scholarly journals MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2253
Author(s):  
Shomereeta Roy ◽  
Audrey Laroche-Clary ◽  
Stephanie Verbeke ◽  
Marie-Alix Derieppe ◽  
Antoine Italiano
Keyword(s):  
Tyrosine Kinases ◽  
Mapk Pathway ◽  
Single Agent ◽  
Immunoblot Analysis ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Synergistic Activity ◽  
Mdm2 Gene ◽  
Mdm2 Antagonist ◽  
The Impact

The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.

Achievements and Challenges of Molecular Targeted Therapy in Melanoma

2015 ◽  
pp. 177-186 ◽  
Author(s):  
Ryan Sullivan ◽  
Patricia LoRusso ◽  
Scott Boerner ◽  
Reinhard Dummer
Keyword(s):  
Tumor Suppressor ◽  
Mapk Pathway ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Clinical Trial Data ◽  
Great Majority ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Early Clinical Trial

The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600targeting, a number of other molecular subsets—such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 ( NF1)—are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.

Preclinical Approach to Sensitize Multiple Myeloma Cells: Combination of the MEK Inhibitor PD0325901 with ABT-737 or Mevinolin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1842-1842
Author(s):  
Maria Rosaria Ricciardi ◽  
Elisabetta Calabrese ◽  
Michele Milella ◽  
Paola Bergamo ◽  
Samantha Decandia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Clinical Investigation ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Synergistic Activity ◽  
Mitochondrial Membrane Depolarization ◽  
The Impact

Abstract Abstract 1842 Poster Board I-868 Multiple myeloma (MM) is a plasma cell malignancy incurable with existing conventional therapies. However, the increased understanding of the molecular mechanisms underlying the growth, progression and drug resistance of MM cells is allowing the development of novel therapies based on target-specific drugs. These agents have shown promising results in pre-clinical trials and some are already in early phase of clinical investigation. However, limitations of this approach are represented by the existence of cross-talking signals among different pathways which results in ineffective inhibition of a single pathway. Therefore, targeted therapy based on the multiple inhibition of key signal transduction pathways represents the present focus of translational research. We have already demonstrated (Haematologica 2008;93[suppl.2]:P195) the potent growth-inhibitory effects of the specific MEK inhibitor PD0325901 and the marked pro-apoptotic activity of the Bcl2/BclXL inhibitor ABT-737 (kindly provided by Abbott Laboratories) on MM cell lines and primary CD138+ cells from MM patients at different disease stages (smoldering, diagnosis, relapse, refractory/resistant). Since it has already been reported that the inhibitor of the mevalonate pathway, Mevinolin, strikingly induces apoptosis by regulating different pathways, including the MEK/ERK module, we aimed in the present study to analyze the impact of the simultaneous inhibition of both pathways on apoptosis and cell growth of MM cell lines and primary samples. We exposed the KMS18, KMS27 and ARH-77 MM cell lines to increasing concentrations of PD0325901 (1–100 nM) and ABT-737 (1–100 nM) or Mevinolin (1–100 μM), alone and in combination. When used as single agents the inhibition of cell-growth was dose-dependent, while if used in combination it was synergistic, with combination indexes (CI) of 0.12 and 0.15 for PD0325901 plus ABT-737 and the same plus Mevinolin, respectively (Chou-Talalay method). We then investigated the effects of these agents on apoptosis, as determined by the sub-G1 DNA peak, and found that PD0325901 mainly showed cytostatic effects, while ABT-737 and Mevinolin needed high concentrations to affect apoptosis. The simultaneous exposure to PD0325901 plus ABT-737 or Mevinolin at lower concentrations, induced apoptosis with highly synergistic effects, as demonstrated by a CI of 0.2 (KMS18) and 0.17 (KMS27) for PD0325901 plus ABT-737 and of 0.135 (KMS18) and 0.128 (KMS27) for PD0325901 plus Mevinolin. Similarly, mitochondrial membrane depolarization was greatly induced with the combination approach. Preliminary experiments performed on primary MM samples confirmed the pro-apoptotic synergistic activity of combination strategies. On the contrary, when we used the MEK-inhibitor resistant MM cell line ARH-77, the effects of ABT-737 and Mevinolin were not potentiated by MEK inhibition with PD0325901. In conclusion, we demonstrated that the simultaneous disruption of the MEK/ERK and Bcl2/BclXL or Mevalonate signalling is effective on apoptosis induction and growth inhibition of MM cells at a greater degree than single agent therapy. Additional ongoing studies on primary samples from MM patients at different stages of the disease will help to determine the feasibility and efficacy of these combinations for clinical use. Disclosures: Petrucci: Celgene: Honoraria; Janssen Cilag: Honoraria.

