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Dive into the research topics where Faye M. Johnson is active.

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Featured researches published by Faye M. Johnson.


Journal of Clinical Oncology | 2009

Phase II Study of the Anti–Insulin-Like Growth Factor Type 1 Receptor Antibody CP-751,871 in Combination With Paclitaxel and Carboplatin in Previously Untreated, Locally Advanced, or Metastatic Non–Small-Cell Lung Cancer

Daniel D. Karp; Luis Paz-Ares; Silvia Novello; Paul Haluska; Linda Garland; Felipe Cardenal; L. Johnetta Blakely; Peter D. Eisenberg; Corey J. Langer; George R. Blumenschein; Faye M. Johnson; Stephanie Green; Antonio Gualberto

PURPOSE We conducted a phase II study of combination of the anti-insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients were randomly assigned (2:1) to paclitaxel 200 mg/m(2), carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI(10-20) patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigators discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI(20) was enrolled on completion of the randomized study. RESULTS A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI(10) and 50 patients received PCI(20) in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI(20)/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship. CONCLUSION These data suggest that PCI(20) is safe and effective in patients with NSCLC.


Cancer | 2008

Epithelial to Mesenchymal Transition in Head and Neck Squamous Carcinoma : Association of Src Activation With E-cadherin Down-regulation, Vimentin Expression, and Aggressive Tumor Features

Mahitosh Mandal; Jeffery N. Myers; Scott M. Lippman; Faye M. Johnson; Michelle D. Williams; Suresh K. Rayala; Kazufumi Ohshiro; David I. Rosenthal; Randal S. Weber; Gary E. Gallick; Adel K. El-Naggar

Epithelial–mesenchymal transformations (EMT) are critical for the invasion, progression, and metastasis of epithelial carcinogenesis. The role of EMT in head and neck squamous carcinoma (HNSC) tumorigenesis remains unexplored. In the current study, the expressions of several factors associated with the induction of EMT in HNSC cell lines and tumor specimens were investigated to define their functional and pathologic role in HNSC.


Journal of Clinical Oncology | 2010

Phase II Study of Dasatinib in Patients With Advanced Non–Small-Cell Lung Cancer

Faye M. Johnson; B. Nebiyou Bekele; Lei Feng; Ignacio I. Wistuba; Xi Ming Tang; Hai T. Tran; Jeremy J. Erasmus; Li Ling Hwang; Naoko Takebe; George R. Blumenschein; Scott M. Lippman; David J. Stewart

PURPOSE Src family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib. PATIENTS AND METHODS Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression. RESULTS Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy. CONCLUSION Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.


Journal of Signal Transduction | 2011

Regulation of SRC family kinases in human cancers.

Banibrata Sen; Faye M. Johnson

The nonreceptor protein tyrosine kinase Src plays a crucial role in the signal transduction pathways involved in cell division, motility, adhesion, and survival in both normal and cancer cells. Although the Src family kinases (SFKs) are activated in various types of cancers, the exact mechanisms through which they contribute to the progression of individual tumors remain to be defined. The activation of Src in human cancers may occur through a variety of mechanisms that include domain interaction and structural remodeling in response to various activators or upstream kinases and phosphatastes. Because of Srcs prominent roles in invasion and tumor progression, epithelial-to-mesenchymal transition, angiogenesis, and the development of metastasis, Src is a promising target for cancer therapy. Several small molecule inhibitors of Src are currently being investigated in clinical trials. In this article, we will summarize the mechanisms regulating Src kinase activity in normal and cancer cells and discuss the status of Src inhibitor development against various types of cancers.


Drug Resistance Updates | 2010

Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: Implications for future therapeutic approaches

Stephen Y. Lai; Faye M. Johnson

Although the role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has been most extensively studied in hematopoietic cells and hematologic malignancies, it is also activated in epithelial tumors, including those originating in the lungs and head and neck. The canonical pathway involves the activation of JAK following ligand binding to cytokine receptors. The activated JAKs then phosphorylate STAT proteins, leading to their dimerization and translocation into the nucleus. In the nucleus, STATs act as transcription factors with pleiotropic downstream effects. STATs can be activated independently of JAKs, most notably by c-Src kinases. In cancer cells, STAT3 and STAT5 activation leads to the increased expression of downstream target genes, leading to increased cell proliferation, cell survival, angiogenesis, and immune system evasion. STAT3 and STAT5 are expressed and activated in head and neck squamous cell carcinoma (HNSCC) where they contribute to cell survival and proliferation. In HNSCC, STATs can be activated by a number of signal transduction pathways, including the epidermal growth factor receptor (EGFR), alpha7 nicotinic receptor, interleukin (IL) receptor, and erythropoietin receptor pathways. Activated STATs are also expressed in lung cancer, but the biological effects of JAK/STAT inhibition in this cancer are variable. In lung cancer, STAT3 can be activated by multiple pathways, including EGFR. Several approaches have been used to inhibit STAT3 in the hopes of developing an antitumor agent. Although several STAT3-specific agents are promising, none are in clinical development, mostly because of drug delivery and stability issues. In contrast, several JAK inhibitors are in clinical development. These orally available, ATP-competitive, small-molecule kinase inhibitors are being tested in myeloproliferative disorders. Future studies will determine whether JAK inhibitors are useful in the treatment of HNSCC or lung cancer.


