • the non-small cell lung cancer cell line object of the present invention is a large cell carcinoma cell line that overexpresses at least 3, 4 or 5 genes selected from: TCF4, PKD3 (also known as PRKD3) , MCAM, SUSD5 and KIAA0960.
  • TCF4 also known as PRKD3
  • MCAM CAM
  • SUSD5 KIAA0960
  • said large cell lung carcinoma cell line overexpresses the genes TCF4, PKD3, MCAM, SUSD5 and KIAA0960.
  • the cell line is obtained by transducing parental cells with at least 3, 4 or 5 of the genes TCF4, PKD3, MCAM, SUSD5 and KIAA0960, that is to say transfected with vectors that express the proteins that said genes encode
  • said lung carcinoma cell line is derived from the NCI-H460 line, for example from subpopulation M5 (ECACC 06091547).
  • the non-small cell lung cancer cell line object of the present invention is a carcinoid cell line that overexpresses at least 3, 4 or 5 genes selected from:
  • the cell line is obtained by transducing parental cells with at least 3, 4 or 5 of the GAL, SPOCK2, CRIP2, ELF5 and EPCR genes.
  • said carcinoid cell line is derived from the H727 line, for example from subpopulation M5 / M2 (ECACC 06091545).
  • the non-small cell lung cancer cell line object of the present invention is a bronchoalveolar adenocarcinoma cell line that overexpresses at least 3, 4, 5 or 6 genes selected from: ILIl, PITX1, HDAC4, RHOB, R0301 and SLC26A2.
  • the cell line is obtained by transducing parental cells with at least 3, 4, 5 or 6 of the ILI genes,
  • said bronchoalveolar adenocarcinoma cell line is derived from the A549 line, for example of the Ml / Ml subpopulation (ECACC 06091546).
  • the present invention relates to a method for obtaining a cell line described above, characterized in that it comprises: a) intracardiac injection into a non-human animal of cells derived from a parental line from said lung cancer, previously transfected with a selection gene; Y b) isolate, expand in culture and select tumor cells from bone metastases generated in said animal.
  • said method preferably comprises: a) intracardially injecting the cells obtained in step b into a non-human animal; and b) isolate, expand in culture and select tumor cells from bone metastases generated in said animal.
  • said selection gene is an antibiotic resistance gene and a gene encoding luciferase.
  • the cell line to be injected into the non-human animal is derived from a large cell carcinoma, and said method comprises selecting the cells that overexpress at least 3, 4 or 5 genes selected from: TCF4, PKD3 , MCAM, SUSD5 and KIAA0960. In a preferred embodiment, said method comprises selecting the cells that overexpress the 5 genes.
  • the cell line to be injected is derived from a carcinoid, and said method comprises selecting the cells that express at least 3, 4 or 5 genes selected from: GAL, SPOCK2, CRIP2, ELF5 and EPCR. In a preferred embodiment, said method comprises selecting the cells that overexpress the 5 genes.
  • the cell line to be injected is derived from a bronchoalveolar adenocarcinoma, and said method comprises selecting the cells that express at least 3, 4, 5 or 6 genes selected from: ILIl, PITXl, HD ⁇ C4, RHOB, ROBOl and SLC26A2 .
  • said method comprises selecting the cells that overexpress the 6 genes.
  • said cells derived from a parental line of non-small cell lung cancer are selected from: NCI-H460, A549 and H727.
  • the present invention relates to a non-human animal model of non-small cell lung cancer with bone metastases characterized in that it comprises injecting tumor cells intracardially into the animal from a cell line described above.
  • the non-human animal object of the present model is an immunosuppressed animal, more preferably it is a rodent.
  • said animal is a nude athletic mouse.
  • the present invention relates to a method for obtaining said non-human animal model of non-small cell lung cancer with bone metastases characterized in that it comprises injecting intracellularly into the animal tumor cells from a cell line defined in the preceding paragraphs.
  • the present invention relates to the use of the cell line or animal model described above and object of the present invention, to test the antimetastatic activity of a compound.
  • said metastatic activity assay comprises: a) culturing cells of said cell line with the compound to be tested; and b) compare the antimetastatic effect produced on said cells with respect to control cells treated with another reference compound or that have not been treated.
  • said antimetastatic activity assay comprises: a) administering the compound to be tested to said model animal, and; b) compare the effect of said compound on the tumors of said animal, with the tumors of control animals treated with another reference compound or that have not been treated.
