Gopal Iyer, PhD

Gopal Iyer, PhD

Assistant Professor

Department of Human Oncology

I am an assistant professor in the Department of Human Oncology. My lab focuses on the molecular mechanisms of lung and pancreatic cancer development and its progression towards metastasis. Towards this effort, we apply experimental biophysical, optical imaging and computational approaches to analyze genes that are dysregulated in these cancers. We decipher the role of these gene mutations identified through genome sequencing efforts through external perturbations in cell lines, tissue slices and mouse models, closely mimicking therapeutic interventions. This approach could eventually lead to tailored treatments of patients and increase survival outcomes.

My laboratory fosters a multidisciplinary environment that bridges physics, chemistry and biology with the aim of training undergraduate, graduate and medical students towards aligning their interests in challenging questions in cancer. We constantly interact with biomedical engineers, medical and radiation oncologists and pathology experts to further our understanding of the clinical manifestations of the various stages of cancer. With our combined efforts, I hope to improve patients’ quality of life.

Education

Postdoc, University of California, Los Angeles & Stanford University, Biophysics (2011)

PhD, University of California, Berkeley & M.S. University of Baroda, India, Microbiology (2004)

MS, M.S. University of Baroda, India, Biotechnology (1990)

BS, M.S. University of Baroda, India, Chemistry, Botany (1988)

Academic Appointments

Assistant Professor, Human Oncology (2016)

Selected Honors and Awards

Rockefeller Foundation Fellowship (1997-2000)

Council of Scientific Industrial Research Scholarship (CSIR-INDIA) (1997-2000)

Department of Biotechnology Scholarship from Government of India for M.Sc Program (1988-1990)

Research Focus

Epigenetics and Phophorylation Processes, Acquired and Intrinsic Resistance to Cancer Therapy


Dr. Gopal Iyer is a cancer biologist whose research focuses on the molecular mechanisms of lung and pancreatic cancer development and progression toward metastasis.

The overarching goal of the Iyer Lab is to decipher the dynamics of signaling bias regulated by epigenetic and phosphorylation processes.

We use a head and neck cancer acquired resistance model and CRISPR models in pancreas and head and neck cancer that have knock-ins and knockouts of various oncogenic genes to decipher the dynamics of signaling bias regulated by epigenetic and phosphorylation processes. We are investigating perturbations of drug, radio and chemo-resistance. I was trained as a biochemist and molecular biologist in graduate school and switched to optical physics, microfluidics and chemistry in my postdoctoral career. My interdisciplinary skills are currently being used in my research to unravel the spatiotemporal kinetics of signaling modules during acquired and intrinsic resistance and apply quantitative methods to unravel the global genomic changes associated with these processes.

Androgen Receptor Signaling in Lung

Androgen receptor (AR) expression is necessary for early lung development. However, the presence of AR protein in non-small lung cancer adenocarcinoma (NSCLC) is intriguing. Recent cancer genome data have revealed the presence of mutations in AR in a subset (8 percent) of NSCLC patients that have unique mutation profiles compared to known mutations in lung cancer. In my lab, we explore the basic mechanism of AR transactivation in KRAS mutated and wild type NSCLC backgrounds. Using gene-editing cell lines, we are currently editing the AR mutations found from patient genome data and exploring its role towards the formation of lung adenocarcinoma by using optical imaging and mice models.

Genomics of Lung-Brain Metastasis

A combination of genetic and cellular events leads to tumor metastasis—the formation of secondary tumors at distant organs from the site of primary tumor. In order to alleviate the morbidity and mortality of this metastatic state, my lab has embarked on genomic approaches to sequence lung cancer patients in collaboration with oncologists and pathologists. We have performed transcriptome sequencing of more than 70 matched normal, primary lung tumor and brain metastatic patients. Extensive bioinformatics analyses revealed a unique set of brain specific genes that have potentially originated from the primary lung tumor site. Currently, we are exploring various approaches to validate these genes for their metastatic potential by fluorescent and bioluminescent tagging in vitro and in vivo models.

