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Pharmacokinetic parameters of S49076 administered orally to female balb/c nu/nu mice

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

Western blot detection of total and phosphorylated MET, AXL, FGFR1/2/3 and phosphorylated FRS2 in cell lines and tumor xenografts used in the study

Supplementary Figure Legends

PDF file, 156K, Histopathological characterization of the tumor samples.

PDF file, 923K, Comparison of gene expression between primary tumor sample, early and late xenograft sample.

PDF file, 129K, Table S1: Description of sequenced exons. Table S2: tumor growth observed in the first engraftment. Table S3: Tumor samples for which development of metastasis has been observed after an engraftment into the cecum. Table S4: Ontology analysis of gene differentially expressed between patient tumors and xenografts.

CCR Translation for This Article from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis.Results: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance.Conclusions: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients. Clin Cancer Res; 18(19); 5314–28. ©2012 AACR.

PDF file, 241K, Frequency of abnormalities detected by aCGH among all samples tested across the genome.

PDF file, 67K, Hierarchical clustering of 82 tumors based on Chromosomal abnormalities analyzed by 244k aCGH.

PDF file, 72K.

Background Although the mainstay of cholera treatment remains rehydration, treatment with antibiotics is recommended in serious forms and on specific sites. However, since the late 1970s, resistance to antibiotics in strains of Vibrio cholerae (Vc) has been observed and now threatens the effective treatment and control of cholera. Objective and Methods This cross-sectional, retro-prospective, descriptive and analytical study aims to describe the long-term evolution of the antibiotic resistance profile of Vibrio choleraeO1 strains isolated at the provincial public health laboratory of North Kivu during cholera epidemics in Eastern Democratic Republic of Congo (DRC) from January 1, 2011 to June 30, 2022. Results A total of 4832 isolates of Vibrio cholerae O1 were collected, more than half of them (72.46%, n=3175) in the province of North Kivu. Of the 3 serotypes, Vc O1 Inaba was the majority (57.6%, n=2522). Among the 4382 strains of Vc O1, very high levels of resistance were found to ampicillin (74.7%), nalidixic acid (83.8%), erythromycin (73.6%), chloramphenicol (68.8%) and Sulfamethoxazole/Trimethoprim (82%). A resistance of 30% (1316/4382) was found to doxycycline, a molecule recommended by the WHO as first-line in the treatment of cholera. We found 27 different resistance profiles (MDR) with respect to the 5 main molecules recommended in anticholera therapy. In the analytical study, we observed a statistically significant evolution over time (p=0.000) of these MDR profiles, including 5% in 2011 against nearly 40% between 2021 and 2022; with a distribution statistically dependent on age (p=0.0003) including 57.4% of cases in children under 15 (27% in those under 5); with a predominance (69%) in the province of North Kivu. Conclusion The resistance of Vibrio cholerae 01 to common antibiotics is high in eastern DRC and tends to increase over time. The abusive and inappropriate use of antibiotics is one of the major causes of this emergence of antimicrobial resistance. Close monitoring and measures for the proper use of antibiotics will be necessary to stem this scourge.

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Risperidone and paliperidone palmitate are two antipsychotic drugs well tolerated in the management of schizophrenia and other psychiatric conditions. There have been few reports of tachycardia induced by either drugs. Here, we report on a 21-year-old man, with a history of schizophrenia, and who developed persistent sinus tachycardia after he was restarted on risperidone, which later worsened after administration of paliperidone palmitate for long-term management. He had no cardiovascular risk factors other than obesity, and a prior well-tolerated risperidone treatment. Clinicians must be aware of the possibility of patients developing sinus tachycardia due to autonomic instability from a prior risperidone treatment, even though overall, these drugs are well tolerated.

International audience; Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, welltolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.

