Jennifer R Grandis

University of California, San Francisco, San Francisco, California, United States

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Publications (309)1969.03 Total impact

  • Julie E Bauman · Jennifer Grandis ·

    11/2015; DOI:10.1001/jamaoncol.2015.4637
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    ABSTRACT: Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.
    Assay and Drug Development Technologies 09/2015; 13(7):356-76. DOI:10.1089/adt.2015.663 · 1.53 Impact Factor
  • Jessica H Maxwell · Jennifer R Grandis · Robert L Ferris ·
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    ABSTRACT: Human papillomavirus (HPV) is a recently identified causative agent for a subset of head and neck cancers, primarily in the oropharynx, and is largely responsible for the rising worldwide incidence of oropharyngeal cancer (OPC). Patients with HPV-positive OPC have distinct risk factor profiles and generally have a better prognosis than patients with traditional, HPV-negative, head and neck cancer. Concurrent chemotherapy and radiation is a widely accepted primary treatment modality for many patients with HPV-positive OPC. However, recent advances in surgical modalities, including transoral laser and robotic surgery, have led to the reemergence of primary surgical treatment for HPV-positive patients. Clinical trials are under way to determine optimal treatment strategies for the growing subset of patients with HPV-positive OPC. Similarly, identifying those patients with HPV-positive cancer who are at risk for recurrence and poor survival is critical in order to tailor individual treatment regimens and avoid potential undertreatment. Expected final online publication date for the Annual Review of Medicine Volume 67 is January 14, 2016. Please see for revised estimates.
    Annual review of medicine 08/2015; 67(1). DOI:10.1146/annurev-med-051914-021907 · 12.93 Impact Factor
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    Noah D Peyser · Yu Du · Hua Li · Vivian Lui · Xiao Xiao · Timothy A Chan · Jennifer R Grandis ·
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    ABSTRACT: Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC. We analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR. Our findings indicate that PTPRD mutation, rather than methylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC. We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells. We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC. PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.
    PLoS ONE 08/2015; 10(8):e0135750. DOI:10.1371/journal.pone.0135750 · 3.23 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4211-4211. DOI:10.1158/1538-7445.AM2015-4211 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):894-894. DOI:10.1158/1538-7445.AM2015-894 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):1674-1674. DOI:10.1158/1538-7445.AM2015-1674 · 9.33 Impact Factor
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    ABSTRACT: In other cancer types, HPV infection has been reported to coincide with overexpression of HER2 and HER3, however the association between HER2 or HER3 expression or dimer formation in HNSCC has not been reported. Overexpression of HER2 and HER3 may contribute to resistance to EGFR inhibitors, including cetuximab, although the contribution of HPV in modulating cetuximab response remains unknown. Determination of heterodimerization of HER receptors is challenging and has not been reported in HNSCC. The present study aimed to determine the expression of HER proteins in HPV[+] versus HPV[-] HNSCC tumors using a proximity-based protein expression assay (VeraTag), and to determine the efficacy of HER targeting agents in HPV[+] and HPV[-] HNSCC cell lines. Expression of total HER1, HER2, and HER3, p95HER2, p-HER3, HER1:HER1 homodimers, HER2:HER3 heterodimers and the HER3-PI3K complex in 88 HNSCC was determined using VeraTag, including 33 baseline tumors from individuals treated in a trial including cetuximab. Inhibition of cell growth and protein activation with cetuximab and afatinib was compared in HPV[+] and HPV[-] cetuximab-resistant cell lines. Expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV[+] HNSCC. Total EGFR was significantly increased in HPV[-] HNSCC where VeraTag assay results correlated with IHC. Afatinib significantly inhibited cell growth when compared to cetuximab in the HPV[+] and HPV[-] cetuximab-resistant HNSCC cell lines. These findings suggest that agents targeting multiple HER proteins may be effective in the setting of HPV[+] HNSCC and/or cetuximab resistance. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 07/2015; DOI:10.1158/1078-0432.CCR-14-3338 · 8.72 Impact Factor
  • Matthew Louis Hedberg · Hua Li · Yan Zeng · Jennifer Rubin Grandis ·