scholarly journals Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Alessandro Tubita ◽  
Ignazia Tusa ◽  
Elisabetta Rovida
Keyword(s):  
Tyrosine Kinases ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Therapies ◽  
New Era ◽  
Mitogen Activated Protein ◽  
The Impact ◽  
The Ideal

Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT. The MAPK ERK5 has been identified as a key signaling molecule in the biology of several types of cancer. In this review, we report pieces of evidence regarding the activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors. We also highlight the known and possible mechanisms underlying the cross-talks between the ERK1/2 and the ERK5 pathways, the characterization of which is of great importance to maximize, in the future, the impact of RAF-MEK1/2-ERK1/2 targeting. Finally, we emphasize the need of developing additional therapeutically relevant MEK5-ERK5 inhibitors to be used for combined treatments, thus preventing the onset of resistance to cancer therapies relying on RAF-MEK1/2-ERK1/2 inhibitors.

scholarly journals Combinations of (lipo)glycopeptides with β-lactams against MRSA: susceptibility insights

2020 ◽  
Vol 75 (10) ◽  
pp. 2894-2901
Author(s):  
Razieh Kebriaei ◽  
Seth A Rice ◽  
Nivedita B Singh ◽  
Kyle C Stamper ◽  
Logan Nguyen ◽  
...  
Keyword(s):  
Single Agent ◽  
Synergistic Activity ◽  
Bacterial Strains ◽  
Fold Reduction ◽  
High Prevalence ◽  
Mrsa Strains ◽  
Susceptibility Tests ◽  
Time Kill ◽  
The Impact ◽  
Microbroth Dilution

Abstract Background Increasing application of vancomycin due to the high prevalence of MRSA infections has led to the emergence of vancomycin intermediate-resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA). Consequently, the need for alternative therapies that target MRSA has become evident. Objectives To evaluate the synergy between (lipo)glycopeptides (LGP/GPs) (vancomycin, teicoplanin, telavancin, dalbavancin and oritavancin) and β-lactams (ceftaroline, cefepime, cefazolin and oxacillin) against MRSA, hVISA, VISA and daptomycin non-susceptible (DNS) phenotypes. Methods Twenty randomly selected clinical MRSA strains (i.e. 5 MRSA, 5 hVISA, 5 VISA and 5 DNS) were assessed versus LGP/GPs alone and LGP/GPs in combination with β-lactams for MICs. Although verification of antibiotic potency against bacterial strains is assessed by the microbroth dilution (MBD) MIC method recommended by the CLSI, some antibiotics need modified assay conditions in order to demonstrate their optimal activity. Results Addition of β-lactams reduced MIC values of LGP/GPs against all strains (up to 160-fold reduction). In general, LGPs (dalbavancin, oritavancin and telavancin) were more active (significant differences in MIC values, up to 8-fold) compared with vancomycin and teicoplanin. The majority of these combinations were bactericidal and superior to any single agent. Conclusions This report has examined the susceptibility patterns of LGP/GPs and their combination with β-lactams. Of interest, the impact of susceptibility tests (in terms of MIC plates and their surface area) on the synergistic activity in 24 h time–kill experiments was apparent for LGPs. Further clinical research is required to investigate synergy with LGP/GPs and β-lactams against these Staphylococcus strains.

MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes

2004 ◽  
Vol 287 (4) ◽  
pp. E758-E766 ◽  
Author(s):  
Anne W. Harmon ◽  
David S. Paul ◽  
Yashomati M. Patel
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Pi3k Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mek Inhibitors ◽  
Transport Assay

In 3T3-L1 adipocytes, insulin activates three major signaling cascades, the phosphoinositide 3-kinase (PI3K) pathway, the Cbl pathway, and the mitogen-activated protein kinase (MAPK) pathway. Although PI3K and Cbl mediate insulin-stimulated glucose uptake by promoting the translocation of the insulin-responsive glucose transporter (GLUT4) to the plasma membrane, the MAPK pathway does not have an established role in insulin-stimulated glucose uptake. We demonstrate in this report that PI3K inhibitors also inhibit the MAPK pathway. To investigate the role of the MAPK pathway separately from that of the PI3K pathway in insulin-stimulated glucose uptake, we used two specific inhibitors of MAPK kinase (MEK) activity, PD-98059 and U-0126, which reduced insulin-stimulated glucose uptake by ∼33 and 50%, respectively. Neither MEK inhibitor affected the activation of Akt or PKCζ/λ, downstream signaling molecules in the PI3K pathway. Inhibition of MEK with U-0126 did not prevent GLUT4 from translocating to the plasma membrane, nor did it inhibit the subsequent docking and fusion of GLUT4- myc with the plasma membrane. MEK inhibitors affected glucose transport mediated by GLUT4 but not GLUT1. Importantly, the presence of MEK inhibitors only at the time of the transport assay markedly impaired both insulin-stimulated glucose uptake and MAPK signaling. Conversely, removal of MEK inhibitors before the transport assay restored glucose uptake and MAPK signaling. Collectively, our studies suggest a possible role for MEK in the activation of GLUT4.

scholarly journals SPDR-1 HSP90 inhibition overcomes resistant to molecular targeted therapy in BRAFV600E mutant glioblastoma

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi3-vi3
Author(s):  
Jo Sasame ◽  
Naoki Ikegaya ◽  
Yohei Miyake ◽  
Takahiro Hayashi ◽  
Akito Oshima ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mtor Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Hsp90 Inhibition ◽  
Pdx Models

Abstract The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.

scholarly journals Enhancing the Therapeutic Efficacy of KRASG12C Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Ying Liu ◽  
Lei Wu ◽  
Hong Lu ◽  
En Wu ◽  
Jun Ni ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Tyrosine Kinases ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Transcriptional Profiling ◽  
Multidrug Resistant ◽  
Mitogen Activated Protein Kinase

Background. KRASG12C inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy. Methods. To understand the comprehensive mechanisms of drug resistance, we treated lung cancer cells with KRASG12C inhibitors for different periods and performed transcriptional profiling and signaling analysis to identify critical factors and pathways that drive drug tolerance and resistance. We also evaluated several drug combinations in vitro and in vivo to identify potentially effective therapeutics. Results. We found that the feedback activation of multiple receptor tyrosine kinases (RTKs) may have cooperatively induced intrinsic and adaptive resistance to KRASG12C inhibitors. Notably, continuous KRAS inhibition induced a multidrug-resistant phenotype, implying that upfront combinatory treatment might be required to treat this group of patients. We also demonstrated that concurrently targeting multiple nodes in the RTK/RAS/RAF/MEK/ERK axis improved the efficacy of KRASG12C inhibitors, mainly by suppressing the reactivation of the mitogen-activated protein kinase (MAPK) pathway. Moreover, the combined use of HSP90 and KRASG12C inhibitors effectively induced tumor regression in lung adenocarcinoma models in vitro and in vivo. Conclusion. Together, our findings revealed mechanisms underlying KRASG12C inhibitors resistance and provided novel candidate combinatory strategies to improve their anticancer activity.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

