Phillip A Dennis

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (101)808.13 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):684-684. DOI:10.1158/1538-7445.AM2015-684 · 9.33 Impact Factor
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    ABSTRACT: Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.
    Oncotarget 05/2015; 6(13):11357-68. DOI:10.18632/oncotarget.3605 · 6.36 Impact Factor
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    ABSTRACT: Many HIV patients on antiretroviral therapy have controlled viremia and restored (albeit partially) immunity. Yet, they have high rates of lung cancer, even after controlling for smoking. We tested the hypothesis that HIV proteins accelerate development/progression of lung cancer in an immunocompetent HIV transgenic mouse model. The expression of HIV proteins did not enhance lung tumorigenesis caused by two different tobacco carcinogens, suggesting that incompletely restored immunity and/or inflammation, which persist(s) in most HIV patients despite controlled viremia, underlie(s) excess risk of lung cancer. Adjuvant therapies that restore immunity and lower inflammation may decrease lung cancer mortality in HIV patients.
    AIDS (London, England) 01/2015; 29(5). DOI:10.1097/QAD.0000000000000588 · 5.55 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2411-2411. DOI:10.1158/1538-7445.AM2014-2411 · 9.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2927-2927. DOI:10.1158/1538-7445.AM2014-2927 · 9.33 Impact Factor
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    ABSTRACT: Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
    Oncotarget 09/2014; 5(18):8161-72. DOI:10.18632/oncotarget.2415 · 6.36 Impact Factor
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    ABSTRACT: Objectives Primary and acquired resistance to EGFR TKIs in EGFR mutant lung cancer occurs primarily through secondary mutations in EGFR or Met amplification. Drug resistance can also be mediated by expression of pluripotency transcription factors, such as OCT4, SOX2 and NANOG that decrease terminal differentiation. In this study, we investigated the expression and role of SOX2 in model systems of EGFR mutant tumors. Materials and Methods Immunoblotting or immunohistochemistry was used to assess expression of pluripotency transcription factors in lungs of transgenic mice or in human NSCLC cell lines. Expression of SOX2 was reduced by shRNA knockdown, and response to erlotinib and cellular proliferation were assessed. Results and Conclusion Induction of mutant EGFR in transgenic CCSP-rtTA/TetO-EGFRL858R/T790M mice correlated with increased OCT4 and SOX2 expression in lung tissue prior to tumor development. Established lung tumors retained SOX2 expression. To assess a role for SOX2 in tumorigenesis, a panel of NSCLC cell lines with activating EGFR mutations was assessed for SOX2 expression. Two of six cell lines with mutant EGFR showed detectable SOX2 levels, suggesting SOX2 expression did not correlate with EGFR mutation status. To assess the role of SOX2 in these cell lines, HCC827 and H1975 cells were infected with lentivirus containing SOX2 shRNA. Knockdown of SOX2 decreased proliferation in both cell lines and increased sensitivity to erlotinib in HCC827 cells. Because constitutive activation of the PI3 K/Akt pathway is associated with EGFR TKI resistance, cells were treated with PI3 K/AKT inhibitors and expression of SOX2 was examined. PI3 K/Akt inhibitors decreased SOX2 expression in a time-dependent manner. These data suggest targeting SOX2 may provide therapeutic benefit in the subset of EGFR-mutant tumors with high constitutive levels of SOX2, and that until more direct means of inhibiting SOX2 are developed, PI3 K/Akt inhibitors might be useful to inhibit SOX2 in EGFR TKI resistant tumors.
    Lung cancer (Amsterdam, Netherlands) 07/2014; 85(1). DOI:10.1016/j.lungcan.2014.03.021 · 3.96 Impact Factor
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    ABSTRACT: Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.
    Cell Reports 06/2014; 7(6). DOI:10.1016/j.celrep.2014.05.039 · 8.36 Impact Factor
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    ABSTRACT: Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.
    Oncotarget 03/2014; 5(6). DOI:10.18632/oncotarget.1891 · 6.36 Impact Factor
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    ABSTRACT: Unlabelled: Nelfinavir (NFV) is an HIV-1 protease inhibitor with demonstrated antiviral activity against herpes simplex virus 1 (HSV-1) and several other herpesviruses. However, the stages of HSV-1 replication inhibited by NFV have not been explored. In this study, we investigated the effects of NFV on capsid assembly and envelopment. We confirmed the inhibitory effects of NFV on HSV-1 replication by plaque assay and found that treatment with NFV did not affect capsid assembly, activity of the HSV-1 maturational protease, or formation of DNA-containing capsids in the nucleus. Confocal and electron microscopy studies showed that these capsids were transported to the cytoplasm but failed to complete secondary envelopment and subsequent exit from the cell. Consistent with the microscopy results, a light-scattering band corresponding to enveloped virions was not evident following sucrose gradient rate-velocity separation of lysates from drug-treated cells. Evidence of a possibly related effect of NFV on viral glycoprotein maturation was also discovered. NFV also inhibited the replication of an HSV-1 thymidine kinase mutant resistant to nucleoside analogues such as acyclovir. Given that NFV is neither a nucleoside mimic nor a known inhibitor of nucleic acid synthesis, this was expected and suggests its potential as a coinhibitor or alternate antiviral therapeutic agent in cases of resistance. Importance: Nelfinavir (NFV) is a clinically important antiviral drug that inhibits production of infectious HIV. It was reported to inhibit herpesviruses in cell culture. Herpes simplex virus 1 (HSV-1) infections are common and often associated with several diseases. The studies we describe here confirm and extend earlier findings by investigating how NFV interferes with HSV-1 replication. We show that early steps in virus formation (e.g., assembly of DNA-containing capsids in the nucleus and their movement into the cytoplasm) appear to be unaffected by NFV, whereas later steps (e.g., final envelopment in the cytoplasm and release of infectious virus from the cell) are severely restricted by the drug. Our findings provide the first insight into how NFV inhibits HSV-1 replication and suggest that this drug may have applications for studying the herpesvirus envelopment process. Additionally, NFV may have therapeutic value alone or in combination with other antivirals in treating herpesvirus infections.
    Journal of Virology 02/2014; 88(10). DOI:10.1128/JVI.03790-13 · 4.44 Impact Factor
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    ABSTRACT: Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.
    Oncotarget 02/2014; 5(4). DOI:10.18632/oncotarget.1760 · 6.36 Impact Factor
  • Cancer Prevention Research 01/2014; 5(11_Supplement):PR-01-PR-01. DOI:10.1158/1940-6207.PREV-12-PR-01 · 4.44 Impact Factor
  • Kristin Lastwika · Willie Wilson · Phillip A. Dennis
    Cancer Research 08/2013; 73(8 Supplement):4981-4981. DOI:10.1158/1538-7445.AM2013-4981 · 9.33 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):1081-1081. DOI:10.1158/1538-7445.AM2013-1081 · 9.33 Impact Factor
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    ABSTRACT: Metformin is the most commonly prescribed drug for type 2 diabetes (T2DM). Retrospective studies show that metformin is associated with decreased cancer risk. This historical correlation has driven vigorous research campaigns to determine the anticancer mechanisms of metformin. Consolidating the preclinical data is a challenge because unanswered questions remain concerning relevant mechanisms, bioavailability, and genetic factors that confer metformin sensitivity. Perhaps the most important unanswered question is whether metformin has activity against cancer in non-diabetics. In this review we highlight the proposed mechanisms of metformin action in cancer and discuss ongoing clinical trials with metformin in cancer. Improved understanding of these issues will increase the chances for successful application of metformin as an inexpensive, well-tolerated, and effective anticancer agent.
