Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2009

Open Access 01-12-2009 | Research

Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response

Authors: Ramaswamy Bhuvaneswari, Yik Yuen Gan, Khee Chee Soo, Malini Olivo

Published in: Molecular Cancer | Issue 1/2009

Login to get access

Abstract

Background

Photodynamic therapy (PDT) is a promising cancer treatment modality that involves the interaction of the photosensitizer, molecular oxygen and light of specific wavelength to destroy tumor cells. Treatment induced hypoxia is one of the main side effects of PDT and efforts are underway to optimize PDT protocols for improved efficacy. The aim of this study was to investigate the anti-tumor effects of PDT plus Erbitux, an angiogenesis inhibitor that targets epidermal growth factor receptor (EGFR), on human bladder cancer model. Tumor-bearing nude mice were assigned to four groups that included control, PDT, Erbitux and PDT plus Erbitux and tumor volume was charted over 90-day period.

Results

Our results demonstrate that combination of Erbitux with PDT strongly inhibits tumor growth in the bladder tumor xenograft model when compared to the other groups. Downregulation of EGFR was detected using immunohistochemistry, immunofluorescence and western blotting. Increased apoptosis was associated with tumor inhibition in the combination therapy group. In addition, we identified the dephosphorylation of ErbB4 at tyrosine 1284 site to play a major role in tumor inhibition. Also, at the RNA level downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT plus Erbitux.

