The Oncogenomics Laboratory includes the Gene Therapy Group and the RNA Interference Functional Oncogenomics Laboratory (RIFOL)
Focus of Gene Therapy research
The Gene Therapy Group aims to design new anti-cancer therapies using tumor-killing adenoviruses. Adenoviruses are relatively harmless viruses causing very common airway infections in children. Because adenoviruses kill cells via a different spectrum of anti-cancer activity than current treatments, they could provide a useful addition to the arsenal of anti-cancer medicines. Our goal is to exploit the inherent capacity of adenoviruses to kill cancer cells. Therefore, we redesign the virus to selectively infect and replicate in cancer cells. Furthermore, we strengthen its cancer cell killing potency, following two complementing approaches: In the first approach, we arm adenoviruses with cell death-promoting genes that are insufficiently expressed in cancer cells. In the second approach, we include RNA interfering molecules in the virus genome to suppress endogenous expression of survival genes in cancer cells.
We also investigate combination treatments of virus therapy and chemotherapy or radiotherapy. We maintain integrated research projects covering the path from fundamental research and target discovery via preclinical evaluation in animal models to early clinical testing in cancer patients. The intellectual property generated by our research is licensed to our spin-off company ORCA Therapeutics . Together, we are developing a lead cancer-selective adenovirus for clinical evaluation and commercialization. Our ultimate goal is to translate new virus-based treatment modalities into clinical applications for cancer patients. Together with the departments of Neurosurgery at VUmc and Erasmus MC, we are currently testing a first adenovirus cancer therapy in a phase I/II clinical trial in patients with glioma.
The RIFOL team performs studies directed at elucidating the molecular causes of aberrant functions in cancer cells. The biological process of RNA interference (RNAi) provides a wealth of opportunities for this research. Using RNAi, the genetic cause of a particular trait in cancer cells can be assessed by suppressing gene products individually and studying if changes in the behavior of the cells occur. Our main interest is to unravel the genetic causes of resistance to therapy. This knowledge is of great importance for devising new, more effective treatments of cancer. The RIFOL is the VUmc core facility for RNAi library screening. It provides researchers access to an RNAi library covering the whole human genome and facilities for high-throughput screening (HTS) in cell-based assays.
The RIFOL brings researchers from different departments together, who actively participate in the RIFOL team, exchanging protocols and experiences to maintain and improve the quality of the library screens. The RIFOL participates in the RNAi Global Initiative, an alliance incorporating currently over 50 international research centers pioneering the use of whole-genome RNAi screening. The scientific exchange in this consortium stimulates development of this new research area to rapidly accelerate basic biological and medical discovery. The RIFOL provides validated HTS applications using uniform well and high content readouts in 96-well and 384-well formats. Several HTS projects are ongoing.
Current RIFOL projects
Chemo-radiation resistance in HNSCC (Sanne de Kemp; Dept. Otolaryngology)
Therapy resistance in invasive glioma (Petra van der Stoop; Dept. Neurosurgery)
Radiation resistance in prostate cancer (Jasmina Hodzic, Dept. Medical Oncology)
Cisplatin resistance in NSCLC (Ellen Siebring; Dept. Pulmonary Diseases)
Doxorubicin resistance in osteosarcoma (Jantine PosthumaDeBoer, Dept. Orthopedic Surgery)
Radiation resistance in lung cancer (Remco Nagel, Dept. Otolaryngology)
Synthetic lethality sister chromatid cohesion defects (Job de Lange, Dept. Clinical Genetics).
Resistance to angiogenesis inhibitors in renal cancer (Koen van der Mijn, Dept. Medical Oncology)
Synthetic lethality in breast cancer (Janine Bakker, Dept. Clinical Genetics).
Targeted therapy of precancerous fields in head and neck mucosa (Vicky de Boer, Dept. Otolaryngology)
Dong WL, van Ginkel JWH, Au KY, Alemany R, Meulenberg JJM, van Beusechem VW. ORCA-010, a novel potency-enhanced oncolytic adenovirus, exerts strong antitumor activity in preclinical models. Hum Gene Ther 2014; 25: 897-904. doi: 10.1089/hum.2013.229.
Belcaid Z, Lamfers ML, van Beusechem VW, Hoeben RC. Changing faces in virology: the dutch shift from oncogenic to oncolytic viruses. Hum Gene Ther 2014; 25: 875-884. doi: 10.1089/hum.2014.092.
Kotov IN, Siebring-van Olst E, Knobel PA, van der Meulen-Muileman IH, Felley-Bosco E, van Beusechem VW, Smit EF, Stahel RA, Marti TM. Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress. Mol Oncol 2014;pii: S1574-7891(14)00163-X. doi: 10.1016/j.molonc.2014.07. 008.
Posthuma-De Boer J, Piersma SR, Pham TV, van Egmond PW, Knol JC, Cleton-Jansen AM, van Geer MA, van Beusechem VW, Kaspers GJL, van Royen BJ, Jiménez CR, Helder MN. Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery. Br J Cancer 2013; 109: 2142-2154.
van de Wiel MA, de Menezes RX, Siebring-van Olst E, van Beusechem VW. Analysis of small-sample clinical genomics studies using multi-parameter shrinkage: application to high-throughput RNA interference screening. BMC Med Genomics 2013; 6(Suppl 2): S1. doi: 10.1186/ 1755-8794-6-S2-S1.
Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, Brakenhoff RH. Functional genetic screens identify genes essential for tumor cell survival in head-and-neck and lung cancer. Clin Cancer Res 2013; 19: 1994-2003.