Targeting Bromodomain and extra-terminal (BET) Proteins in Solid Tumors

Bromodomains (BRDs) are evolutionarily conserved protein domains that interact with acetylated histones and set off a chain of events that includes recruiting transcription factors and other chromatin binding proteins to initiate RNA transcription. Using a pan-cancer approach, my lab is interested in exploring whether the inhibition of BRDs can lead to tumor regression either as a monotherapy or in combination with other drugs and chemo-radiation perturbations. The rationale of this approach is to block transcription of oncogenes like MYC and other onco-proteins that do not have inhibitors, leading to a block in cancer progression. Using nanomolar affinity inhibitors to BRDs, we unraveled a novel set of transcription factors that regulated differentially in several pancreatic and head and neck cancer lines leading to a remarkable suppression in cell proliferation and increased apoptosis. These findings have led us to explore if perturbation of BRDs across solid tumors is a conserved mechanism or has tissue specificity with respect to its transcriptional network. Using a systematic approach of RNA-sequencing, optical imaging and mice models, we are focused on addressing the relationship between BRD-BET inhibition with the mutational landscape of these solid tumors and whether we can tailor these inhibitors towards solid tumors that have specific mutations to create a more personalized treatment approach.

  • Network analyses: Inhibition of androgen receptor signaling reduces inflammation in the lung through AR-MAF-IL6 signaling axes Genes & diseases
    Wang AR, Baschnagel AM, Ni Z, Brennan SR, Newton HK, Buehler D, Kendziorski C, Kimple RJ, Iyer G
    2023 Aug 18;11(3):101072. doi: 10.1016/j.gendis.2023.07.001. eCollection 2024 May.
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      PMID:38292196 | PMC:PMC10825295 | DOI:10.1016/j.gendis.2023.07.001


      View details for PubMedID 38292196
  • Targeted inhibition of BET proteins in HPV-16 associated head and neck squamous cell carcinoma reveals heterogeneous transcription response bioRxiv : the preprint server for biology
    Rao A, Ni Z, Suresh D, Mohanty C, Wang AR, Lee DL, Nickel KP, Varambally RJ, Lambert PF, Kendziorski C, Iyer G
    2023 Oct 4:2023.10.02.560587. doi: 10.1101/2023.10.02.560587.
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      Integrated human papillomavirus (HPV-16) associated head and neck squamous cell carcinoma (HNSCC) tumors have worse survival outcomes compared to episomal HPV-16 HNSCC tumors. Therefore, there is a need to differentiate treatment for HPV-16 integrated HNSCC from other viral forms. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. However, the mechanism of BET protein-mediated transcription of viral-cellular genes in the integrated viral-HNSCC genomes needs to be better understood. We show that BET inhibition downregulates E6 significantly independent of the viral transcription factor, E2, and there was overall heterogeneity in the downregulation of viral transcription in response to the effects of BET inhibition across HPV-associated cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4 and mirrored downregulation of viral E6 and E7 expression. Strikingly, there was heterogeneity in the reactivation of p53 levels despite E6 downregulation, while E7 downregulation did not alter Rb levels significantly. We identified that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A expression. Overall, our studies show that BET inhibition provokes a G1-cell cycle arrest with apoptotic activity and suggests that BET inhibition regulates both viral and cellular gene expression in HPV-associated HNSCC.

      PMID:37873389 | PMC:PMC10592929 | DOI:10.1101/2023.10.02.560587


      View details for PubMedID 37873389
  • Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge medRxiv : the preprint server for health sciences
    Shireman JM, White Q, Agrawal N, Ni Z, Chen G, Zhao L, Gonugunta N, Wang X, Mccarthy L, Kasulabada V, Pattnaik A, Ahmed AU, Miller J, Kulwin C, Cohen-Gadol A, Payner T, Lin C, Savage JJ, Lane B, Shiue K, Kamer A, Shah M, Iyer G, Watson G, Kendziorski C, Dey M
    2023 Apr 24:2023.04.15.23288491. doi: 10.1101/2023.04.15.23288491.
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      Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

      PMID:37131583 | PMC:PMC10153341 | DOI:10.1101/2023.04.15.23288491


      View details for PubMedID 37131583
  • Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases Scientific reports
    Baschnagel AM, Kaushik S, Durmaz A, Goldstein S, Ong IM, Abel L, Clark PA, Gurel Z, Leal T, Buehler D, Iyer G, Scott JG, Kimple RJ
    2021 Jan 28;11(1):2520. doi: 10.1038/s41598-021-81832-1.
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      Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

      PMID:33510214 | PMC:PMC7843608 | DOI:10.1038/s41598-021-81832-1


      View details for PubMedID 33510214
  • FGFR Inhibition Enhances Sensitivity to Radiation in Non-Small Cell Lung Cancer Molecular cancer therapeutics
    SenthilKumar G, Fisher MM, Skiba JH, Miller MC, Brennan SR, Kaushik S, Bradley ST, Longhurst CA, Buehler D, Nickel KP, Iyer G, Kimple RJ, Baschnagel AM
    2020 Jun;19(6):1255-1265. doi: 10.1158/1535-7163.MCT-19-0931. Epub 2020 May 5.
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      FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. In vivo xenografts and IHC were used to confirm in vitro results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. In vitro clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.