Conclusion

The combination therapy of PDT and Erbitux effectively inhibits tumor growth and is a promising therapeutic approach in the treatment of bladder tumors.
Appendix
Available only for authorised users
Literature
1.
Sibata CH, Colussi VC, Oleinick NL, Kinsella TJ: Photodynamic therapy in oncology. Expert Opin Pharmacother. 2001, 2: 917-927. 10.1517/14656566.2.6.917CrossRefPubMed
2.
Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q: Photodynamic therapy. J Natl Cancer Inst. 1998, 90: 889-905. 10.1093/jnci/90.12.889CrossRefPubMed
3.
Dolmans DE, Fukumura D, Jain RK: Photodynamic therapy for cancer. Nat Rev Cancer. 2003, 3: 380-387. 10.1038/nrc1071CrossRefPubMed
4.
Henderson BW, Gollnick SO, Snyder JW, Busch TM, Kousis PC, Cheney RT, Morgan J: Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors. Cancer Res. 2004, 64: 2120-2126. 10.1158/0008-5472.CAN-03-3513CrossRefPubMed
5.
Ferrario A, von Tiehl KF, Rucker N, Schwarz MA, Gill PS, Gomer CJ: Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma. Cancer Res. 2000, 60: 4066-4069.PubMed
6.
7.
Seow AKW, Chia KS, Shi L, Lee HP, Shanmugaratnam K: Trends in cancer incidence in Singapore 1968-2002. Singapore Cancer Registry Report Singapore. 2004, 6:
8.
Borden LS, Clark PE, Hall MC: Bladder cancer. Curr Opin Oncol. 2003, 15: 227-233. 10.1097/00001622-200305000-00009CrossRefPubMed
9.
Jichlinski P, Leisinger HJ: Photodynamic therapy in superficial bladder cancer: past, present and future. Urol Res. 2001, 29: 396-405. 10.1007/s002400100215CrossRefPubMed
10.
Waidelich R, Beyer W, Knuchel R, Stepp H, Baumgartner R, Schroder J, Hofstetter A, Kriegmair M: Whole bladder photodynamic therapy with 5-aminolevulinic acid using a white light source. Urology. 2003, 61: 332-337. 10.1016/S0090-4295(02)02164-7CrossRefPubMed
11.
Baffa R, Letko J, McClung C, LeNoir J, Vecchione A, Gomella LG: Molecular genetics of bladder cancer: targets for diagnosis and therapy. J Exp Clin Cancer Res. 2006, 25: 145-160.PubMed
12.
Neal DE, Mellon K: Epidermal growth factor receptor and bladder cancer: a review. Urol Int. 1992, 48: 365-371.CrossRefPubMed
13.
Kassouf W, Black PC, Tuziak T, Bondaruk J, Lee S, Brown GA, Adam L, Wei C, Baggerly K, Bar-Eli M: Distinctive expression pattern of ErbB family receptors signifies an aggressive variant of bladder cancer. J Urol. 2008, 179: 353-358. 10.1016/j.juro.2007.08.087PubMedCentralCrossRefPubMed
14.
Mendelsohn J, Dinney CP: The Willet F. Whitmore, Jr., Lectureship: blockade of epidermal growth factor receptors as anticancer therapy. J Urol. 2001, 165: 1152-1157. 10.1016/S0022-5347(05)66453-1CrossRefPubMed
15.
Kulik G, Klippel A, Weber MJ: Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol. 1997, 17: 1595-1606.PubMedCentralPubMed
16.
Kim ES, Khuri FR, Herbst RS: Epidermal growth factor receptor biology (IMC-C225). Curr Opin Oncol. 2001, 13: 506-513. 10.1097/00001622-200111000-00014CrossRefPubMed
17.
Mendelsohn J, Baselga J: Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006, 33: 369-385. 10.1053/j.seminoncol.2006.04.003CrossRefPubMed
18.
Harding J, Burtness B: Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody. Drugs Today (Barc). 2005, 41: 107-127. 10.1358/dot.2005.41.2.882662CrossRef
19.
Vokes EE, Chu E: Anti-EGFR therapies: clinical experience in colorectal, lung, and head and neck cancers. Oncology (Williston Park). 2006, 20: 15-25.
20.
Bellmunt J, Hussain M, Dinney CP: Novel approaches with targeted therapies in bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family. Crit Rev Oncol Hematol. 2003, 46 (Suppl): S85-104. 10.1016/S1040-8428(03)00067-2CrossRefPubMed
21.
Huang Z, Xu H, Meyers AD, Musani AI, Wang L, Tagg R, Barqawi AB, Chen YK: Photodynamic therapy for treatment of solid tumors--potential and technical challenges. Technol Cancer Res Treat. 2008, 7: 309-320.PubMedCentralCrossRefPubMed
22.
Solban N, Selbo PK, Sinha AK, Chang SK, Hasan T: Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer. Cancer Res. 2006, 66: 5633-5640. 10.1158/0008-5472.CAN-06-0604CrossRefPubMed
23.
Ferrario A, Fisher AM, Rucker N, Gomer CJ: Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors. Cancer Res. 2005, 65: 9473-9478. 10.1158/0008-5472.CAN-05-1659CrossRefPubMed