Molecular Cancer Therapeutics | 2007

Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion

Anne S. Tsao; Dandan He; Babita Saigal; Suyu Liu; J. Jack Lee; Srinivasa Bakkannagari; Nelson G. Ordonez; Waun Ki Hong; Ignacio I. Wistuba; Faye M. Johnson

Malignant pleural mesothelioma (MPM) is a deadly disease with few systemic treatment options. One potential therapeutic target, the non–receptor tyrosine kinase c-Src, causes changes in proliferation, motility, invasion, survival, and angiogenesis in cancer cells and may be a valid therapeutic target in MPM. To test this hypothesis, we determined the effects of c-Src inhibition in MPM cell lines and examined c-Src expression and activation in tissue samples. We analyzed four MPM cell lines and found that all expressed total and activated c-Src. Three of the four cell lines were sensitive by in vitro cytotoxicity assays to the c-Src inhibitor dasatinib, which led to cell cycle arrest and increased apoptosis. Dasatinib also inhibited migration and invasion independent of the cytotoxic effects, and led to the rapid and durable inhibition of c-Src and its downstream pathways. We used immunohistochemical analysis to determine the levels of c-Src expression and activation in 46 archived MPM tumor specimens. The Src protein was highly expressed in tumor cells, but expression did not correlate with survival. However, expression of activated Src (p-Src Y419) on the tumor cell membrane was higher in patients with advanced-stage disease; the presence of metastasis correlated with higher membrane (P = 0.03) and cytoplasmic (P = 0.04) expression of p-Src Y419. Lower levels of membrane expression of inactive c-Src (p-Src Y530) correlated with advanced N stage (P = 0.02). Activated c-Src may play a role in survival, metastasis, and invasion of MPM, and targeting c-Src may be an important therapeutic strategy. [Mol Cancer Ther 2007;6(7):1962–72]


Cancer Research | 2009

Sustained Src Inhibition Results in Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Cancer Cell Survival via Altered Janus-Activated Kinase–STAT3 Binding

Banibrata Sen; Babita Saigal; Nila U. Parikh; Gary E. Gallick; Faye M. Johnson

Locoregional and distant recurrence remains common and usually fatal for patients with advanced head and neck squamous cell carcinoma (HNSCC). One promising molecular target in HNSCC is the Src family kinases (SFK). SFKs can affect cellular proliferation and survival by activating the signal transducer and activator of transcription (STAT) family of transcription factors, especially STAT3. Surprisingly, sustained SFK inhibition resulted in only transient inhibition of STAT3. We investigated the mechanism underlying STAT3 activation and its biological importance. Specific c-Src knockdown with small interfering RNA (siRNA) resulted in STAT3 activation showing specificity, which was inhibited by Janus-activated kinase (JAK; TYK2 and JAK2) depletion with siRNA. Sustained SFK inhibition also resulted in recovered JAK-STAT3 binding and JAK kinase activity after an initial reduction, although JAK phosphorylation paradoxically decreased. To determine the biological significance of STAT3 activation, we combined specific STAT3 depletion with a pharmacologic SFK inhibitor and observed increased cell cycle arrest and apoptosis. Likewise, the addition of STAT3- or JAK-specific siRNA to c-Src-depleted cells enhanced cytotoxicity relative to cells incubated with c-Src siRNA alone. These results show that reactivation of STAT3 after sustained, specific c-Src inhibition is mediated through altered JAK-STAT3 binding and JAK kinase activity and that this compensatory pathway allows for cancer cell survival and proliferation despite durable c-Src inhibition. To our knowledge, this novel feedback pathway has never been described previously. Given that pharmacologic SFK inhibitors are currently being evaluated in clinical trials, these results have potential clinical implications for cancer therapy.


Cancer | 2010

Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors

Faye M. Johnson; Shruti Agrawal; Howard A. Burris; Lee S. Rosen; Navneet Dhillon; David S. Hong; Anne Blackwood-Chirchir; Feng R. Luo; Oumar Sy; Sanjeev Kaul; Alberto Chiappori

The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once‐daily dasatinib regimen.


Science Translational Medicine | 2012

Kinase-Impaired BRAF Mutations in Lung Cancer Confer Sensitivity to Dasatinib

Banibrata Sen; Shaohua Peng; Ximing Tang; Heidi S. Erickson; Hector Galindo; Tuhina Mazumdar; David J. Stewart; Ignacio I. Wistuba; Faye M. Johnson