      PMID:32371583 | PMC:PMC7272291 | DOI:10.1158/1535-7163.MCT-19-0931


      View details for PubMedID 32371583
  • Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas International journal of radiation oncology, biology, physics
    Fisher MM, SenthilKumar G, Hu R, Goldstein S, Ong IM, Miller MC, Brennan SR, Kaushik S, Abel L, Nickel KP, Iyer G, Harari PM, Kimple RJ, Baschnagel AM
    2020 Jul 15;107(4):793-803. doi: 10.1016/j.ijrobp.2020.03.040. Epub 2020 Apr 13.
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      PURPOSE: We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.

      METHODS AND MATERIALS: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models.

      RESULTS: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX.

      CONCLUSIONS: These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.

      PMID:32298810 | PMC:PMC7321889 | DOI:10.1016/j.ijrobp.2020.03.040


      View details for PubMedID 32298810
  • <sup>177</sup>Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer Journal of nuclear medicine : official publication, Society of Nuclear Medicine
    Hernandez R, Grudzinski JJ, Aluicio-Sarduy E, Massey CF, Pinchuk AN, Bitton AN, Patel R, Zhang R, Rao AV, Iyer G, Engle JW, Weichert JP
    2020 Aug;61(8):1187-1194. doi: 10.2967/jnumed.119.236265. Epub 2019 Dec 20.
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      There is a clinically unmet need for effective treatments for triple-negative breast cancer (TNBC), as it remains the most aggressive subtype of breast cancer. Herein, we demonstrate a promising strategy using a tumor-targeting alkylphosphocholine (NM600) for targeted radionuclide therapy of TNBC. Methods: NM600 was radiolabeled with 86Y for PET imaging and 177Lu for targeted radionuclide therapy. 86Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n = 3-5). Quantitative data derived from a PET-image region-of-interest analysis, which was corroborated by ex vivo biodistribution, were used to estimate the dosimetry of 177Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177Lu-NM600 toxicity in naïve BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n = 5-6) received excipient or 9.25 or 18.5 MBq of 177Lu-NM600 as a single or fractionated schedule, and tumor growth and overall survival were monitored. Results: Excellent tumor targeting and rapid normal-tissue clearance of 86Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86Y-NM600 as a surrogate for 177Lu-NM600. 177Lu-NM600 dosimetry showed absorbed doses of 2.04 ± 0.32 and 1.68 ± 0.06 Gy/MBq to 4T07 and 4T1 tumors, respectively, which were larger than those delivered to liver (1.28 ± 0.09 Gy/MBq) and to bone marrow (0.31 ± 0.05 Gy/MBq). The 177Lu-NM600 injected activities used for treatment were well tolerated and resulted in significant tumor growth inhibition and prolonged overall survival in both tested TNBC models. A complete response was attained in 60% of treated mice bearing 4T07 grafts. Conclusion: Overall, our results suggest that 177Lu-NM600 targeted radionuclide therapy has potential for TNBC and merits further exploration in a clinical setting.

      PMID:31862799 | PMC:PMC7413241 | DOI:10.2967/jnumed.119.236265


      View details for PubMedID 31862799
  • Defining Reprogramming Checkpoints from Single-Cell Analyses of Induced Pluripotency Cell reports
    Tran KA, Pietrzak SJ, Zaidan NZ, Siahpirani AF, McCalla SG, Zhou AS, Iyer G, Roy S, Sridharan R
    2019 May 7;27(6):1726-1741.e5. doi: 10.1016/j.celrep.2019.04.056.
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      Elucidating the mechanism of reprogramming is confounded by heterogeneity due to the low efficiency and differential kinetics of obtaining induced pluripotent stem cells (iPSCs) from somatic cells. Therefore, we increased the efficiency with a combination of epigenomic modifiers and signaling molecules and profiled the transcriptomes of individual reprogramming cells. Contrary to the established temporal order, somatic gene inactivation and upregulation of cell cycle, epithelial, and early pluripotency genes can be triggered independently such that any combination of these events can occur in single cells. Sustained co-expression of Epcam, Nanog, and Sox2 with other genes is required to progress toward iPSCs. Ehf, Phlda2, and translation initiation factor Eif4a1 play functional roles in robust iPSC generation. Using regulatory network analysis, we identify a critical role for signaling inhibition by 2i in repressing somatic expression and synergy between the epigenomic modifiers ascorbic acid and a Dot1L inhibitor for pluripotency gene activation.

