Wells A Messersmith

Sarah Cannon Research Institute, Nashville, Tennessee, United States

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Publications (98)561.15 Total impact

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    ABSTRACT: Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors. Experimental Design: A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily (QD) in continuous 28-day treatment cycles. The starting dose was 80 mg. Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640-mg dose level was 33.3% and the MTD was estimated to be 320 mg QD. The recommended phase 2 dose was not determined. PF-04449913 was generally well tolerated at doses of 80-320 mg QD. The most common treatment-related adverse events (AEs) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg QD. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting QD dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% down-regulation of GLI1 expression in the skin of treated patients. Eight (34.8%) patients achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months). Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 11/2014;
  • A Scott, W A Messersmith, A Jimeno, S L Davies
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    ABSTRACT: Panitumumab is a fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR) approved for use in colorectal cancer (CRC). Critical information regarding biomarkers in CRC has been discovered through the investigation of panitumumab treatment. The discovery of anti-EGFR resistance in the setting of Kirsten rat sarcoma viral oncogene (KRAS) and more recently, neuroblastoma RAS viral oncogene (NRAS) mutations in CRC has changed the focus of therapy for metastatic disease to one based on the molecular characteristics of the tumor. This review will give a brief background on panitumumab and its current uses in CRC.
    Drugs of today (Barcelona, Spain: 1998) 10/2014; 50(10):679-90. · 1.22 Impact Factor
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    ABSTRACT: Purpose: To estimate the maximum tolerated dose (MTD) for continuous oral administration of the gamma-secretase inhibitor PF-03084014, determine the recommended phase 2 dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors. Experimental Design: This open-label, phase I study consisted of a dose-finding portion based on a 3+3 design, followed by an expansion cohort. PF-03084014 was administered orally, twice daily (BID) for 21 continuous days. Tested doses ranged from 20 to 330 mg BID. In the expansion cohort, patients were to receive the estimated MTD or a lower dose of PF-03084014. Results: A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related AEs were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent down-modulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients. Conclusions: Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 09/2014;
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    ABSTRACT: Anti-angiogenic therapy is commonly used for the treatment of CRC. Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to anti-angiogenic therapy. MET is upregulated in response to VEGF pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study we set out to determine the efficacy of cabozantinib in a preclinical CRC PDTX model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; · 6.20 Impact Factor
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    ABSTRACT: Purpose The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). Methods A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. Results Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. Conclusions RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
    Investigational New Drugs 03/2014; · 3.50 Impact Factor
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    ABSTRACT: MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined. Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m(2) (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A. Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in >20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed. The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.
    Cancer Chemotherapy and Pharmacology 03/2014; · 2.80 Impact Factor
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    ABSTRACT: To determine the pharmacokinetics (PK), maximum-tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphatidyl-inositol 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. Patients with advanced solid malignancies received rigosertib twice daily (BID) continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCCs) underwent exome sequencing. Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg BID. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway. The recommended phase 2 dose of oral rigosertib is 560 mg BID given continuously. Urinary toxicity is the dose limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
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    ABSTRACT: Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.
    Marine Drugs 01/2014; 12(9):4833-4850. · 3.98 Impact Factor
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    ABSTRACT: The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).
    PLoS ONE 01/2014; 9(11):e113037. · 3.53 Impact Factor
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    ABSTRACT: The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer. A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.
    Clinical Colorectal Cancer 09/2013; · 1.80 Impact Factor
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    ABSTRACT: Background:Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.Methods:A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.Results:We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.Conclusion:This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.British Journal of Cancer advance online publication, 18 July 2013; doi:10.1038/bjc.2013.361 www.bjcancer.com.
    British Journal of Cancer 07/2013; · 5.08 Impact Factor
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    ABSTRACT: PURPOSE: The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS mutant colorectal cancer (CRC) who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in CRC, indicating that rational combination strategies are needed. EXPERIMENTAL DESIGN: In this study, we performed unbiased GSEA and synthetic lethality screens with selumetinib, which identified the non-canonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we utilized shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in CRC cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and demonstrated synergistic antiproliferative effects in in vitro and in vivo models of CRC. RESULTS: Importantly, this combination not only demonstrated tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of CRC. In mechanistic studies, we observed a trend towards increased markers of apoptosis in response to the combination of MEK and WntCa++ inhibitors, which may explain the observed synergistic antitumor effects. CONCLUSIONS: These results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for metastatic CRC patients.
    Clinical Cancer Research 06/2013; · 7.84 Impact Factor