    Molecular Cancer Therapeutics 07/2015; 14(7 Supplement):A39-A39. DOI:10.1158/1538-8514.PI3K14-A39 · 5.68 Impact Factor
  • N D Peyser · M Freilino · L Wang · Y Zeng · H Li · D E Johnson · J R Grandis ·
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    ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) overactivation is a common event in many cancers, including head and neck squamous cell carcinoma (HNSCC), where STAT3 represents a promising therapeutic target. HNSCC is not characterized by frequent kinase mutations, in contrast to some malignancies where mutational activation of kinases upstream of STAT3 is common. Instead, STAT3 may be activated by loss-of-function of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers, including HNSCC (60.1% of tumors analyzed) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression. These findings were confirmed in an independent cohort of HNSCC tumors by methylation-specific PCR and immunohistochemistry. We demonstrate that PTPRT promoter methylation and gene silencing is reversible in HNSCC cells, leading to PTPRT-specific downregulation of pSTAT3 expression. We further show that PTPRT promoter methylation is significantly associated with sensitivity to STAT3 inhibition in HNSCC cells, suggesting that PTPRT promoter methylation may serve as a predictive biomarker for responsiveness to STAT3 inhibitors in clinical development.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.171.
    Oncogene 05/2015; DOI:10.1038/onc.2015.171 · 8.46 Impact Factor
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    ABSTRACT: Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response. To determine a mechanism of exceptional response to erlotinib therapy in HNSCC. Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response. A brief course of erlotinib monotherapy followed by surgical resection. Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants. No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells. Selective erlotinib use in HNSCC may be informed by precision oncology approaches.
    05/2015; 1(2). DOI:10.1001/jamaoncol.2015.34
  • Yihui Wen · Jennifer R Grandis ·
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    ABSTRACT: Introduction: Despite improvements in treatment, survival rates of head and neck squamous cell carcinoma (HNSCC) are stagnant. The existing chemotherapeutic agents are non-selective and associated with toxicities. Combinations of the only the US FDA-approved epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, with chemotherapy or radiation improves overall survival. However, the response rates to cetuximab are modest. Thus, there is an urgent need for new agents that can be safely integrated into current treatment regimens to improve outcome. Areas covered: Current EGFR-targeted drugs under clinical development include mAbs and tyrosine kinase inhibitors. The modest efficacy of these drugs implicates intrinsic or acquired resistance. Novel molecular agents inhibiting alternative targets to overcome anti-EGFR resistance in HNSCC are under investigation. Gene therapy and immunotherapy are also promising strategies to improve efficacy and reduce toxicity. Expert opinion: To date, only six drugs have been FDA-approved for the treatment of head and neck cancer. Cetuximab is the only approved molecular targeting agent for HNSCC and despite ubiquitous expression of EGFR in HNSCC tumors, clinical responses are limited. Genetic and epigenetic characterization of HNSCC tumors, coupled with improved preclinical models, should facilitate the development of more effective drugs.
    Expert Opinion on Emerging Drugs 03/2015; 20(2):1-17. DOI:10.1517/14728214.2015.1031653 · 3.06 Impact Factor
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    ABSTRACT: Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) 3 has been implicated in cell proliferation and survival of many cancers including head and neck squamous cell carcinoma (HNSCC). AZD1480, an orally active pharmacologic inhibitor of JAK1/JAK2, has been tested in several cancer models. In the present study, the in vitro and in vivo effects of AZD1480 were evaluated in HNSCC preclinical models to test the potential use of JAK kinase inhibition for HNSCC therapy. AZD1480 treatment decreased HNSCC proliferation in HNSCC cell lines with half maximal effective concentration (EC50) values ranging from 0.9 to 4 μM in conjunction with reduction of pSTAT3Tyr705 expression. In vivo antitumor efficacy of AZD1480 was demonstrated in patient-derived xenograft (PDX) models derived from two independent HNSCC tumors. Oral administration of AZD1480 reduced tumor growth in conjunction with decreased pSTAT3Tyr705 expression that was observed in both PDX models. These findings suggest that the JAK1/2 inhibitors abrogate STAT3 signaling and may be effective in HNSCC treatment approaches. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 03/2015; 3(3). DOI:10.1016/j.neo.2015.01.003 · 4.25 Impact Factor
  • Pei Zhou · Hua Li · Sarah Wheeler · Jennifer R. Grandis · Laura A. Stabile · Ann Marie Egloff ·