      PMID:31067459 | PMC:PMC6555151 | DOI:10.1016/j.celrep.2019.04.056


      View details for PubMedID 31067459
  • Enhanced Radiosensitivity in Solid Tumors using a Tumor-selective Alkyl Phospholipid Ether Analog Molecular cancer therapeutics
    Elsaid MY, Shahi A, Wang AR, Baiu DC, Li C, Werner LR, Singhal S, Hall LT, Weichert JP, Armstrong EA, Bednarz BP, Harari PM, Iyer G, Otto M
    2018 Nov;17(11):2320-2328. doi: 10.1158/1535-7163.MCT-17-0897. Epub 2018 Aug 14.
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      Antitumor alkyl phospholipid (APL) analogs comprise a group of structurally related molecules with remarkable tumor selectivity. Some of these compounds have shown radiosensitizing capabilities. CLR127 is a novel, clinical-grade antitumor APL ether analog, a subtype of synthetic APL broadly targeting cancer cells with limited uptake in normal tissues. The purpose of this study was to investigate the effect of CLR127 to modulate radiation response across several adult and pediatric cancer types in vitro as well as in murine xenograft models of human prostate adenocarcinoma, neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma. In vitro, CLR127 demonstrated selective uptake in cancer cells compared to normal cells. In cancer cells, CLR127 treatment prior to radiation significantly decreased clonogenic survival in vitro, and led to increased radiation-induced double-stranded DNA (dsDNA) breakage compared with radiation alone, which was not observed in normal controls. In animal models, CLR127 effectively increased the antitumor response to fractionated radiotherapy and led to delayed tumor regrowth at potentially clinically achievable doses. In conclusion, our study highlights the ability of CLR127 to increase radiation response in several cancer types. Given almost universal uptake of CLR127 in malignant cells, future research should test whether the observed effects can be extended to other tumor types. Our data provide a strong rationale for clinical testing of CLR127 as a tumor-targeted radiosensitizing agent. Mol Cancer Ther; 17(11); 2320-8. ©2018 AACR.

      PMID:30108133 | PMC:PMC6215514 | DOI:10.1158/1535-7163.MCT-17-0897


      View details for PubMedID 30108133
  • Compartmentalization of HP1 Proteins in Pluripotency Acquisition and Maintenance Stem cell reports
    Zaidan NZ, Walker KJ, Brown JE, Schaffer LV, Scalf M, Shortreed MR, Iyer G, Smith LM, Sridharan R
    2018 Feb 13;10(2):627-641. doi: 10.1016/j.stemcr.2017.12.016.
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      The heterochromatin protein 1 (HP1) family is involved in various functions with maintenance of chromatin structure. During murine somatic cell reprogramming, we find that early depletion of HP1γ reduces the generation of induced pluripotent stem cells, while late depletion enhances the process, with a concomitant change from a centromeric to nucleoplasmic localization and elongation-associated histone H3.3 enrichment. Depletion of heterochromatin anchoring protein SENP7 increased reprogramming efficiency to a similar extent as HP1γ, indicating the importance of HP1γ release from chromatin for pluripotency acquisition. HP1γ interacted with OCT4 and DPPA4 in HP1α and HP1β knockouts and in H3K9 methylation depleted H3K9M embryonic stem cell (ESC) lines. HP1α and HP1γ complexes in ESCs differed in association with histones, the histone chaperone CAF1 complex, and specific components of chromatin-modifying complexes such as DPY30, implying distinct functional contributions. Taken together, our results reveal the complex contribution of the HP1 proteins to pluripotency.