International audience; Reaction of a [Mo6Br8F6]2- octahedral cluster unit with functional carboxylic acid leads to the formation of the corresponding carboxylate along with the elimination of HF and the formation of a Mo-O bond between the cluster and the carboxylate. This offers an easy way to prep. Mo6 cluster functionalized surfaces by simple reaction of carboxylic acid-modified n-type Si(111) surfaces in a soln. of [Mo6Br8F6]2- cluster units. The surface coverage of metallic clusters has been controlled in the range 0.3-5.8 × 1013 cm-2 by diln. of the carboxylic acid-terminated org. chains with inert n-dodecyl chains. The homogeneity of the grafted films on the oxide-free Si surface was followed by combined XPS and STM analyses whereas the electronic gap corresponding to the difference between the conduction band min. (CBM) and the valence band max. (VBM) of a single immobilized cluster was detd. from tunneling spectroscopy data obtained from a surface with a low cluster coverage. The energy position of the VBM of the functional surface was detd. by UPS for a surface with a high cluster coverage and charge transport characteristics through Hg//[Mo6Br8F6]-terminated org. monolayer (OML)//n-Si junctions were measured using the mercury drop technique. These studies allow the detn. of the electronic band diagram at the cluster-org. layer-Si(111) interfaces. Results are discussed and compared with other covalent assemblies of metallic clusters onto Si surfaces differing by the nature of cluster cores, [Re6Sei8]2+ or [Mo6Ii8]4+, and linker functionality, carboxylic acid or pyridine.

Mcl-1 is highly expressed in a variety of human cancers (including those of hematopoietic and lymphoid origin) and is exploited by cancer cells to evade cell death and to develop resistance to diverse chemotherapeutic agents. We disclose, for the first time, the structure of S64315 (also named MIK665) a highly potent and selective inhibitor of Mcl-1 with improved potency over its predecessor S63845 (Kotschy et al, Nature, 2016). S64315/MIK665 is currently in phase 1 in AML (Acute Myeloid Leukemia) and MDS (Myelodysplastic Syndrome) (EudraCT 2016-003768-38, NCT 02979366) and in MM (Multiple Myeloma) and lymphoma (NCT02992483). A fragment-based, structure-guided drug discovery effort led to the identification of S64315/MIK665 that binds to human Mcl-1 with a sub-nanomolar affinity (Ki 0.048 nM) and selectively over other anti-apoptotic Bcl-2 family members. It has similar affinity for human, rat, dog and monkey Mcl-1 but about a ten-fold lower affinity for mouse Mcl-1. S64315/MIK665 causes dose-dependent activation of the intrinsic apoptosis pathway in a Bax/Bak-dependent manner, as measured by increased caspase activity and cleaved PARP. S64315/MIK665 shows strong cell killing activity in a diverse panel of human hematological tumor cell lines, including AML, lymphoma and MM. The activity profile of S64315/MIK665 is distinct from that of venetoclax, a selective Bcl2 inhibitor. In vivo, S64315 as single agent demonstrated potent and dose-dependent apoptotic and antitumor response after intravenous administration in several human hematological tumor models grafted in immuno-compromised mice and rats. Complete regression of established tumors, at well tolerated doses, was achieved using different intravenous dosing regimens in rats as well as in mice. Finally, dual BH3-mimetic targeting approach combining S64315/MIK665 with BCL2 inhibitors showed strong and durable antitumor responses in several hematological tumor models both in vitro and in vivo. Citation Format: Ana Leticia Maragno, Prakash Mistry, András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Alain Bruno, Audrey Claperon, Heiko Maacke, Erick Morris, Youzhen Wang, Alix Derreal, Márton Csekei, Attila Paczal, Zoltán Szabo, Szabolcs Sipos, Agnes Proszenyak, Balázs Balint, Allan Surgenor, Pawel Dokurno, Natalia Matassova, Ijen Chen, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Grave, Frédéric Colland, Ensar Halilovic, Olivier Geneste. S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4482.

