scholarly journals PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

2015 ◽  
Vol 112 (11) ◽  
pp. 3493-3498 ◽  
Author(s):  
Helen Y. Zou ◽  
Qiuhua Li ◽  
Lars D. Engstrom ◽  
Melissa West ◽  
Vicky Appleman ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Clinical Evidence ◽  
Point Mutations ◽  
Genetically Engineered ◽  
Clinical Activity ◽  
Small Cell Lung ◽  
Molecule Inhibitor ◽  
Genetically Engineered Mouse Model

Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a variety of human cancers and are attractive targets for cancer therapy. The MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF-02341066) has demonstrated promising clinical activity in ROS1 fusion-positive non-small cell lung cancer. However, emerging clinical evidence has shown that patients can develop resistance by acquiring secondary point mutations in ROS1 kinase. In this study we characterized the ROS1 activity of PF-06463922, a novel, orally available, CNS-penetrant, ATP-competitive small-molecule inhibitor of ALK/ROS1. In vitro, PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1 fusions and inhibited the crizotinib-refractory ROS1G2032Rmutation and the ROS1G2026Mgatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase. A crystal structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions contributing to the high-affinity binding. In vivo, PF-06463922 showed marked antitumor activity in tumor models expressing FIG-ROS1, CD74-ROS1, and the CD74-ROS1G2032Rmutation. Furthermore, PF-06463922 demonstrated antitumor activity in a genetically engineered mouse model of FIG-ROS1 glioblastoma. Taken together, our results indicate that PF-06463922 has potential for treating ROS1 fusion-positive cancers, including those requiring agents with CNS-penetrating properties, as well as for overcoming crizotinib resistance driven by ROS1 mutation.

scholarly journals Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

2011 ◽  
pp. 141-151
Author(s):  
Daniele Santini ◽  
Maria Elisabetta Fratto ◽  
Bruno Vincenzi ◽  
Silvia Angeletti ◽  
Giordano Dicuonzo ◽  
...  
Keyword(s):  
Clinical Data ◽  
Survival Data ◽  
Clinical Evidence ◽  
Bisphosphonate Therapy ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Phase Iii Trial ◽  
Skeletal Disease

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

scholarly journals Ganetespib (STA-9090), a Nongeldanamycin HSP90 Inhibitor, Has Potent Antitumor Activity in In Vitro and In Vivo Models of Non–Small Cell Lung Cancer

2012 ◽  
Vol 18 (18) ◽  
pp. 4973-4985 ◽  
Author(s):  
Takeshi Shimamura ◽  
Samanthi A. Perera ◽  
Kevin P. Foley ◽  
Jim Sang ◽  
Scott J. Rodig ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Hsp90 Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
In Vivo Models

scholarly journals CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms

2014 ◽  
Vol 21 (6) ◽  
pp. 879-890 ◽  
Author(s):  
Sebastian Krug ◽  
Benjamin Kühnemuth ◽  
Heidi Griesmann ◽  
Albrecht Neesse ◽  
Leonie Mühlberg ◽  
...  
Keyword(s):  
Tumour Progression ◽  
Treatment Options ◽  
Genetically Engineered ◽  
Neuroendocrine Neoplasms ◽  
Dependent Manner ◽  
Rare Tumour ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Genetically Engineered Mouse Model

Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function ofCUX1were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally,CUX1expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data.CUX1expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinantCUX1expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesisin vitroandin vivo. Mechanistically, the pro-angiogenic effect ofCUX1was mediated via upregulation of effectors such as HIF1α and MMP9.CUX1mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas.