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    ABSTRACT: PURPOSE: Unresectable intrahepatic cholangiocarcinoma represents a devastating illness with poor outcomes when treated with standard systemic therapies. Several smaller nonrandomized outcomes studies have been reported for such patients undergoing transarterial therapies. A metaanalysis was performed to assess primary clinical and imaging outcomes, as well as complication rates, following transarterial interventions in this patient population. MATERIALS AND METHODS: By using standard search techniques and metaanalysis methodology, published reports (published in 2012 and before) evaluating survival, complications, and imaging response following transarterial treatments for patients with unresectable intrahepatic cholangiocarcinoma were identified and evaluated. RESULTS: A total of 16 articles (N = 542 subjects) met the inclusion criteria and are included. Overall survival times were 15.7 months±5.8 and 13.4 months±6.7 from the time of diagnosis and time of first treatment, respectively. The overall weighted 1-year survival rate was 58.0%±14.5. More than three fourths of all subjects (76.8%) exhibited a response or stable disease on postprocedure imaging; 18.9% of all subjects experienced severe toxicities (National Cancer Institute/World Health Organization grade≥3), and most experienced some form of postembolization syndrome. Overall 30-day mortality rate was 0.7%. CONCLUSIONS: As demonstrated by this metaanalysis, transarterial chemotherapy-based treatments for cholangiocarcinoma appears to confer a survival benefit of 2-7 months compared with systemic therapies, demonstrate a favorable response by imaging criteria, and have an acceptable postprocedural complication profile. Such therapies should be strongly considered in the treatment of patients with this devastating illness.
    Journal of vascular and interventional radiology: JVIR 05/2013; · 1.81 Impact Factor
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    ABSTRACT: Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV-, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX-866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab-resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab-sensitive strains. The PI3K inhibitor PX-866 had anti-tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine.
    Molecular oncology 04/2013; · 6.70 Impact Factor
  • S L Davis, S G Eckhardt, W A Messersmith, A Jimeno
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    ABSTRACT: Regorafenib is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types, in preclinical and clinical studies. Preclinical data show inhibitory activity of angiogenic, stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1, 2 and 3, tyrosine-protein kinase receptor TIE-2, platelet-derived growth factor receptor β, fibroblast growth factor receptor 1, proto-oncogene tyrosine-protein kinase receptor Ret, mast/stem cell growth factor receptor Kit, RAF proto-oncogene serine/threonine-protein kinase and wild-type and V600E mutant serine/threonine-protein kinase B-raf. Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3-weeks-on/1-week-off schedule, or 100 mg daily on a continuous schedule, with adverse effects typical of other multikinase inhibitors. Phase II studies demonstrated clinical benefit in a variety of tumor types, mostly associated with prolonged stable disease. Phase III studies include the CORRECT trial, which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies. There is still much work to be done to determine the role of regorafenib in the future of cancer therapy. This review will focus on the development of regorafenib, from early preclinical work through phase I, II and III trials, as well as highlighting the current role and potential future directions of this novel agent.
    Drugs of today (Barcelona, Spain: 1998) 02/2013; 49(2):105-15. · 1.22 Impact Factor
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    ABSTRACT: The p21-activated kinase (PAK) family of serine/threonine kinases, which are overexpressed in several cancer types, are critical mediators of cell survival, motility, mitosis, transcription, and translation. In the study presented here, we utilized a panel of colorectal cancer (CRC) cell lines to identify potential biomarkers of sensitivity or resistance that may be used to individualize therapy to the PAK inhibitor PF-03758309. We observed a wide range of proliferative responses in the CRC cell lines exposed to PF-03758309, this response was recapitulated in other phenotypic assays such as anchorage-independent growth, three-dimensional (3D) tumor spheroid formation, and migration. Interestingly, we observed that cells most sensitive to PF-03758309 exhibited up-regulation of genes associated with a mesenchymal phenotype (CALD1, VIM, ZEB1) and cells more resistant had an up-regulation of genes associated with an epithelial phenotype (CLDN2, CDH1, CLDN3, CDH17) allowing us to derive an epithelial-to-mesenchymal transition (EMT) gene signature for this agent. We assessed the functional role of EMT-associated genes in mediating responsiveness to PF-3758309, by targeting known genes and transcriptional regulators of EMT. We observed that suppression of genes associated with the mesenchymal phenotype conferred resistance to PF-3758309, in vitro and in vivo. These results indicate that PAK inhibition is associated with a unique response phenotype in CRC and that further studies should be conducted to facilitate both patient selection and rational combination strategies with these agents.
    Frontiers in Pharmacology 01/2013; 4:35.
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    ABSTRACT: BACKGROUND: Vascular endothelial growth factor is up-regulated in hepatocellular carcinoma (HCC) and is further up-regulated after transhepatic arterial chemoembolization. The authors of this report conducted a phase 2 trial to evaluate the safety and efficacy of bevacizumab combined with chemoembolization in patients with unresectable HCC. METHODS: Patients who had an Eastern Cooperative Oncology Group performance of status 0 to 2, a Child-Pugh score of A or B, and Barcelona Clinic Liver Cancer stage B or C HCC were eligible. Treatment consisted of bevacizumab every 2 weeks and chemoembolization during the third week of a 6-week cycle for up to 3 cycles over 6 months. The primary endpoints were safety and efficacy. RESULTS: Twenty-five patients received chemoembolization and bevacizumab. The most common grade 3 and 4 events after the first treatment cycle were leukocytopenia (12%), fatigue (12%), and hyponatremia (12%). Serious toxicities that had a known association with bevacizumab were observed in 4 patients. Thirty-day mortality was 0%. The median time to tumor progression for the targeted lesions was not reached, and overall survival was 10.8 months. The objective response rate was 60% using enhancement response evaluation criteria, and the disease control rate was 100%. CONCLUSIONS: Concurrent treatment with bevacizumab and chemoembolization was safe in carefully selected patients and demonstrated antitumor activity in patients with unresectable HCC. These results support the further development of bevacizumab combined with chemoembolization as a treatment for unresectable HCC. Cancer 2012. © 2012 American Cancer Society.
    Cancer 11/2012; · 5.20 Impact Factor
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    ABSTRACT: Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.
    Cancer Medicine 10/2012; 1(2):207-17.
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    ABSTRACT: The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer. Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated. Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression. SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.
    Neoplasia (New York, N.Y.) 08/2012; 14(8):690-701. · 5.48 Impact Factor
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    ABSTRACT: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. GlaxoSmithKline.
    The Lancet Oncology 07/2012; 13(8):773-81. · 25.12 Impact Factor

Publication Stats

2k Citations
561.15 Total Impact Points

Institutions

  • 2012
    • Sarah Cannon Research Institute
      Nashville, Tennessee, United States
  • 2009–2012
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2008–2012
    • University of Colorado
      • Division of Medical Oncology
      Denver, CO, United States
  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 2005–2010
    • Johns Hopkins University
      Baltimore, Maryland, United States