In this study, InAs metal-oxide-semiconductor field effect transistors (MOSFETs) ultra-thin body (UTB) were fabricated with self-aligned method. 4 nm thick Al 2 O 3 gate oxide was deposited by Atomic Layer Deposition (ALD) technique. Ni-alloyed ohmic contacts for n-type source and drain (S/D) regions were formed at low annealing temperature (250°C). For a MOSFET with a gate length (L G ) of 150 nm, we obtained a maximum drain current (Ion) of 700 mA/mm, and the extrinsic transconductance (G M , max) showed a peak value of 500 mS/mm. The devices exhibited a current gain cutoff frequency f T of 100 GHz and maximum oscillation frequency f MAX of 60 GHz for drain to source voltage (V DS ) of 0.7 V.

Tuberculosis (TB) continues to represent an important public health challenge in the world and the USA, especially given its association with HIV infection and population migration. Cervical tuberculous lymphadenitis represents the most common extrapulmonary presentation of TB in the USA. Considerations for other causes of neck mass often contribute to delay in diagnosis. In this report, we describe the case of a 41-year-old man who presented with painful swelling of the neck and was diagnosed with tuberculous lymphadenitis, complicated by HIV therapy-associated immune reconstitution syndrome. Prior to this diagnosis, he presented with a chronic intermittent cough, repeatedly treated as bronchitis. Furthermore, TB is a recognised occupational risk for primary care physician, as they are often the first contact for patients. With the Patient Protection and Affordable Care Act in the USA, the risk is likely to increase with the influx of newly insured often poor, and/or immigrants.

International audience; Tetrahedral amorphous carbon (a-C) films have been grown by pulsed laser deposition to investigate a liquid phase process for surface immobilization of electroactive [Mo6Ii8]4 + transition metal cluster cores using a complexation reaction with a pyridine-terminated alkyl monolayer covalently bonded to the a-C surface (PyS–alkyl/a-C). These films are stable against thermally-assisted grafting of alkene molecules and the covalent Csingle bondC interface provides a robust monolayer/a-C assembly. Octahedral [Mo6Ii8]4 + cluster cores with iodine inner ligands and labile triflate apical ligands [Mo6Ii8(CF3SO3)a6]2 − have been immobilized through partial complexation in apical positions by surface pyridine groups (PyS). The remaining CF3SO3− apical ligands of [Mo6Ii8 (PyS)ay(CF3SO3)a6 − y] cluster units were further substituted with bromopyridine (Py-Br) to obtain air stable surface with expected final composition [Mo6Ii8 (PyS)ay(Py-Br)a6 − y]. The yield of the different reaction steps is followed by X-ray photoelectron spectroscopy, providing cluster coverage ΣMo6I8 = 9 × 1012 cm− 2. Each [Mo6I8]4 + cluster is bound to the carbon surface through multiple anchoring metal sites (NPYR = 3 or 4), indicating that pyridine-terminated alkyl chains are flexible enough to accommodate four bonds. Electrical transport through Hg//Mo6I8–PyS–alkyl/a-C/p-Si(111) junctions shows rectifying current–voltage characteristics but does not reveal any signature of cluster immobilization.

Previous studies have established that reciprocal interactions between the low-affinity p75 nerve growth factor (NGF) receptor (p75(NTR)) and the high-affinity TrkA NGF receptor can dictate the cellular response to NGF. As the most important interaction, TrkA signaling was found to inhibit p75(NTR)-mediated sphingomyelinase (SMase) stimulation, ceramide production, and apoptosis. However, the mechanism by which TrkA counteracts p75(NTR)-coupled sphingolipid signaling is still unclear. Considering the stimulatory effect of NGF on protein kinase C (PKC) activity, we investigated the role of PKC in TrkA/p75(NTR) signaling interaction. In this study, we found that, in SK-N-BE cells, which selectively express p75(NTR), phorbol ester-induced PKC stimulation resulted in the abrogation of SMase stimulation and ceramide production induced by NGF. Moreover, in SK-N-BE neuroblastoma cells, which selectively express TrkA, NGF stimulated global PKC activity through two independent pathways involving phospholipase Cgamma (PLCgamma) and phosphoinositide-3 kinase (PI3K). In SH-SY5Y, another neuroblastoma cell line, which coexpresses TrkA and p75(NTR), NGF induced PKC stimulation through a TrkA/PI3K signaling pathway, whereas there was no ceramide production. However, in these cells, the inhibition of TrkA, PI3K, and PKC resulted in the restoration of NGF-induced ceramide production. Thus, our study demonstrates for the first time that TrkA interferes with p75(NTR) signaling through a PI3K/PKC-dependent mechanism.

Many reports support that xenografts from patient-derived xenografts (PDXs) in mice or rats well recapitulate the molecular diversity, cellular heterogeneity, and histology seen in patient tumors. However, shortcomings including limited clinical diversity of the PDXs, absence of influence of human microbiome, absence of drug human metabolism and reduced immune system restrain the predictive values of these PDX models. To set-up a holistic integration of these criticisms, we have associated efforts from public hospitals, academic groups, biotechs and private pharmaceutical companies with the financial support of the French Ministry of Industry. Patient surgical specimens from different breast tumor subtypes, among 9 other cancer pathologies, are collected to establish large collections of PDXs in mice. In addition, in vitro primary cultures of cells from these samples are conducted to establish a collection of cell lines from the stromal and the tumoral compartments. The 40 established breast PDX models represent the 4 major molecular clinical subtypes among which 37% are triple negative, 33% are Luminal B HER2-, 22% are Luminal B Her2+ and 8% Her2+. The models are evaluated for ex vivo and in vivo sensitivities to 4 clinically relevant anticancer drugs, for histology, immune infiltrates, and molecular characteristics including the analysis of gene polymorphism, RNAseq gene expression and NGS exome sequencing of 112 genes. The metagenomic sequencing of the gut microbiota from stools collected in both patients and tumor-bearing mice before and after chemotherapeutic treatments improves our knowledge on the role of microbiota in cancer progression and treatment. Secondly, to increase the predictability of the models, we are generating mice with humanized liver showing distinct drug pharmacokinetic profiles as compared with parental mice. Finally, the humanization of the immune system in mice is developed by several approaches including the use of induced pluripotent stem cells from cancer patients. These tumor collection and model characterization were performed under harmonized procedures within the consortium, allowing high quality material and results. All model characteristics are being compiled in a web-based database for efficient features search and data mining. We will present the first characterized breast cancer models and will discuss their usefulness and chance to bring benefit to patients via this holistic strategy developed within the IMODI initiative. Citation Format: Olivier Duchamp, Severine Tabone-Eglinger, Caroline Mignard, Isabelle Goddard, Alain Bruno, Maia Chanrion, Loreley Calvet, Olivier Degoul, Kevin Dhondt, Liliane Goetsch, Julie Miralves, Christophe Lautrette, Cindy Pensec, Françoise Le Vacon, Isabelle Treilleux, Laurent Arnould, Philippe Vaglio, Grégoire Prevost, Olivier Tredan. Innovative and predictive models against breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5015. doi:10.1158/1538-7445.AM2017-5015

International audience; The relaxation dynamics of surface-bound n-alkyl chains was studied by broadband admittance spectroscopy (10 mHz−10 MHz) measured at low temperature (130−300 K) in the reverse bias regime of rectifying Hg// organic monolayer (OML)−n-doped Si tunnel junctions. To obtain molecularlevel information on the structure and dynamics of grafted monolayers, carboxyl or amide dipolar moieties were located either at the top free surface with variable acid concentration (0%, 5%, and 100%) or at the inner position in the alkyl backbone (100% amide units). Two classes of dipolar relaxation mechanisms are found with different thermally activated behavior. At low T, only peak A is observed (f ≈ 102−105 Hz) with very small activation energy (EA = 20−40 meV) and pre-exponential factor (f 0 A ≈ 103−106 Hz). With increasing T, peak B also appears, with higher values of activation energy, EB = 0.25−0.40 eV, and pre-exponential factor ( f 0 B ≈ 108−1010 Hz). The biasindependent relaxation mechanism A, with very low activation energy typical of dipole−dipole interaction, is attributed to extrinsic relaxation of adventitious H2O molecules in hydrogen-bond clusters. Mechanism B is attributed to intrinsic relaxation of the alkyl chain assembly. In the acid series, the relative intensity of peak B is consistent with the acid group coverage given by XPS, in contrast with peak A, and its activation energy reveals increased motional constraints in the acid-substituted OML. The shape of dipolar relaxation peaks, discussed in the framework of Dissado- Hill/Jonscher theories for many-body interactions, is useful to discriminate near-substrate and molecular tail relaxations through order/disorder effects.

The subcellular origin of ceramide signaling in ionizing radiation-triggered apoptosis was investigated using two previously described subclones of the autonomous erythro-myeloblastic cell line TF-1, radio-resistant and -sensitive TF-1-34 and TF-1-33, respectively. We show in nuclei-free lysates and cytoplasts that both cell lines failed to generate ceramide in response to ionizing radiation. Moreover, whereas cytoplasts did respond to anti-Fas stimulation through phosphatidylserine externalization, no effect was observed with ionizing radiation. Only in highly purified nuclei preparations did we observe ceramide generation, neutral sphingomyelinase activation, and apoptotic features (PARP cleavage, nuclear fragmentation, DNA laddering) in TF-1-33, but not in TF-1-34 cells. These observations suggest that nuclear sphingomyelinase and ceramide formation may contribute to ionizing radiation-triggered apoptosis.

Granzyme B (GrB) and perforin (PFN) are the major components of cytoplasmic granules contained in immune cellular effectors. The granule secretory pathway is one of the mechanisms by which these cells exert their cellular cytotoxicity. Recently, it has been reported that GrB and PFN are also present in circulating hemopoietic CD34+ progenitor cells mobilized by chemotherapy and granulocyte-colony stimulating factor, whereas these proteins are undetected in steady-state peripheral CD34+ cells. In this study, we hypothesized that anticancer agents may increase GrB and PFN expression in immature myeloid leukemic cells and that these treated leukemic cells become cellular effectors through a granule-dependent mechanism. Our results show that KG1a, HEL, and TF-1 CD34+acute myeloblastic leukemia cells expressed both GrB and PFN. Moreover, ionizing radiation, aracytine, and etoposide not only increase GrB and PFN expression but also conferred potent cellular cytotoxicity to these cells toward various cellular targets. Cellular cytotoxicity required cell-cell contact, was not influenced by anti-tumor necrosis factor α or anti-Fas blocking antibodies, and was abrogated by GrB inhibitors or antisense. These results suggest that, when exposed to genotoxic agents, immature leukemic cells acquire potent GrB- and PFN-dependent cellular cytotoxicity that can be potentially directed against normal residual myeloid progenitors or immune effectors.