24.
Bhuvaneswari R, Yuen GY, Chee SK, Olivo M: Hypericin-mediated photodynamic therapy in combination with Avastin (bevacizumab) improves tumor response by downregulating angiogenic proteins. Photochem Photobiol Sci. 2007, 6: 1275-1283. 10.1039/b705763fCrossRefPubMed
25.
Bhuvaneswari R, Gan YY, Lucky SS, Chin WW, Ali SM, Soo KC, Olivo M: Molecular profiling of angiogenesis in hypericin mediated photodynamic therapy. Mol Cancer. 2008, 7: 56- 10.1186/1476-4598-7-56PubMedCentralCrossRefPubMed
26.
Berger AP, Steiner H, Stenzl A, Akkad T, Bartsch G, Holtl L: Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study. Urology. 2003, 61: 338-341. 10.1016/S0090-4295(02)02123-4CrossRefPubMed
27.
Nseyo UO: Photodynamic therapy. Urol Clin North Am. 1992, 19: 591-599.PubMed
28.
Nseyo UO, DeHaven J, Dougherty TJ, Potter WR, Merrill DL, Lundahl SL, Lamm DL: Photodynamic therapy (PDT) in the treatment of patients with resistant superficial bladder cancer: a long-term experience. J Clin Laser Med Surg. 1998, 16: 61-68.PubMed
29.
Manyak MJ, Ogan K: Photodynamic therapy for refractory superficial bladder cancer: long-term clinical outcomes of single treatment using intravesical diffusion medium. J Endourol. 2003, 17: 633-639. 10.1089/089277903322518644CrossRefPubMed
30.
Blick SK, Scott LJ: Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs. 2007, 67: 2585-2607. 10.2165/00003495-200767170-00008CrossRefPubMed
31.
Wong SF: Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther. 2005, 27: 684-694. 10.1016/j.clinthera.2005.06.003CrossRefPubMed
32.
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004, 351: 337-345. 10.1056/NEJMoa033025CrossRefPubMed
33.
Burtness B: The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther. 2005, 5: 1085-1093. 10.1517/14712598.5.8.1085CrossRefPubMed
34.
Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, Dyker A, Ferrie L, Gilfillan C, Horsley W: Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck. Health Technol Assess. 2009, 13 (Suppl 1): 49-54.PubMed
35.
Bernier J, Schneider D: Cetuximab combined with radiotherapy: an alternative to chemoradiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck?. Eur J Cancer. 2007, 43: 35-45. 10.1016/j.ejca.2006.08.035CrossRefPubMed
36.
del Carmen MG, Rizvi I, Chang Y, Moor AC, Oliva E, Sherwood M, Pogue B, Hasan T: Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo. J Natl Cancer Inst. 2005, 97: 1516-1524.CrossRefPubMed
37.
Vallbohmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA, Rhodes KE, Sherrod AE, Iqbal S, Danenberg KD: Molecular determinants of cetuximab efficacy. J Clin Oncol. 2005, 23: 3536-3544. 10.1200/JCO.2005.09.100CrossRefPubMed
38.
Ellis LM, Hoff PM: Targeting the epidermal growth factor receptor: an important incremental step in the battle against colorectal cancer. J Clin Oncol. 2004, 22: 1177-1179. 10.1200/JCO.2004.01.971CrossRefPubMed
39.
Bhuvaneswari R, Gan YY, Yee KK, Soo KC, Olivo M: Effect of hypericin-mediated photodynamic therapy on the expression of vascular endothelial growth factor in human nasopharyngeal carcinoma. Int J Mol Med. 2007, 20: 421-428.PubMed
40.
Franovic A, Gunaratnam L, Smith K, Robert I, Patten D, Lee S: Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci USA. 2007, 104: 13092-13097. 10.1073/pnas.0702387104PubMedCentralCrossRefPubMed
41.
Tsai T, Ji HT, Chiang PC, Chou RH, Chang WS, Chen CT: ALA-PDT results in phenotypic changes and decreased cellular invasion in surviving cancer cells. Lasers Surg Med. 2009, 41: 305-315. 10.1002/lsm.20761CrossRefPubMed
42.
Ahmad N, Kalka K, Mukhtar H: In vitro and in vivo inhibition of epidermal growth factor receptor-tyrosine kinase pathway by photodynamic therapy. Oncogene. 2001, 20: 2314-2317. 10.1038/sj.onc.1204313CrossRefPubMed
43.
Mahtani RL, Macdonald JS: Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract. Oncologist. 2008, 13: 39-50. 10.1634/theoncologist.2006-0049CrossRefPubMed
44.
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999, 59: 1935-1940.PubMed
45.