Siebring-van Olst E, Vermeulen C, de Menezes RX, Howell M, Smit EF, van Beusechem VW. Affordable luciferase reporter assay for cell-based high-throughput screening. J Biomol Screen 2013; 453-461.
Posthuma- de Boer J, van Egmond PW, Helder MN, de Menezes RX, Cleton-Jansen AM, Beliën JA, Verheul HM, van Royen BJ, Kaspers GJ, van Beusechem VW. Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin. Oncotarget 2012; 3: 1169-1181.
Meliopoulos VA, Andersen LE, Birrer KF, Simpson KJ, Lowenthal JW, Bean AG, Stambas J, Stewart CR, Tompkins SM, van Beusechem VW, Fraser I, Mhlanga M, Barichievy S, Smith Q, Leake D, Karpilow J, Buck A, Jona G, Tripp RA. Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens. FASEB J 2012; 26: 1372-1386.
Idema S, Caretti V, Lamfers ML, van Beusechem VW, Noske DP, Vandertop WP, Dirven CM. Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain. Plos One 2011; 6: e24396.
Hangalapura BN, Oosterhoff D, de Groot J, Boon L, Tuting T, van den Eertwegh AJ, Gerritsen WR, van Beusechem VW, Pereboev A, Curiel DT, Scheper RJ, de Gruijl TD. Potent anti-tumor immunity generated by a CD40-targeted adenoviral vaccine. Cancer Res 2011; 71:5827-5837.
Posthuma-DeBoer J , Wurdinger T , Graat HCA, van Beusechem VW, Helder MN , van Royen BJ, Kaspers GJL. WEE1 inhibition sensitizes osteosarcoma to radiotherapy. BMC Cancer 2011; 11:156.
Hangalapura BN, Oosterhoff D, Gupta T, de Groot J, Wijnands PG, van Beusechem VW, den Haan J, Tüting T, van den Eertwegh AJ, Curiel DT, Scheper RJ, de Gruijl TD. Delivery route, MyD88 signaling and cross-priming events determine the anti-tumor efficacy of an adenovirus based melanoma vaccine. Vaccine 2011; 29:2313-2321.
van Zeeburg HJ, Huizenga A, Brink A, van den Doel PB, Zhu ZB, McCormick F, Brakenhoff RH, van Beusechem VW. Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions. Gene Ther 2010; 17:1517-1524.
Idema S, Dirven CM, van Beusechem VW, Carette JE, Planqué R, Noske DP, Lamfers ML, Vandertop WP. Objective determination of the oncolytic potency of conditionally-replicating adenoviruses using mathematical modeling. J Gene Med 2010; 12:564-571.
van Zeeburg HJ, van Beusechem VW, Huizenga A, Haisma HJ, Korokhov N, Gibbs S, Leemans CR, Brakenhoff RH. Adenovirus retargeting to surface expressed antigens on oral mucosa. J Gene Med 2010; 12:365-376.
Verheije MH, Lamfers MLM, Würdinger T, Grinwis GCM, Gerritsen WR, Van Beusechem VW, Rottier PJM. Coronavirus genetically redirected to the EGF receptor exhibits effective antitumor activity against a malignant glioblastoma. J Virol 2009; 83: 7507-7516.
Graat HCA, Van Beusechem VW, Schagen FHE, Witlox MA, Kleinerman ES, Helder MN, Gerritsen WR, Kaspers GJL, Wuisman PIJM. Intravenous administration of the conditionally replicative adenovirus Ad5-.24RGD induces regression of osteosarcoma lung metastases. Mol Cancer 2008; 7: 9.
Schagen FHE, Graat HCA, Carette JE, Vellinga J, Van Geer MA, Hoeben RC, Dermody TS, Van Beusechem VW. Replacement of native adenovirus receptor-binding sites with a new attachment moiety diminishes hepatic tropism and enhances bioavailability in mice. Hum Gene Ther 2008; 19: 783-794.
Carette JE, Graat HCA, Schagen FHE, Mastenbroek, DCJ, Rots MG, Haisma HJ, Groothuis GMM, Schaap GR, Bras J, Kaspers GJL, Wuisman PIJM, Gerritsen WR, Van Beusechem VW. A conditionally replicating adenovirus with strict selectivity in killing cells expressing epidermal growth factor receptor. Virology 2007; 361: 56-67.
Graat HCA, Carette JE, Schagen FHE, Vassilev LT, Gerritsen WR, Kaspers GJL, Wuisman PIJM, Van Beusechem VW. Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of MDM2 and adenoviruses encoding p53. Mol Cancer Ther 2007; 6: 1552-1561.
Idema S, Lamfers MLM, Van Beusechem VW, Heukelom S, Moeniralm S, Gerritsen WR, Vandertop PW, Dirven CMF. Ad.24 and the p53-expressing variant AdDelta24-p53 achieve potent anti-tumor activity in glioma when combined with radiotherapy. J Gene Med 2007; 9: 1046-1056.
Lamfers MLM, Idema S, Bosscher L, Heukelom S, Moeniralm S, Van der Meulen-Muileman IH, Overmeer RM, Van der Valk P, Van Beusechem VW, Gerritsen WR, Vandertop WP, Dirven CMF. Differential effects of combination treatment with the oncolytic adenovirus Ad.24RGD and radiotherapy in in vitro versus in vivo models for malignant glioma. Clin Cancer Res 2007; 13: 7451-7458.