  • said antimetastatic activity to be tested is selected from: prevention of metastasis, damping of the deleterious effects of metastasis, and a blocking action of tissue-specific tropism.
  • the present invention relates to the use of a cell line described above, in a method for identifying markers associated with non-small cell lung cancer characterized in that it comprises comparing the presence, absence, or level of gene expression in tumor tissue samples of said cell line, with gene expression in control cells.
  • the present invention also relates to the use of an animal model described above, in a method for identifying markers associated with non-small cell lung cancer characterized in that it comprises comparing the presence, absence, or level of gene expression in samples of Tumor tissue said model animal, with the gene expression in the tissue of a second animal that has not received cell injection.
  • FIG. 1 RT-PCR analysis of a panel of microcytic (SCLC) and non-microcytic lung cancer lines
  • NSCLC Neurotrophic factor-containing cell sorting
  • the genes involved in, metastases in other models include MIP-l ⁇ , osteopontin, PTHrP, MMP-2, Galectin-3, CTGF were compared with a control gene, ⁇ -actin.
  • the cells used included SCLC: 1. H69; 2. H82; 3. H187; 4. H345; 5. H446; 6. H510 and NSCLC: 7. H460; 8. A549; 9. H441; 10. HTB58; 11. H676; 12. H727; 13. H720; 14. H1299.
  • Figure 2 Chemotaxis test. Induced or non-induced cells with 10% serum (FCS) in the lower compartment of a Boyden chamber for 6 hours. The cells that migrated to the lower compartment were stained with fluorescent staining. Total fluorescence was measured using a 480/520 nm filter.
  • Figure 3 Kaplan-Meier curve of several groups of atomic mice inoculated with different human tumor cell lines: H460, H157, H1299 and A549.
  • Figure 4 Bioluminescence image in vivo. Cells stably transfected with CMV-Luc were selected and inoculated into the left ventricle of the heart of atomic mice. Two weeks later they were visualized. A. H1299 cells. B. A549 cells. Control mice are at the bottom. C. H460 cells. The control mouse is in the center of the bottom.
  • FIG. 5 X-ray analysis of the dorsal vertebrae of a control mouse and a mouse inoculated with tumor line A. A549. As shown, osteolytic lesions appear concomitantly with reactive periodic osteogenesis (right panel, arrows) .B. H460 Osteolytic lesions were observed in the distal and proximal epiphyses of the femur and tibia.
  • Figure 6 Bioluminescence images in vivo. The cells were transfected with ON-Luc (osteonectin promoter with luciferase). After selection, the cells were inoculated into the left ventricle of nude atomic mice. Two months after the injection the cells were visualized. A. H727 cells. B. HTB58 cells. The Control mice are the first on the left in both panels.
  • ON-Luc osteonectin promoter with luciferase
  • Figure 7 In vivo strategy to find out the target tissues of metastasis.
  • Figure 8 Kaplan-Meier curve of parental H460 (CMV) and metastatic subpopulations (Ml, M4 and M5).
  • Figure 9 Number of SCC (colonies derived from a single cell) derived from the inoculation of 10 mice with parental H460 (CMV) and metastatic subpopulations (Ml, M4 and M5).
  • Figure 10 Metastatic area in the long bones of mice inoculated with parental H460 (CMV) and metastatic subpopulations (Ml, M4 and M5).
  • FIG 11 Kaplan-Meier curve of parental A549 (CMV) and metastatic subpopulations (Ml, Ml / Ml, M1 / M3 and M1 / M4).
  • Figure 12 Metastatic area in the long bones of mice inoculated with parental A549 (CMV) and metastatic subpopulations (Ml, Ml / Ml and M1 / M3).
  • Figure 13 Total number of metastatic subpopulations isolated from femurs and tibiae of 7 of the 8 mice inoculated with highly metastatic cell lines
  • mice Twenty-five days post-inoculation, the mice were sacrificed and the bone marrow cells were cultured in selection medium containing G-418, for 5 days. After that time the SCC (colonies derived from a single cell) were counted.
  • Figure 14 A. Number of isolated subpopulations of long bones from 8 mice inoculated with YiI21 cells, 59 days after inoculation (upper panel) and in 7 mice inoculated with A549 cells, 29 days after inoculation (lower panel). B. Radiography of the lower limb of a mouse inoculated with H727 and A549 cells, showing metastatic lesions. The total number of subpopulations isolated after "flushing" of the bone marrow was 192 for H727 and 3190 for A549. Observe the injuries prominent induced by H727 and the small number of isolated subpopulations compared to A549.