      PMID:29358085 | PMC:PMC5830946 | DOI:10.1016/j.stemcr.2017.12.016


      View details for PubMedID 29358085
  • Identification of stable housekeeping genes in response to ionizing radiation in cancer research Scientific reports
    Iyer G, Wang AR, Brennan SR, Bourgeois S, Armstrong E, Shah P, Harari PM
    2017 Mar 6;7:43763. doi: 10.1038/srep43763.
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      Housekeeping genes (HKGs) are essential for basic maintenance of a variety of cellular processes. They ideally maintain uniform expression independent of experimental conditions. However, the effects of ionizing radiation (IR) on HKG expression is unclear. Statistical algorithms, geNorm and Normfinder were used for estimating the stability of HKGs as raw quantification cycle (Cq) values were not a reliable factor for normalization. Head and neck, non-small lung and pancreas cells were exposed to 2, 4 and 6 Gy IR doses and expression of fourteen HKGs was measured at 5 min to 48 h post-irradiation within a given tissue. Paired and single cell line analyses under these experimental conditions identified TATA-Box Binding Protein (TBP) and Importin 8 (IPO8) to be stable in non-small cell lung cancer. In addition to these two genes, Ubiquitin C (UBC) in head and neck cancer and Transferrin receptor (TFRC) and β-Glucuronidase (GUSB) in pancreatic cancer were identified to be stable as well. In summary we present a resource for top ranked five stable HKGs and their transcriptional behavior in commonly used cancer model cell lines and suggest the use of multiple HKGs under radiation treatment conditions is a reliable metric for quantifying gene expression.

      PMID:28262749 | PMC:PMC5338320 | DOI:10.1038/srep43763


      View details for PubMedID 28262749
  • Erratum to: Insulin-like growth factor 1 receptor mediated tyrosine 845 phosphorylation of epidermal growth factor receptor in the presence of monoclonal antibody cetuximab BMC cancer
    Iyer G, Price J, Bourgeois S, Armstrong E, Huang S, Harari PM
    2016 Dec 1;16(1):928. doi: 10.1186/s12885-016-2958-x.
  • Insulin-like growth factor 1 receptor mediated tyrosine 845 phosphorylation of epidermal growth factor receptor in the presence of monoclonal antibody cetuximab BMC cancer
    Iyer G, Price J, Bourgeois S, Armstrong E, Huang S, Harari PM
    2016 Oct 6;16(1):773. doi: 10.1186/s12885-016-2796-x.
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      BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood.

      METHODS: In this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab. Co-immunoprecipitation, small molecule inhibitors against phospho-Src and IGF-1R, quantitative western blot of EGFR and Src phosphorylation, cell proliferation assays were used to suggest the role of IGF-1R mediated phosphorylation of specific tyrosine Y845 on EGFR via increased heterodimerization of EGFR and IGF-1R in cetuximab resistant cells.

      RESULTS: Heterodimerization of EGFR with IGF-1R was increased in cetuximab resistant HNSCC cell line UMSCC6. Basal levels of phosphorylated EGFR Y845 showed significant increase in the presence of cetuximab. Surprisingly, this activated Y845 level was not inhibited in the presence of Src inhibitor PP1. Instead, inhibition of IGF-1R by picropodophyllin (PPP) reduced the EGFR Y845 levels. Taken together, these results suggest that heterodimerization of EGFR with IGF-1R can lead to increased activity of EGFR and may be an important platform for cetuximab mediated signaling in head and neck tumors that have become resistant to anti-EGFR therapy.

      CONCLUSIONS: EGFR-IGF-1R interaction has a functional consequence of phosphorylation of EGFR Y845 in cetuximab resistant HNSCC cells and dual targeting of EGFR and IGF-1R is a promising therapeutic strategy.

      PMID:27716204 | PMC:PMC5054590 | DOI:10.1186/s12885-016-2796-x


      View details for PubMedID 27716204
  • Small Molecule Inhibition of MDM2-p53 Interaction Augments Radiation Response in Human Tumors Molecular cancer therapeutics
    Werner LR, Huang S, Francis DM, Armstrong EA, Ma F, Li C, Iyer G, Canon J, Harari PM
    2015 Sep;14(9):1994-2003. doi: 10.1158/1535-7163.MCT-14-1056-T. Epub 2015 Jul 10.
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      MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.

      PMID:26162687 | DOI:10.1158/1535-7163.MCT-14-1056-T


      View details for PubMedID 26162687

Contact Information

Gopal Iyer, PhD

1111 Highland Avenue,
3133 WIMR
Madison, WI 53705
(608) 263-0662