A G-Quadruplex-Interactive Potent Small-Molecule Inhibitor of Telomerase Exhibiting in Vitro and in Vivo Antitumor Activity

2002 ◽  
Vol 61 (5) ◽  
pp. 1154-1162 ◽  
Author(s):  
Sharon M. Gowan ◽  
John R. Harrison ◽  
Lisa Patterson ◽  
Melanie Valenti ◽  
Martin A. Read ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
In Vivo Antitumor Activity ◽  
Molecule Inhibitor ◽  
G Quadruplex

scholarly journals Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 627 ◽  
Author(s):  
Yanhua Fan ◽  
Huaiwei Ding ◽  
Donghwa Kim ◽  
Duc-Hiep Bach ◽  
Ji-Young Hong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Pik3ca Mutation ◽  
A549 Cells ◽  
Small Cell ◽  
Small Cell Lung

Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients.

scholarly journals Blocking gephyrin phosphorylation or microglia BDNF signaling prevents synapse loss and reduces infarct volume after ischemia

2020 ◽  
Author(s):  
Teresa Cramer ◽  
Raminder Gill ◽  
Zahra S Thirouin ◽  
Markus Vaas ◽  
Suchita Sampath ◽  
...  
Keyword(s):  
Hippocampal Formation ◽  
Infarct Volume ◽  
Point Mutations ◽  
Null Point ◽  
Genetically Engineered ◽  
Infarct Area ◽  
Synapse Plasticity ◽  
Genetically Engineered Mice

AbstractMicroglia interact with neurons to facilitate synapse plasticity; however, signal transducers between microglia and neuron remain unknown. Here, using in vitro organotypic hippocampal slice cultures and transient MCAO in genetically-engineered mice in vivo, we report that at 24 h post-ischemia microglia release BDNF to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the CA1 hippocampal formation in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75NTR and TrkB receptors respectively. Post-MCAO, we report that in the peri- infarct area and in the corresponding contralateral hemisphere similar neuroplasticity occur through microglia activation and gephyrin phosphorylation at Ser268, Ser270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point-mutations protect against ischemic brain damage, neuroinflamation and synapse downregulation normally seen post-MCAO. Collectively, we report that gephyrin phosphorylation and microglia derived BDNF faciliate synapse plasticity after transient ischemia.

scholarly journals Pre-Clinical Activity of Novel Hypoxia-Activated FLT3 Inhibitors in FLT3-Mutated AML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5210-5210
Author(s):  
Antonio Cavazos ◽  
Helen Ma ◽  
Juliana Maria Benito ◽  
Mark J. Levis ◽  
Naval Daver ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Research Funding ◽  
Growth Arrest ◽  
Genetically Engineered ◽  
Clinical Activity ◽  
Treatment Groups ◽  
Molecular Abnormalities ◽  
Electron Reduction

Abstract Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) are most frequently observed molecular abnormalities in AML, which lead to constitutive activation of the tyrosine kinase. While several mechanisms of resistance to FLT3 tyrosine kinase inhibitors (TKIs) have been identified, commonly failure is associated with lack of complete and sustained inhibition of FLT3 tyrosine kinase activity. FLT3 inhibition is particularly challenging in blasts within the hypoxic bone marrow (BM) microenvironment, which plays a crucial role in AML survival. Widespread hypoxia has been shown by us and others to be prevalent within the confines of the leukemic BM space, and to limit the efficacy of standard chemotherapy (Benito et al., PLoS One 6(8):e23108, 2011). With the goal of exploiting hypoxia as a physiological target and increasing selectivity to FLT3-mutant AML blasts, we have developed a series of hypoxia-activated prodrugs of FLT3 TKIs (HA-TKIs) based on the known clinical compounds sunitinib, AC220, MLN-518 and crenolanib. Bioreductive trigger conjugation was performed at the final step of the synthesis to provide the prodrugs as previously described (Lu et al., Tetrahedron, 69, p9130-9138, 2013). Under hypoxia, these compounds can undergo enzymatic one-electron reduction and then fragment selectively to release the cell permeable TKI, generating higher local concentrations of TKIs and limiting normal tissue exposures. Pulse radiolysis was used to determine the electron affinity (E(1)) and rate of fragmentation of each prodrug. The E(1) values ranged from -430 mV to -497 mV, while the rate of fragmentation of the prodrugs following one-electron reduction under hypoxia ranged from 28 s-1 to 400 s-1. SN37156 and SN37169 in particular demonstrated E(1) and kfrag parameters ideal for hypoxia-selective cellular metabolism (-449 mV, 85 s-1; -449 mV, 62 s-1, respectively). With the purpose of identifying the HA-TKIs with the most selective and dose-potent in vitro efficacy, we first performed an Oxic/Hypoxic screening of the hypoxia-dependent activity of HA-TKIs against FLT3-mutant AML cell lines. From the 10 compounds originally developed, SN37156 and SN37169 showed hypoxia-dependent apoptosis and growth arrest. SN37156 demonstrated the best activity against Molm13, Molm14 and MV4-11 cells under hypoxia with hypoxic cytotoxicity ratios (oxic/hypoxic IC50 ratios) of 4.9, 11 and 17.6, respectively. In our secondary screening we compared the activity of SN37156, SN37169 and their parental inhibitors on target modulation. Both HA-TKIs selectively inhibited FLT3 and ERK auto phosphorylation in MV4-11 cell line under hypoxic but not oxic conditions, with similar potency to the parental inhibitor under normal oxygen culture conditions. We next investigated the effects of both HA-TKIs on inhibition of FLT3 downstream targets, including AKT, ERK, pS6 and STAT5 using time-of-flight mass cytometry (CyTOF). The data demonstrated distinct patterns of signaling inhibition, with a dose-dependent p-ERK and p-S6 inhibition in MV4-11 and Molm-14 cells upon treatment with both HA-TKIs. In turn, both compounds at 100nM inhibited p-AKT and p-STAT5. Single dose tolerability studies were conducted in tumor-free C57BL6 mice. Prodrugs were administered by IP injection in 20% β-hydroxypropylcyclodextrin solution starting at 17.8 µmol/kg and escalating in 1.33-fold increments until lethality or severe mortality (mean body weight loss of >10%) was observed. The maximal tolerated dose for both, SN37156 and SN37169 was established at 56.1 µmol/kg. To test efficacy of HA-TKIs in vivo, we injected C57BL6 mice with genetically engineered Baf3-ITD/luc/GFP cells. Mice were randomized to treatment groups on day 8 when engraftment was documented by bioluminescent imaging (BLI), and treated with either vehicle or 56.1 µmol/kg of SN37156 or SN37169 I.P. every 3 days. Multiple doses (up to 10 so far; study is ongoing) were well tolerated. BLI demonstrated reduced leukemia burden in both treatment groups compared to control. In summary, our data indicate that HA-TKIs SN37156 and SN37169 inhibit mutant FLT3 and its selected downstream signaling targets under conditions resembling marrow hypoxia, and induce hypoxia-dependent growth arrest and apoptosis in FLT3-mutant AML cells. Planned studies in FLT3-mutant AML PDX will evaluate in vivo efficacy to eliminate primary human AML cells from hypoxic BM microenvironment. Disclosures Daver: Kiromic: Research Funding; Ariad: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Cyclocreatine suppresses prostate tumorigenesis through dual effects on SAM and creatine metabolism

2021 ◽  
Author(s):  
Rachana Patel ◽  
Lisa Rodgers ◽  
Catriona A. Ford ◽  
Linda K Rushworth ◽  
Janis Fleming ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
De Novo ◽  
Basal Respiration ◽  
Genetically Engineered ◽  
Prostate Tumorigenesis ◽  
Genetically Engineered Mouse Model ◽  
Creatine Metabolism

ABSTRACTProstate cancer is highly prevalent, being the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of PTEN and SPRY2 (Sprouty 2) tumour suppressors, we identified enhanced creatine metabolism within the phosphagen system in progressive disease. Altered creatine metabolism was validated in in vitro and in vivo prostate cancer models and in clinical cases. Upregulated creatine levels were due to increased uptake through the SLC6A8 creatine transporter and de novo synthesis, resulting in enhanced cellular basal respiration. Treatment with cyclocreatine (a creatine analogue that potently and specifically blocks the phosphagen system) dramatically reduces creatine and phosphocreatine levels. Blockade of creatine biosynthesis by cyclocreatine leads to cellular accumulation of S-adenosyl methionine (SAM), an intermediary of creatine biosynthesis, and suppresses prostate cancer growth in vitro. Furthermore, cyclocreatine treatment impairs cancer progression in our GEMM and in a xenograft liver metastasis model. Hence, by targeting the phosphagen system, cyclocreatine results in anti-tumourigenic effects from both SAM accumulation and suppressed phosphagen system.