  • Figure 15 A. Hematoxylin-Eosin of femoral sections of mice treated with vehicle and inoculated with H460 cells intracardiacly. B. Count of the number of osteoclasts induced by the H460 line.
  • Figure 16 Count of the percentage of the metastatic area of total osteolysis with respect to the total bone area on radiographs, obtained by image analysis of the long bones (femurs and tibiae) of mice inoculated with control H460 cells, or H460 transduced with A. TCF4, PRKD3, MCAM and SUSD5.
  • B H460 transduced with three genes, PRKD3, SUSD5, TCF4 or, PRKD3, MCAM and TCF4.
  • Figure 17 A. Kaplan-Meier curve of parental transfected H727 cells (ON-LUC) and metastatic subpopulations (M4 / M2, M4 / M3, M5 / M2 and M5 / M4) derived from the parental line.
  • ON-LUC parental transfected H727 cells
  • EXAMPLE 1 Development of highly metastatic cell lines with bone tropism. Material and methods The cell lines used were: H460 (ATCC No. HTB-177): from a mixed non-small cell lung cancer obtained from a lung biopsy of a 54-year-old black man with stage 3A tumor at the time of diagnosis.
  • H727 from a carcinoid tumor obtained from a lung biopsy of a 65-year-old Caucasian woman with stage 3A tumor at the time of diagnosis.
  • H157 ATCC No. CRL-5802: from a squamous cell carcinoma obtained from the pleural effusion of a 59-year-old caucasoid man, with a stage 3A tumor at the time of diagnosis.
  • H1299 ATCC No. CRL-5803: from a lung carcinoma obtained from the biopsy of a lymph node from a caucasoid man of 43 years, with a stage 3A tumor at the time of diagnosis.
  • A549 (ATCC No. CCL-185): from a lung carcinoma obtained from the biopsy of a tumor of a 58-year-old caucasoid man.
  • HTB58 from a squamous cell carcinoma obtained from the pleural effusion of a 65-year-old Caucasian man.
  • Intracardiac injection was performed according to the protocols known to a person skilled in the art. A total of 200,000 cells in which a selection gene has previously been inserted, with a viability greater than 95% in 100 ⁇ l of PBS were injected. Cellular invasion was determined using a modified two chamber migration assay (8 ⁇ m pore diameter, Chemicon International, Inc) according to the manufacturer's instructions. The cells were seeded in the upper chamber in a medium containing 0.4% serum and migrated to 10% bovine serum from Calf (FCS) in the lower chamber for 8 hours. The cells of the lower membrane were peeled, used and stained with CyQuant GR Dye. Fluorescence was analyzed in a plate reader using 480/520 nm filters.
  • mice were sacrificed according to the protocols approved by the Animal Experimentation Committee of the institution where the trials were conducted.
  • the long bones were removed and cleaned of all soft tissues.
  • the marrow cells were released by dragging, introducing 5 ml of ⁇ -MEM with a 27G diameter needle into the distal epiphysis through the bone marrow.
  • the cells were plated on p-100 and p-150 plates and expanded for 5 days in medium supplemented with G-418. This procedure was performed separately for each femur and tibia. Subpopulations were quantified under the microscope after staining with violet crystal.
  • the X-ray analysis was performed using a Faxitron MX-20 with a high sensitivity film MNR-2000 (Kodak), using an exposure of 2OkW and 20 seconds and 2 x magnifications.
  • CMV-luc luciferase reporter gene
  • the B727 parental line showed bioluminescence at sites compatible with a bone location in 7 of 8 animals ( Figure 6). Intracardiac inoculation of HTB58 cells induces the formation of tumors in the dorsal region of the scapula in 5 of the 7 animals studied ( Figure 6).
  • Subtle differences between the three parental lines H460, H727 and A549 were detected by histological examination. Although the location was similar, the histological examination revealed specific patterns of invasion and colonization. Lesions of the three parental lines were in the lower extremities. Lesions caused by H460 always appeared in the metaphyses proximal tibial and distal femoral.
  • the subperiosteal surface is a frequent target of metastasis, especially around the epiphyseal region. The growth of periosteal tumors progresses between the periosteum and the cortical bone, often inducing a reactive osteogenesis in the cortical bone.
  • Both line A549 and H460 induce a new osteoid formation from the periosteum of the epiphyseal-metaphyseal region.