Induction of tumor cell senescence may explain the response of a patient with BRAF kinase–impaired lung cancer to the multikinase inhibitor dasatinib. A Lucky Break with BRAF The prognosis for those with metastatic non–small cell lung cancer (NSCLC) is bleak—the median survival time is measured in months. Therapeutic benefits have been achieved with targeted drugs in subpopulations of NSCLC patients with specific mutations, but the genetic changes responsible for this disease are undefined in most cases. Understanding why certain tumors respond to a given treatment might help determine useful therapeutic targets. Sen et al. now describe a striking case—the mutation responsible for the strong response of one patient with metastatic NSCLC to treatment with the tyrosine kinase inhibitor dasatinib. In a previous clinical trial of dasatinib treatment for metastatic NSCLC that lasted for 12 weeks, only a single patient responded to treatment; his tumor shrank and continued to shrink after treatment ended. Four years later, he appears free of active cancer. The researchers analyzed this patient’s tumor tissue and did not detect mutations that had been associated with NSCLC in other patients, but did find a mutation in the serine-threonine kinase BRAF that markedly impaired its kinase activity. (In contrast, another well-characterized oncogenic mutation in BRAF is kinase-activating.) Sen et al. found that in NSCLC cell lines with other kinase-inactivating BRAF mutations, dasatinib induced largely irreversible senescence—cell cycle arrest. Overexpression of kinase-active BRAF, however, increased dasatinib resistance in these cells, indicating that the inactive BRAF kinase was required for their dasatinib sensitivity. Furthermore, treatment of dasatinib-resistant cancer cells that express wild-type BRAF with a BRAF inhibitor increased their sensitivity to dasatinib. Exactly how dasatinib induces senescence in NSCLC cells with kinase-impaired BRAF is not yet clear, but the finding opens new possibilities for treatment. Cancers in which BRAF is impaired may respond well to dasatinib; more broadly, dasatinib in combination with BRAF inhibitors may be useful for treating tumors that express wild-type BRAF. During a clinical trial of the tyrosine kinase inhibitor dasatinib for advanced non–small cell lung cancer (NSCLC), one patient responded dramatically and remains cancer-free 4 years later. A comprehensive analysis of his tumor revealed a previously undescribed, kinase-inactivating BRAF mutation (Y472CBRAF); no inactivating BRAF mutations were found in the nonresponding tumors taken from other patients. Cells transfected with Y472CBRAF exhibited CRAF, MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase), and ERK (extracellular signal–regulated kinase) activation—characteristics identical to signaling changes that occur with previously known kinase-inactivating BRAF mutants. Dasatinib selectively induced senescence in NSCLC cells with inactivating BRAF mutations. Transfection of other NSCLC cells with these BRAF mutations also increased these cells’ dasatinib sensitivity, whereas transfection with an activating BRAF mutation led to their increased dasatinib resistance. The sensitivity induced by Y472CBRAF was reversed by the introduction of a BRAF mutation that impairs RAF dimerization. Dasatinib inhibited CRAF modestly, but concurrently induced RAF dimerization, resulting in ERK activation in NSCLC cells with kinase-inactivating BRAF mutations. The sensitivity of NSCLC with kinase-impaired BRAF to dasatinib suggested synthetic lethality of BRAF and an unknown dasatinib target. Inhibiting BRAF in NSCLC cells expressing wild-type BRAF likewise enhanced these cells’ dasatinib sensitivity. Thus, the patient’s BRAF mutation was likely responsible for his tumor’s marked response to dasatinib, suggesting that tumors bearing kinase-impaired BRAF mutations may be exquisitely sensitive to dasatinib. Moreover, the potential synthetic lethality of combination therapy including dasatinib and BRAF inhibitors may lead to additional therapeutic options against cancers with wild-type BRAF.


Anti-cancer Agents in Medicinal Chemistry | 2007

Src family nonreceptor tyrosine kinases as molecular targets for cancer therapy

Faye M. Johnson; Gary E. Gallick

The Src family of kinases has nine known members, all of which are nonreceptor tyrosine kinases involved in signal transduction in both normal and cancer cells. Interest in these kinases has increased recently because of the development, initial clinical success, and low toxicity of pharmacologic inhibitors. c-Src is the best-studied member of the Src family and the one most often implicated in cancer progression. c-Src has multiple substrates that lead to diverse biologic effects, including changes in proliferation, motility, invasion, survival, and angiogenesis. c-Src has been most extensively studied in colon cancer where correlative and direct experimental evidence has shown that it mediates several aspects of cancer cell progression. c-Src has a similar role in multiple tumor types, including pancreatic cancer, breast cancer, lung cancer, head and neck squamous cell carcinoma, and prostate cancer. Several inhibitors of the Src family kinases are in clinical development; three are currently being studied in clinical trials. Initial data from these trials suggest that these agents are well tolerated. Future clinical development of these inhibitors will include trials in patients with solid tumors and of combination therapy.

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Jing Wang

University of Texas MD Anderson Cancer Center

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Bonnie S. Glisson

University of Texas MD Anderson Cancer Center

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Shaohua Peng

University of Texas MD Anderson Cancer Center

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Jeffrey N. Myers

University of Texas MD Anderson Cancer Center

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Ignacio I. Wistuba

University of Texas MD Anderson Cancer Center

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Tuhina Mazumdar

University of Texas MD Anderson Cancer Center

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John V. Heymach

University of Texas MD Anderson Cancer Center

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Lauren Averett Byers

University of Texas MD Anderson Cancer Center

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Banibrata Sen

University of Texas MD Anderson Cancer Center

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Pan Tong

University of Texas MD Anderson Cancer Center

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