Iwase M, Takaoka S, Uchida M, Yoshiba S, Kondo G, Watanabe H, Ohashi M, Nagumo M: Epidermal growth factor receptor inhibitors enhance susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells. Oral Oncol. 2008, 44: 361-368. 10.1016/j.oraloncology.2007.04.006CrossRefPubMed
46.
Ouyang X, Gulliford T, Zhang H, Huang GC, Epstein R: Human cancer cells exhibit protein kinase C-dependent c-erbB-2 transmodulation that correlates with phosphatase sensitivity and kinase activity. J Biol Chem. 1996, 271: 21786-21792. 10.1074/jbc.271.36.21786CrossRefPubMed
47.
Monje PV, Athauda G, Wood PM: Protein kinase A-mediated gating of neuregulin-dependent ErbB2-ErbB3 activation underlies the synergistic action of cAMP on Schwann cell proliferation. J Biol Chem. 2008, 283: 34087-34100. 10.1074/jbc.M802318200PubMedCentralCrossRefPubMed
48.
Cooper JA, Howell B: The when and how of Src regulation. Cell. 1993, 73: 1051-1054. 10.1016/0092-8674(93)90634-3CrossRefPubMed
49.
Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ: c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 1999, 274: 8335-8343. 10.1074/jbc.274.12.8335CrossRefPubMed
50.
Kwon YK, Bhattacharyya A, Alberta JA, Giannobile WV, Cheon K, Stiles CD, Pomeroy SL: Activation of ErbB2 during wallerian degeneration of sciatic nerve. J Neurosci. 1997, 17: 8293-8299.PubMed
51.
Frogne T, Laenkholm AV, Lyng MB, Henriksen KL, Lykkesfeldt AE: Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors. Breast Cancer Res. 2009, 11: R11- 10.1186/bcr2230PubMedCentralCrossRefPubMed
52.
Cohen BD, Green JM, Foy L, Fell HP: HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers. J Biol Chem. 1996, 271: 4813-4818. 10.1074/jbc.271.9.4813CrossRefPubMed
53.
Gallo RM, Bryant I, Fry R, Williams EE, Riese DJ: Phosphorylation of ErbB4 on Tyr1056 is critical for inhibition of colony formation by prostate tumor cell lines. Biochem Biophys Res Commun. 2006, 349: 372-382. 10.1016/j.bbrc.2006.08.055PubMedCentralCrossRefPubMed
54.
Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66: 3992-3995. 10.1158/0008-5472.CAN-06-0191CrossRefPubMed
55.
Riely GJ, Marks J, Pao W: KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009, 6: 201-205. 10.1513/pats.200809-107LCCrossRefPubMed
56.
Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B: BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer. 2006, 5: 2- 10.1186/1476-4598-5-2CrossRefPubMed
57.
Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M: EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res. 2009, 15: 4554-4560. 10.1158/1078-0432.CCR-09-0089CrossRefPubMed
58.
Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS: Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res. 2006, 66: 7864-7869. 10.1158/0008-5472.CAN-04-4392CrossRefPubMed
59.
Le Marchand L, Seifried A, Lum-Jones A, Donlon T, Wilkens LR: Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. JAMA. 2003, 290: 2843-2848. 10.1001/jama.290.21.2843CrossRefPubMed
60.
Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H: EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol. 2005, 70: 1568-1578. 10.1016/j.bcp.2005.09.007CrossRefPubMed
61.
Peng H, Diss T, Isaacson PG, Pan L: c-myc gene abnormalities in mucosa-associated lymphoid tissue (MALT) lymphomas. J Pathol. 1997, 181: 381-386. 10.1002/(SICI)1096-9896(199704)181:4<381::AID-PATH787>3.0.CO;2-ICrossRefPubMed
Metadata
Title
Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response
Authors
Ramaswamy Bhuvaneswari
Yik Yuen Gan
Khee Chee Soo
Malini Olivo
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2009
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-8-94

Other articles of this Issue 1/2009

Molecular Cancer 1/2009 Go to the issue

Research

CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation

Research

Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis

Research

Aurora-A down-regulates IkappaBα via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival

Short communication

Selective depletion of a minor subpopulation of B-chronic lymphocytic leukemia cells is followed by a delayed but progressive loss of bulk tumor cells and disease regression

Research

Genomic imbalances in precancerous tissues signal oral cancer risk

Research

Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits