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The molecular basis for resistance to targeted anti-cancer agents
Interactions of the oncogenes NEDD9 and Aurora-A kinase in cancer and polycystic kidney disease.
Targeting HSP90 to improve therapy: new strategies.
Defining the underlying basis for cancer risk.
The Golemis laboratory focuses on understanding factors contributing to the basis for aggressive tumor growth, and on evaluation of protein-targeted drugs. Oncogenic pathways of particular interest include definition of the role of Aurora-A/NEDD9 signaling in cell cycle and metastasis, and dissection of RAS signaling in distinct cellular contexts. We also investigate the role of cilia - spatially restricted hubs for signaling relevant to cell differentiation – as contributors to the biological effects of targeted therapies. To address these topics, the group uses bioinformatic analysis of genomic data to identify specific genetic features associated with specific patterns of therapeutic response in head and neck, lung, and colorectal cancers. We integrate this work with use of animal models and cell-based strategies to elucidate the activity of signaling proteins and targeted therapies.
In disease states such as cancer, tumors reprogram their signaling to support abnormal growth processes. Our laboratory is interested in defining the changes in cell signaling that occur as tumors initiate, progress, and develop resistance to drugs, with the ultimate goal of inhibiting these processes. We hope through these studies to better define the interactions of signaling pathways in malignant versus normal cells, allowing improvements in cancer diagnosis and treatment. In specific projects, our work divides between a body of translational studies focused on the optimal use of therapeutic drugs, and more basic investigations into fundamental cell signaling mechanisms.
One focus of laboratory interest is in the study of smoking-related cancers. Work by Alexander Deneka addresses head and neck cancer (HNC), a disease commonly arising from chronic exposure to tobacco smoke and ethanol use, which cause damaging mutations in tumor suppressor gene TP53. Cells with TP53 mutations have impaired cell cycle checkpoints, and evade radiation- and cisplatin-induced cellular damage, resulting in rapid emergence of therapeutic resistance. In collaboration with the laboratory of Barbara Burtness (Yale Cancer Center), we have explored synergistic combinations of drugs targeting cell cycle transitions, identifying several effective combinations which will soon be examined in early phase clinical trials. Dr. Deneka is also collaborating with researchers at Caris to analyze patterns of mutation in HNC that provide potential biomarkers for use of these and other drug combinations under preclinical and clinical evaluation. The goal of this work is to develop new and effective modality for treating TP53-mutated cancers.
In other work, Dr. Deneka has been identifying new mechanisms regulating invasiveness in lung cancer and evaluating new therapeutic approaches for this disease. Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the vast majority of deaths. Dr. Deneka has used knockout mouse models and complementary studies in human NSCLC cell models to define a role for the scaffolding protein NEDD9 as a regulator of NSCLC growth and therapeutic response. Mechanistically, he has shown that NEDD9 regulates autophagy and glycolysis, metabolic processes that fuel the early growth of NSCLC tumors (Deneka et al, submitted), suggesting that NEDD9 expression may be a potential biomarker for in vivo response to drugs targeting tumor metabolism.
In collaboration with the laboratory of Igor Astsaturov, Anna Lilly is exploring the function of sterol response element binding proteins (SREBPs) and SREBP cleavage-activating protein (SCAP) in regulating pancreatic epithelial differentiation, with the ultimate goal of better understanding how lipid profile affects pancreatic cancer risk. To this end, Lilly is using engineered mouse models with conditional pancreatic loss of SCAP, a critical chaperone regulating SREBP stability and activation. In pilot experiments with one such model (Pdx1-Cre;Scapf/f), mice lacking Scap expression during pancreatic development had selective and severe impairment of acinar differentiation, but not on ductal architecture, or integrity of endocrine islets. In mice genetically predisposed to pancreatic cancer, this phenotype was linked to a significant change in the frequency and gross presentation of tumors. Our data suggest SCAP function is essential in controlling differentiation or survival of specific cell populations within the pancreas, potentially affecting the availability of progenitor populations subject to tumorigenesis; we are investigating this idea.
Compromised barrier function of colon epithelial tissue is associated with inflammatory bowel diseases (IBDs), and increases the risk of colorectal cancer (CRC) through a process of tumor-elicited inflammation (TEI). Tight junction (TJ) proteins, including specific claudins, are critical regulators of epithelial barrier function and paracellular permeability. Changes in claudin composition in the kidney are strongly linked to the etiology of autosomal dominant polycystic kidney disease (ADPKD), an inherited disease affecting ~ 1 in 1000 individuals. ADPKD-inducing mutations in PKD1 causing non-leaky barriers that can withstand high hydrostatic pressure within renal cysts a hallmark of this common disease. Intriguingly, a large population study suggested decreased incidence of CRC in ADPKD patients, while other studies implicated PKD1 in control of epithelial-mesenchymal transition (EMT) and invasion. After years of working in both ADPKD and cancer, we had become struck by the fact that many of the signaling networks activated in ADPKD were extremely similar to those activated and oncogenic in cancer: but ADPKD did not result in increased incidence of tumors. Anna Nikonova is investigating the role of PKD1 in the initiation and progression of colorectal cancer, based on a model in which the PKD1 gene plays a central role in controlling barrier integrity and function in colonic epithelia, regulating cancer risk and progression. This work may reveal specific therapeutic combinations for use in limiting tumor growth, which could help in prevention and treatment for individuals with CRC.