scholarly journals Disrupting Ectopic Super-Enhancers to Treat Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1593-1593
Author(s):  
Seth Welsh ◽  
Daniel Riggs ◽  
Erin Meermeier ◽  
Chang-Xin Shi ◽  
Victoria Garbitt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Mouse Model ◽  
Therapeutic Response ◽  
Genetically Engineered ◽  
Therapeutic Window ◽  
Super Enhancer ◽  
Genetically Engineered Mouse Model

Abstract Multiple myeloma (MM) is an incurable form of plasma cell cancer in which primary and secondary chromosomal translocations routinely juxtapose oncogenes to plasma cell-specific super-enhancers. Coincidentally, drugs which target super-enhancers have had success clinically. For example, immunomodulatory imide drugs (IMiDs) degrade super-enhancer-binding pioneer factors IKAROS and AIOLOS, while glucocorticoids (Dexamethasone) and proteasome inhibitors (Bortezomib) have the ability to transrepress or block the processing of super-enhancer-forming NF-κB proteins, respectively. Currently, alternative enhancer-targeting drugs are also in clinical development, like p300 inhibitors which target the acetyl-binding bromodomains and/or histone acetyl transferase activity of the chromatin-regulating coactivator homologs CBP and EP300. Despite showing therapeutic promise, our understanding of how these drugs function, alone or together, remains incomplete. Case in point, we find that IMiD-induced degradation of its target proteins IKAROS and AIOLOS does not guarantee a therapeutic response in vitro, and patients successfully treated with IMiDs eventually relapse; meanwhile, coactivator-targeting therapies like p300 inhibitors are often too toxic in vivo, and lack a therapeutic window. To improve the outcomes of MM patients we need to understand the heterogeneous genetics and transcription-factor milieus of the myeloma enhancer landscape, as well as how to increase the precision of enhancer-disrupting drugs. To accomplish this, our lab utilizes more than 60 human myeloma cell lines that have been extensively characterized at the genetic, proteomic, and drug-therapeutic-response levels. Additionally, we have generated a highly-predictive immunocompetent mouse model (Vk*MYC hCRBN+) that develops human-like MM and is sensitive to both IMiDs and a new class of therapeutics termed "degronimids" (normal mice do not respond to IMiDs or degronimids). Our central hypothesis is that combining a broad coactivator-targeting drug (e.g., the p300 inhibitor GNE-781), with a MM-specific transcription factor-targeting drug (e.g., IMiDs) restricts toxicities to myeloma cells and thus improves the therapeutic window. Currently, we are testing a variety of coactivator-targeting compounds alongside traditional IMiD therapies and other preclinical transcription factor-targeting drugs both in vivo and in vitro. We show that Vk*MYC hCRBN+ mice are exquisitely sensitive to GNE-781, requiring one fourth of the dose needed to treat other cancers and therefore avoiding the neutropenia and thrombocytopenia seen at higher doses. Second, we show that although IMiDs and GNE-781 induce an effective but transient response in vivo as single agents, the combination of the two drugs proved curative, with a progressive deepening of the anti-tumor response occurring even after therapy is discontinued. Ongoing experiments aim to determine how this drug combination, and other coactivator + transcription factor-targeting combinations, permanently disrupt myeloma-specific super-enhancers. Disclosures Neri: BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bahlis: Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy. Boise: AstraZeneca: Honoraria, Research Funding; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Chesi: Abcuro: Patents & Royalties: Genetically engineered mouse model of myeloma; Pi Therapeutics: Patents & Royalties: Genetically engineered mouse model of myeloma; Pfizer: Consultancy; Novartis: Consultancy, Patents & Royalties: human CRBN transgenic mouse; Palleon Pharmaceuticals: Patents & Royalties: Genetically engineered mouse model of myeloma.

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