Receptor tyrosine kinase–GPCR signal complexes

2003 ◽  
Vol 31 (6) ◽  
pp. 1220-1225 ◽  
Author(s):  
N.J. Pyne ◽  
C. Waters ◽  
N.A. Moughal ◽  
B.S. Sambi ◽  
S. Pyne
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Mapk Pathway ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
S1p1 Receptor ◽  
Receptor Complexes ◽  
Molecular Events ◽  
Lpa1 Receptor ◽  
Trk A

The formation of complexes between growth factor receptors and members of a family of G-protein-coupled receptors whose natural ligands are S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) represents a new signalling entity. This receptor complex allows for integrated signalling in response to growth factor and/or S1P/LPA and provides a mechanism for more efficient activation (due to integrated close-proximity signalling from both receptor classes) of the p42/p44 MAPK (mitogen-activated protein kinase) pathway. This article provides information on the molecular events at the interface between receptor tyrosine kinases and S1P/LPA receptors. Examples include the PDGF (platelet-derived growth factor)-induced tyrosine phosphorylation of Giα, released upon S1P1 receptor activation, which is required for initiation of the p42/p44 MAPK pathway. Critical to this event is the formation of endocytic vesicles containing functionally active PDGFβ receptor–S1P1 receptor complexes, which are internalized and relocated with components of the p42/p44 MAPK pathway. We also report examples of cross-talk signal integration between the Trk A (tropomyosin receptor kinase A) receptor and the LPA1 receptor in terms of the NGF (nerve growth factor)-dependent regulation of the p42/p44 MAPK pathway. NGF induces recruitment of the LPA1 receptor to the nucleus (delivery might be Trk A-dependent), whereupon the LPA1 receptor may govern gene expression via novel nuclear signalling processes.

A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13600-e13600 ◽  
Author(s):  
Razelle Kurzrock ◽  
Jean-Yves Blay ◽  
Binh Bui Nguyen ◽  
Andrew J. Wagner ◽  
Robert G. Maki ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Rt Pcr ◽  
Mdm2 Gene ◽  
Ki 67 ◽  
Mdm2 Antagonist ◽  
Flt Pet ◽  
Flat Dose ◽  
Heavily Pretreated ◽  
P53 Activation

e13600^ Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m2, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and [18F]-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m2/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m2). Evidence of activity included: 1) concentration dependent increase in plasma MIC-1 (% baseline), 2) decrease in [18F]-FLT PET and PR each in liposarcoma pts at 1800 mg/m2 and 1440 mg/m2, respectively. EXT: Grade3/ 4 cytopenias at MTD precluded subsequent cycles in 6/8 pts (10 day schedule). Dosing was changed to 5 days, and only 3 patients had Gr3/4 cytopenias. 8/22 pts remained on study for >4 cycles, including 2 pts with SD for 7 and 9 cycles respectively. 3 of 4 EXT pts had decreased [18F]-FLT-PET activity. Biopsies (pre- and on treatment) demonstrated: 1) increase in p53 (median 1.5 fold change (X) by IHC, n=15); 2) increase in p21 (median 2.7X by IHC, n=14); 3) increase in MDM2 (median 2.5X by RT-PCR, n = 27); 4) decrease in % Ki-67(+) cells (median % change from baseline -65.4%, range -91% to +275%, n=17 ); 5) increase in TUNEL(+) cells of 9.0 (density of + cells/mm2, range -26.2 to +45.5, n=22). These results were seen both in tumors with and without MDM2 gene amplification, and in multiple sarcoma subtypes. Conclusions: RG7112 has manageable AEs (GI ) and cytopenias correlating with AUC. Single agent disease control, and biomarker activity was seen in both MDM2 amplified and non-amplified, heavily pretreated soft tissue sarcoma pts, with changes reflecting activation of p53-related pathways.

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