    Clinical Cancer Research 02/2015; 21(4 Supplement):B39-B39. DOI:10.1158/1557-3265.PMS14-B39 · 8.72 Impact Factor
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) accounts for more than 5% of all cancers worldwide. The mortality rate of HNSCC has remained unchanged (approximately 50%) over the last few decades. Ubiquitous overexpression of wild type EGFR in many solid tumors has led to the development of EGFR targeted therapies. EGFR can be constitutively activated via several mechanisms including the truncated, EGFR variant III isoform (EGFRvIII). EGFRvIII lacks exons 2-7 and has been reported to be present in up to 20-40% of HNSCC. EGFRvIII has been shown to contribute to cetuximab resistance. The mechanisms leading to EGFRvIII expression in HNSCC are unknown. The present investigation was undertaken to determine the etiology of EGFRvIII in HNSCC. Fixed HNSCC and glioma tissues were analyzed by fluorescence in situ hybridization for EGFR amplification. DNA and RNA from fresh frozen specimens were used to determine the presence of EGFRvIII transcripts and the mechanisms of expression via PCR, RT-PCR and RNA sequencing. Unlike glioma, EGFRvIII expression in HNSCC did not correlate with EGFR amplification. We found evidence of genomic deletion of the exon 2-7 in 6 of 7 HNSCC cases examined, however, the presence of genomic deletion did not always result in mRNA expression of EGFRvIII. RNA sequencing with automated alignment did not identify EGFRvIII due to microhomology between intron 1 and exon 8. RNA sequencing analyzed by manual alignment methods did not correlate well with RT-PCR and PCR findings. These findings suggest that genomic deletion as well as additional regulatory mechanisms may contribute to EGFRvIII expression in HNSCC. Further, large scale automated alignment of sequencing are unlikely to identify EGFRvIII and an assay specifically designed to detect EGFRvIII may be necessary to detect this altered form of EGFR in HNSCC tumors.
    PLoS ONE 02/2015; 10(2):e0117781. DOI:10.1371/journal.pone.0117781 · 3.23 Impact Factor
  • Peter S Hammerman · D Neil Hayes · Jennifer R Grandis ·
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    ABSTRACT: Large and comprehensive genomic surveys of head and neck squamous cell carcinomas (HNSCC) are now greatly increasing our understanding of the diversity of this disease and the key genomic changes that drive these tumors. The results from these studies are beginning to inform the introduction of novel therapies for patients with HNSCCs. Here, we review some of the key findings from recent genomic studies of head and neck cancers, including the most comprehensive study to date from The Cancer Genome Atlas Network. Cancer Discov; 5(3); 1-6. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Discovery 02/2015; 5(3). DOI:10.1158/2159-8290.CD-14-1205 · 19.45 Impact Factor
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    ABSTRACT: The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.
    Nature 01/2015; 517(7536):576-582. DOI:10.1038/nature14129 · 41.46 Impact Factor
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    ABSTRACT: EGFR polymorphisms have not been thoroughly evaluated for association with head and neck squamous cell carcinoma (HNSCC) risk. We genotyped 578 HNSCC patients and 588 cancer-free controls for 60 EGFR single nucleotide polymorphisms (SNPs) and tested associations with HNSCC risk. EGFR intronic SNPs rs12535536, rs2075110, rs1253871, rs845561 and rs6970262 and synonymous SNP rs2072454 were associated with HNSCC risk among all subjects (p<0.05). SNPs rs12538371, rs845561, and rs6970262 were significantly associated with HNSCC risk (p<0.05) among never tobacco users. We identified EGFR variants that likely modify risk for HNSCC including three variants that contribute to tobacco-independent risk. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.008 · 5.62 Impact Factor
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    ABSTRACT: BACKGROUND Earlier detection and diagnosis of head and neck squamous cell carcinoma (HNSCC) should lead to improved outcomes. However, to the authors' knowledge, no effective screening strategy has been identified to date. In the current study, the authors evaluated whether it would be useful to screen subjects targeted for lung cancer screening for HNSCC as well.METHODS Medical records, death certificates, and cancer registry and questionnaire data were used to determine the number of observed incident HNSCC cases in the Pittsburgh Lung Screening Study (PLuSS), a cohort of current and former smokers aged ≥50 years with a ≥12.5 pack-year smoking history. The expected number of cases was estimated using stratum-specific incidence rates obtained from Surveillance, Epidemiology, and End Results data for 2000 through 2011. The standardized incidence ratio was calculated to examine the difference between the observed and expected number of cases.RESULTSOf the 3587 at-risk participants in the PLuSS, 23 (0.64%) developed HNSCC over a total of 32,201 person-years of follow-up. This finding was significantly higher than expected based on incidence rates obtained from the Surveillance, Epidemiology, and End Results program (13.70 cases expected; standardized incidence ratio, 1.68 [95% confidence interval, 1.06-2.52]). The excess burden of HNSCC in the PLuSS was 28.9 cases per 100,000 person-years. Observed incident cases were significantly more often male, had started smoking at a younger age, smoked more per day, and had more pack-years of smoking than the rest of the PLuSS at-risk participants.CONCLUSIONS The results of the current study provide a rationale for offering head and neck cancer screening along with computed tomography screening for lung cancer. Randomized controlled trials that assess the effectiveness of adding examination of the head and neck area to lung cancer screening programs are warranted. Cancer 2015. © 2015 American Cancer Society.
    Cancer 12/2014; 121(9). DOI:10.1002/cncr.29189 · 4.89 Impact Factor
  • Netanya I Pollock · Jennifer R Grandis ·
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    ABSTRACT: The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. Current standard of care is surgery followed by adjuvant radiation therapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 11/2014; 21(3). DOI:10.1158/1078-0432.CCR-14-1432 · 8.72 Impact Factor

Publication Stats

12k Citations
1,969.03 Total Impact Points


  • 2015
    • University of California, San Francisco
      San Francisco, California, United States
  • 1970-2015
    • University of Pittsburgh
      • • Department of Otolaryngology
      • • Department of Medicine
      • • Pittsburgh Cancer Institute
      • • Department of Pathology
      Pittsburgh, Pennsylvania, United States
  • 2011
    • Broad Institute of MIT and Harvard
      • Cancer Program
      Cambridge, Massachusetts, United States
  • 2009
    • University of Wisconsin, Madison
      • Department of Human Oncology
      Madison, MS, United States
  • 2007
    • The Chinese University of Hong Kong
      Hong Kong, Hong Kong
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2006
    • Duke University
      Durham, North Carolina, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2002-2003
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1998
    • Childrens Hospital of Pittsburgh
      • Division of Pediatric Otolaryngology (ENT)
      Pittsburgh, Pennsylvania, United States