    Trends in Endocrinology and Metabolism 06/2013; 24(9). DOI:10.1016/j.tem.2013.05.004 · 9.39 Impact Factor
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    ABSTRACT: Metformin is the most commonly prescribed drug for type II diabetes and is associated with decreased cancer risk. Previously, we showed that metformin prevented tobacco carcinogen (NNK)-induced lung tumorigenesis in a non-diabetic mouse model, which was associated with decreased IGF-I/insulin receptor signaling but not activation of AMPK in lung tissues, as well as decreased circulating levels of IGF-1 and insulin. Here, we used liver-IGF-1-deficient (LID) mice to determine the importance of IGF-1 in NNK-induced lung tumorigenesis and chemoprevention by metformin. LID mice had decreased lung tumor multiplicity and burden compared to WT mice. Metformin further decreased lung tumorigenesis in LID mice without affecting IGF-1 levels, suggesting that metformin can act through IGF-1-independent mechanisms. In lung tissues, metformin decreased phosphorylation of multiple receptor tyrosine kinases (RTKs) as well as levels of GTP-bound Ras independently of AMPK. Metformin also diminished plasma levels of several cognate ligands for these RTKs. Tissue distribution studies using [14C]-metformin showed that uptake of metformin was high in liver but 4 fold lower in lungs, suggesting that the suppression of RTK activation by metformin occurs predominantly via systemic, indirect effects. Systemic inhibition of circulating growth factors and local RTK signaling are new AMPK-independent mechanisms of action of metformin that could underlie its ability to prevent tobacco carcinogen-induced lung tumorigenesis.
    Cancer Prevention Research 06/2013; 6(8). DOI:10.1158/1940-6207.CAPR-13-0058-T · 4.44 Impact Factor
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    ABSTRACT: Purpose: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. Materials and methods: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. Results: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. Conclusions: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.
    The Journal of urology 06/2013; 190(6). DOI:10.1016/j.juro.2013.06.012 · 4.47 Impact Factor
  • 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR); 04/2013
  • Clinical Lung Cancer 03/2013; 14(4). DOI:10.1016/j.cllc.2013.01.005 · 3.10 Impact Factor
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    ABSTRACT: Background: Cowden syndrome is an autosomal-dominant condition associated with mutations in the tumor suppressor gene PTEN. Gynecologic malignancies are common with a 5-10% risk of endometrial cancer and 25-50% risk of breast cancer. Case: A 37-year-old woman with a history of breast cancer, other neoplasms, and multiple skin lesions was diagnosed with Cowden syndrome after a germline PTEN mutation was identified. The endometrium had high glucose uptake on positron emission tomography scan and was irregularly thickened on ultrasonography; biopsy revealed endometrial polyps and simple hyperplasia. Fifteen months later, hysteroscopy again confirmed numerous benign endometrial polyps. Conclusion: Recurrent, multiple endometrial polyps portend a high risk of endometrial cancer in women with Cowden syndrome. Monitoring for malignancy and consideration of hysterectomy after childbearing is completed is warranted.
    Obstetrics and Gynecology 02/2013; 121(2):461-464. DOI:10.1097/AOG.0b013e318270444f · 5.18 Impact Factor

Publication Stats

7k Citations
808.13 Total Impact Points


  • 2013–2015
    • Johns Hopkins University
      • Department of Pharmacology and Molecular Sciences
      Baltimore, Maryland, United States
  • 2014
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2001–2013
    • National Cancer Institute (USA)
      • • Medical Oncology Branch and Affiliates
      • • Center for Cancer Research
      Maryland, United States
  • 2004–2012
    • National Institutes of Health
      • • Branch of Medical Oncology Branch and Affiliates
      • • Center for Cancer Research
      • • Branch of Cancer Cell Biology
      Maryland, United States
    • Advanced Cancer Therapeutics
      Louisville, Kentucky, United States
  • 2005–2011
    • NCI-Frederick
      Maryland, United States
  • 2005–2007
    • George Washington University
      Washington, Washington, D.C., United States
  • 2006
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
    • University of Illinois at Chicago
      • Department of Medicinal Chemistry and Pharmacognosy
      Chicago, Illinois, United States
  • 2003
    • Council for Chemical Research
      Concord, California, United States