Reciprocally, Dr. Nikonova is using insights from her studies of PKD1 signaling at cilia with the goal of developing safe and effective therapeutic options for patients with ADPKD. This work follows directly from our extensive prior studies of ciliation, and are aimed both at identifying new and potentially beneficial therapeutic combinations for ADPKD, and assessing the risks versus benefits to ADPKD patients of therapies employed for cancer (as it is estimated that 35-40% of all individuals, including patients with ADPKD, will develop cancer at some point in their lifetime). Hence, study of the relationship of ADPKD and cancer signaling is important not only to potentially improve outcomes in ADPKD patients, but also to avoid inducing harm.
Ilya Serebriiskii has led collaborative studies with Joshua Meyer and Foundation Medicine that have investigated mutational profiles in CRC. This work has focused on differences in mutations associated with early- versus late-onset CRC, and in the colon versus rectum tumor subsite. Initial studies analyzed data from 18,000 tumors to establish overall mutational frequencies, and to analyze in detail the frequency of distinct disease-associated mutations in the oncogenic drivers KRAS and NRAS. This work is ongoing to elucidate additional trends in RAS mutational profiles using a larger set of 34,000 tumors, and also is expanded to analyze other oncogenes and tumor suppresors pertinent to CRC, such as PTEN.
Beyond CRC, mutational hyperactivation of KRAS, NRAS, or HRAS occurs in 25% of human cancers overall, and in a subset of developmental syndromes. Mitchell Parker, a joint graduate student with the laboratory of Roland Dunbrack, has been working with large datasets to refine understanding of the structural determinants of RAS activation, inactivation, and inhibition. His analysis is based on use of a machine learning approach to dissect structural features of the 646 human KRAS, NRAS, and HRAS structures deposited in the Protein Data Bank (PDB) from 1990-2021, including RAS WT and mutated structures in complex with various entities, such as biological ligands, metal ions, drug candidates, chemical compounds, and bound proteins or peptides. The goal is to develop a unified structural classification of RAS conformations that can guide the design of targeted inhibitors.
Adjunct, Cell and Molecular Biology group, University of Pennsylvania
Adjunct, Department of Biochemistry, Drexel University School of Medicine
Adjunct, Department of Biochemistry, Lewis Katz School of Medicine, Temple University
Deneka A.Y., Baca Y., Serebriiskii I.G., Nicolas E., Parker M.I., Nguyen T.T., Xiu J., Korn W.M., Demeure M.J., Wise-Draper T., Sukari A., Burtness B.,Golemis E.A., Association of tp53 and cdkn2a mutation profile with tumor mutation burden in head and neck cancer. Clin Cancer Res. 28(9): 1925-1937, 2022. https://www.ncbi.nlm.nih.gov/pubmed/35491653.
Serebriiskii I.G., Pavlov V., Tricarico R., Andrianov G., Nicolas E., Parker M.I., Newberg J., Frampton G., Meyer J.E.,Golemis E.A., Comprehensive characterization of pten mutational profile in a series of 34,129 colorectal cancers. Nat Commun. 13(1): 1618, 2022.PMC8956741. https://www.ncbi.nlm.nih.gov/pubmed/35338148.
Deneka A.Y., Kopp M.C., Nikonova A.S., Gaponova A.V., Kiseleva A.A., Hensley H.H., Flieder D.B., Serebriiskii I.G.,Golemis E.A., Nedd9 restrains autophagy to limit growth of early stage non-small cell lung cancer. Cancer Res. 81(13): 3717-3726, 2021.PMC8277748. https://www.ncbi.nlm.nih.gov/pubmed/34006524.
Gabitova-Cornell L, Surumbayeva A, Peri S, Franco-Barraza J, Restifo D, Weitz N, Ogier C, Goldman AR, Hartman TR, Francescone R, Tan Y, Nicolas E, Shah N, Handorf EA, Cai KQ, O'Reilly AM, Sloma I, Chiaverelli R, Moffitt RA, Khazak V, Fang CY, Golemis EA, Cukierman E, Astsaturov I. Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer. Cancer Cell. 2020 Oct 12;38(4):567-583.e11, PMID: 32976774, PMCID: PMC7572882.
Deneka, A.Y., Einarson, M.B., Bennett, J., Nikonova, A.S., Elmekawy, M., Zhou, Y., Lee, J.W., Burtness, B.A., and Golemis E.A. Synthetic lethal targeting of mitotic checkpoints in HPV-negative head and neck cancer. Cancers (Basel). 2020 Jan 28;12(2). pii: E306. doi: 10.3390/cancers12020306. PMID: 32012873, PMCID: PMC7072436
Tricarico, R., Nicolas, E., Hall, M.J., and Golemis, E.A. X- and Y-linked chromatin-modifying genes as regulators of sex-specific cancer incidence and prognosis. Clin Cancer Res, 2020 Nov 1;26(21):5567-5578, PMID: 32732223, PMCID: PMC7642178
Serebriiskii, I.G., Connelly, C., Frampton, G., Newberg, J., Cooke, M., Miller, V., Ali, S., Ross, J., Handorf, E., Arora, S., Lieu, C., Golemis, E.A., and Meyer, J.E. RAS mutational profile differs between colon and rectal cancers, and in old versus young patients. Nat Commun, 2019 Aug 19;10(1):3722. doi: 10.1038/s41467-019-11530-0. PMID: 31427573, PMCID: PMC6700103.
Kiseleva, A.A., Korobeynikov, V.A., Deneka, A.Y., Nikonova, A.S., Zhang, P., Makhov, P., Einarson, M.B., Kolenko, V., Serebriiskii, I.G., Liu, H., Peterson, J.R., and Golemis, E.A. Unexpected activities in regulating ciliation contribute to off-target effects of targeted drugs. Clin Cancer Res, 2019 Mar 13. pii: clincanres.3535.2018. doi: 10.1158/1078-0432.CCR-18-3535. [Epub ahead of print] PMID: 30867219, PMCID: PMC6606352.
Lieu, C., Golemis, E., Serebriiskii, I., Newberg, J., Hemmerich, A., Connelly, C., Messersmith, W., Eng, C., Eckhardt, S.G., Frampton, G., Cooke, M., and Meyer, J. Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer, Clinical Cancer Research, Oct 1;25(19):5852-5858., PMID: 31243121, PMCID: PMC6774873.
Lee, J.W., Parameswaran, J., Sandoval-Schaefer, T., Eoh, K.J., Yang, D., Zhu, F., Mehra, R., Sharma, R., Gaffney, S.G., Perry, E.B., Townsend, J.P., Serebriiskii, I.G., Golemis E.A., Issaeva, N., Yarbrough, W.G., Koo, J.S., and Burtness, B. Combined Aurora kinase A (AURKA) and WEE1 inhibition demonstrates synergistic antitumor effect in squamous cell carcinoma of the head and neck. Clin Cancer 2019 Jun 1;25(11):3430-3442. doi: 10.1158/1078-0432. PMID:30755439, PMCID: PMC6548643
Nicolas E, Tricarico R, Savage M, Golemis EA, Hall MJ. Disease-Associated Genetic Variation in Human Mitochondrial Protein Import. American Journal of Human Genetics, 2019. PubMed
Golemis EA, Scheet P, Beck TN, Scolnick EM, Hunter DJ, Hawk E, Hopkins N. Molecular mechanisms of the preventable causes of cancer in the United States. Genes & development, 32(13-14):868-902, 2018. PMC6075032
Gabbasov R, Xiao F, Howe CG, Bickel LE, O'Brien SW, Benrubi D, Do TV, Zhou Y, Nicolas E, Cai KQ, Litwin S, Seo S, Golemis EA, Connolly DC. NEDD9 promotes oncogenic signaling, a stem/mesenchymal gene signature, and aggressive ovarian cancer growth in mice. Oncogene, 2018. PubMed
Nikonova AS, Deneka AY, Kiseleva AA, Korobeynikov V, Gaponova A, Serebriiskii IG, Kopp MC, Hensley HH, Seeger-Nukpezah TN, Somlo S, Proia DA, Golemis EA. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD). FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 32(5):2735-46, 2018. PMC5901382
Peri S, Izumchenko E, Schubert AD, Slifker MJ, Ruth K, Serebriiskii IG, Guo T, Burtness BA, Mehra R, Ross EA, Sidransky D, Golemis EA. NSD1- and NSD2-damaging mutations define a subset of laryngeal tumors with favorable prognosis. Nat Commun, 8(1):1772, 2017. PMC5701248
Franco-Barraza, J., Francescone, R., Luong, T., Shah, N., Madhani, R., Gukierman, G., Malik, R., Dulaimi, E., Devarajan, K., Egleston, B.L., Nicolas, E., Alpaugh, R.K., Uzzo, R.G., Hoffman, J.P., Golemis, E.A., and Cukierman, E. Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence. Elife 6:e20600, 2017.
Peri, S., Izumchenko, E., Schubert, A.D., Slifker, M.J., Ruth, K., Serebriiskii, I.G., Guo, T., Burtness, B.A., Mehra, R., Ross, E.A., Sidransky, D., and Golemis, E.A. NSD1- and NSD2-damaging mutations defina subset of laryngeal tumors with favorable prognosis. Nat Commun, 2017 Nov 24;8(1):1772.