  • the progression of the lesions is driven by tumor growth by colonizing the bone marrow and destroying the primary spongy.
  • the A549 line has the ability to target the vertebrae in addition to the lower extremities.
  • macroscopic osteolytic lesions could be detected in the cortical bone, arising from the periosteum and progressing to the medulla.
  • a strong osteoclastic activity was detected in the endostium by TRAP staining ( Figure 15).
  • EXAMPLE 2 Development of an animal model of bone metastasis of non-small cell lung cancer. Material and methods
  • the H460 subpopulation M5, A549 subpopulation Ml / Ml and H727 lines have been used as cell lines subpopulation M5 / M2, which were grown in RPMI at 10% FBS, supplemented with 0.4 mg / ml G418.
  • mice Female 4-week-old nu / nu mice were used, which were anesthetized with ketamine (100 mg / kg) and xylazine (10 mg / kg) prior to intracardiac injection.
  • the procedure consisted of injecting 200,000 cells from one of the H460 subpopulation M5 cell lines (ECACC).
  • this animal After a latency period of 7 days, this animal can be considered a model of bone metastasis of lung cancer that can be used to study the development of such metastases, to test the effect of potential antimetastatic agents, etc.
  • EXAMPLE 3 Profile of genetic expression associated with bone metastasis.
  • H460, H727 and A459 selected for their ability to generate bone metastases. In all cases a differential expression analysis was performed against the parental line from which they were derived.
  • the gene expression of the subpopulations Ml, M4 and M5 was analyzed. Differentially expressed genes were selected by contrasting under highly restrictive conditions using the algorithm described previously (Irizarry, 2003) and FDR ⁇ 0.02. Highly metastatic subpopulations showed a unique transcriptional pattern of 43 genes. Most of these genes were overexpressed more than 1.5 times. These proteins include MCAM, a transmembrane adhesion molecule previously associated with melanoma metastases. Two intracellular components were also identified: TCF4, a transcription factor, and PKD3, a poorly characterized serine / threonine kinase.
  • transient cells grew at a rate similar to the parental cell line in culture and in vivo after subcutaneous injection. Which means that its greater activity of bone destruction is not simply due to the faster reproliferation of cells, but to its specific effect on the bone.
  • the gene expression of the subpopulations Ml, Ml / Ml and Ml / M3 was analyzed, in a similar way as it was done for the subpopulations of the H460 line.
  • Highly metastatic subpopulations showed 6 genes that were overexpressed more than 1.5 times. These genes include ILIl encoding a cytokine of the gpl30 family, PITXl encoding a factor that acts as a transcriptional regulator, HDAC4 encoding the histone deacetylase 4 involved in the cell cycle, the RHOB shrink, ROBOl a member of the immunoglobulin superfamily and SLC26A2 encoding a membrane protein.
  • EXAMPLE 4 Test of potential antimetastatic agents in cell lines and / or animal model described in the previous examples.
  • this animal After a latency period of 7 days, this animal can be considered a model of bone metastasis of lung cancer. After these 7 days the antimetastatic agent to be studied is administered, following a previously designed administration regimen. At 21 days after inoculation the animal is sacrificed. By comparing the femurs of animals that have received the antimetastatic and control animals (who have developed the metastasis without any additional treatment or having received vehicle doses) the antimetastatic activity of the agent in question can be determined.

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Abstract

La présente invention se rapport à différentes lignées cellulaires du cancer du poumon non microcytaire à capacité de métastase osseuse à efficacité élevée. L'invention se rapporte aussi aux procédés d'obtention des lignées cellulaires, aux modèles animaux correspondants et à l'utilisation de ceux-ci.
PCT/ES2007/000519 2006-09-15 2007-09-14 Modèles expérimentaux pour la métastase osseuse du cancer du poumon non microcytaires Ceased WO2008031910A2 (fr)

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Publication number Priority date Publication date Assignee Title
WO2010023340A3 (fr) * 2008-08-28 2010-05-20 Proyecto De Biomedicina Cima, S.L. Nouveau biomarqueur utilisé comme cible thérapeutique dans le cancer du poumon

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US20050181375A1 (en) * 2003-01-10 2005-08-18 Natasha Aziz Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of metastatic cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023340A3 (fr) * 2008-08-28 2010-05-20 Proyecto De Biomedicina Cima, S.L. Nouveau biomarqueur utilisé comme cible thérapeutique dans le cancer du poumon

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