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

Many reports support that xenografts from patient-derived xenografts in mice or rat recapitulate well the molecular diversity, cellular heterogeneity, and histology seen in patient tumors. However, several lacks such as the limited clinical diversity of the PDXs, the absence of influence of human microbiome, the absence of human drug metabolism and the reduced immune system are limiting the predictive values of these PDX models. To set-up a holistic integration of these criticisms, we have associated efforts from public hospitals, academic groups, biotechs and private pharmaceutical companies with the financial support of the French Ministry of Industry. First, to improve the clinical diversity of the PDX collections, surgical specimens or biopsies from patients with 8 different types of cancers (lung, breast, ovary, pancreas, liver, prostate, AML, myeloma) are collected since 2013 to establish large collections of PDXs in mice. In addition, primary cultures of cells from these samples are established leading to a collection of cell lines from the stroma and the tumoral compartment. The established models are being evaluated for ex vivo and in vivo sensitivities to relevant anticancer drugs, histological and molecular characteristics. All model characteristics are being compiled in a web-based database for efficient features search and interconnection. Second, to improve our knowledge on the role of the human microbiote, feces and feeding habits are collected from patients with cancer and from mice with PDXs before and after treatment allowing a comparison of the microbiote profiles. In order to mimic the human drug metabolism, we are generating mice with humanized liver showing distinct drug pharmacokinetic profiles from the ones observed in parental mice. Finally, humanization of the immune system in mice is developed by several approaches including the use of induced pluripotent stem cells from cancer patients. We will present the first models characterized and will discuss their usefulness and chance to bring benefit to patients via this holistic strategy developed within IMODI initiative. Citation Format: Francoise LE VACON, Laurent Arnould, Alain Bruno, Loreley Calvet, Marc Colombel, Jill Corre, Olivier Cuvillier, Benedicte Eckel, Nico Forraz, Alexandra Gonzalez-Jouhanneaud, Dominique Guenot, Juan Iovanna, Mariana Kuras, Christophe Lautrette, Bernard Malavaud, Philippe Merle, Florence Meyer-Losic, Francoise Praz, Olivier Rosmorduc, Jean-Emmanuel Sarry, Severine Tabone, Philippe Vaglio, Loic Ysebaert, Olivier Duchamp. IMODI initiative: a novel holistic and integrative approach with patient-derived tumor models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A38.

Many reports support that xenografts from patient-derived xenografts (PDXs) in mice or rats well recapitulate the molecular diversity, cellular heterogeneity, and histology seen in patient tumors. However, shortcomings including limited clinical diversity of the PDXs, absence of influence of human microbiome, absence of drug human metabolism and reduced immune system restrain the predictive values of these PDX models. To set-up a holistic integration of these criticisms, we have associated efforts from public hospitals, academic groups, biotechs and private pharmaceutical companies with the financial support of the French Ministry of Industry. First, to improve the clinical cancer diversity, surgical specimens from patients obtained from 8 different tumor locations (lung, breast, ovary, pancreas, liver, prostate, AML, myelome) are collected to establish large collections of PDXs in mice. In addition, in vitro primary cultures of cells from these samples are conducted to establish a collection of cell lines from the stromal and the tumoral compartments. The established models are evaluated for ex vivo and in vivo sensitivities to relevant anticancer drugs, histological and molecular characteristics. All model characteristics are being compiled in a web-based database for efficient features search and interconnection. These tumor collection and model characterization were performed under specific procedures that are followed by all partners within the consortium, which allows to have harmonized results and high quality material. Second, to improve our knowledge on the role of the human gut microbiota, stools are collected from patients with cancer and from mice bearing PDXs before and after chemotherapeutic treatments allowing a comparison of the microbiota profiles. In order to increase the predictability of the models, we are generating mice with humanized liver showing distinct drug pharmacokinetic profiles as compared with parental mice. Finally, the humanization of the immune system in mice is developed by several approaches including the use of induced pluripotent stem cells from cancer patients. We will present the first characterized models and will discuss their usefulness and chance to bring benefit to patients via this holistic strategy developed within the IMODI initiative. Citation Format: Caroline Mignard, Laurent Arnould, Alain Bruno, Loreley Calvet, Marc Colombel, Jill Corre, Olivier Cuvillier, Bénédicte Eckel, Nico Forraz, Alexandra Gonzalez-Jouhanneaud, Liliane Goetsch, Dominique Guenot, Juan Iovanna, Mariana Kuras, Christophe Lautrette, Françoise Le Vacon, Bernard Malavaud, Philippe Merle, Florence Meyer-Losic, Françoise Praz, Olivier Rosmorduc, Jean-Emmanuel Sarry, Séverine Tabone, Philippe Vaglio, Loïc Ysebaert, Olivier Duchamp, IMODI Consortium. Innovative and predictive models against cancer: an IMODI integrative approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5203.

International audience