Therapeutic integration of new molecule-targeted therapies with radiotherapy in lung cancer

Introduction

Lung cancer is the most common form of this disease and the leading cause of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancers. Forty percent of all cases presents with stage III, and many of them will be considered inoperable (staged IIIA with mediastinal lymph node involvement) or stage IIIB disease. Concurrent platinum-based chemotherapy and thoracic radiation has demonstrated survival benefits in these patients (1,2). We review the role of new agents that selectively target tumor-specific pathways used in combination with radiotherapy in stage III NSCLC. Research, which takes into consideration the tumor and toxicity profile, is focused on the identification of new cytotoxic or targeted agents that can be combined and integrate concomitantly with chemoradiotherapy to provide greater efficacy. It is important to identify potential biological targets, the blockade of which would affect multiple downstream signalling cascades. The most promising new agents for use in combination with radiotherapy to treat lung cancer are shown in Table 1.

Table 1 Mayor new agents in combination with radiotherapy
Full table

Antiangiogenics

Tumor cells increase their expression of proangiogenic growth factors in response to endothelial damage and hypoxia (3,4), and radiation induces cell death as a result of damage to cell membranes, DNA and microvascular endothelial cells within the tumor stroma (5,6). Combined antiangiogenic therapy and radiotherapy may improve tumor control (7) and targeting the VEGFR2 pathway could provide a way to overcome radioresistance. Preclinical data indicate that a hypoxic microenvironment contributes to radioresistance, and suppression of angiogenesis significantly enhances the radiosensitivity of cancer cells.

Vandetanib (ZD 6474), a potent orally available VEGFR2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, enhanced the therapeutic efficacy of irradiation in an orthotropic model of human NSCLC (8). Bevacizumab, in a phase II clinical trial study with chemotherapy and radiotherapy (9), showed serious adverse events including tracheobronchial fistulas. When used in combination with erlotinib (10) the principal toxicity was esophagitis but there was a lack of efficacy. Thalidomide showed significant toxicity when combined with chemotherapy and radiation but no additional efficacy (11). Endostatin in concurrent chemoradiotherapy did not show any benefit in overall response (12). Although these agents are often highly active in preclinical studies, the application of antiangiogenic therapy and radiotherapy in the clinical setting requires logical treatment schemes in an appropriate patient group to bring about any potential benefits (13).

Anti-EGFR

EGFR induces receptor homo- or hetero-dimerization and results in the activation of an intracellular tyrosine kinase domain. Receptor activation causes downstream signalling events through activation of the Ras/Raf/MEK/MAPK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways and has been involved in cellular proliferation, inhibition of apoptosis, angiogenesis, metastasis and chemoradioresistance (14). Radiation activates EGFR autophosphorylation increasing the activity of protein tyrosine kinase, and initiates downstream processes leading to radioresistance. In preclinical studies, NSCLC cells with EGFR mutations have increased radiation-induced apoptosis (15).

The monoclonal antibody cetuximab combined with radiotherapy (16) has shown synergistic activity in preclinical models. However, the addition of cetuximab to a combination of pemetrexed, carboplatin, and thoracic radiotherapy did not confer any benefit to NSCLC patients in a phase II randomized study (17). Similarly, no benefits in overall or progression free survival were shown when cetuximab was added to radiotherapy in a phase III trial (18). The safety of the cetuximab combination with radiotherapy was established in the SCRATCH (19) study, where synchronous cetuximab with radical RT were administered to patients with stage III NSCLC, and the results suggest that the early and late toxicities of synchronous cetuximab and radical RT are acceptable. The NEAR trial (20) was designed to evaluate the toxicities and feasibility of combined treatment with cetuximab and intensity-modulated radiation therapy (IMRT) locoregional irradiation in patients unfit for chemoradiation regimens. With an overall response rate of 63% and median locoregional, distant, overall progression-free survival of 20.5, 10.9, and 8.5 months, respectively, the median overall survival was 19.5 months and only mild toxicity was reported. Combined radioimmunotherapy with cetuximab is both safe and feasible, especially in elderly patients with multiple comorbidities.

Panitumumab, a fully human monoclonal antibody specific to the EGFR, has been tested in preclinical models. RTOG 0839 is a phase II study of preoperative chemoradiotherapy with or without panitumumab in potentially operable, locally advanced stage IIIA NSCLC (21). Nimotuzumab is a humanised monoclonal antibody specific to the EGFR with similar preclinical and clinical activity to other anti-EGFR monoclonal antibodies, and characterized by a lack of severe skin toxicity. In vitro studies have demonstrated that nimotuzumab increases the radiosensitivity of NSCLC cell lines (22). Nimotuzumab in combination with palliative radiotherapy has been studied in two phase I trials which showed low toxicity and absence of rash (23,24). A phase II trial in combination with carboplatin/docetaxel and radiotherapy is awaiting final results (25).

Gefitinib, an EGFR-TKI, has a radiosensitizing effect that was confirmed in cell lines (26). It was studied in combination with radiotherapy in unresectable stage III NSCLC and showed a median overall survival of 16 months with esophagitis (19.5%) being the main toxicity (27). Erlotinib has been shown to enhance radiation response at several levels (cell cycle arrest, apoptosis, induction, accelerated cellular repopulation, and DNA damage repair) (28). In lung cancer cell lines, the radiosensitizing effects of erlotinib differed when the drug was administered using different administration schedules. The highest lethal effect was obtained when radiation was administered after erlotinib, which may be related to PI3K signal transduction (29). A phase II trial (30) investigated concurrent erlotinib, carboplatin, and paclitaxel with radiotherapy in 48 patients, followed by two cycles of chemotherapy. No grade 4 toxicities were reported. Median progression free survival and overall survival were 13.6 and 25.8 months, respectively, and 1-year overall survival was 84%. EGFR mutation analysis was performed on 41 tumor samples and only detected in 5; the local control rate was significantly higher among patients with an EGFR mutation. In a prospective randomized phase II study (31), RT with or without concurrent erlotinib was administered to unresectable stage I to IIIA NSCLC patients who were not candidates for chemotherapy. The toxicities associated to erlotinib were skin rash (61.5%) and diarrhea (23%), however, erlotinib did not increase the toxicity associated to radiotherapy. The response rate was 55.5% in the radiotherapy arm and 83.3% in the concomitant arm.

m-TOR pathway

The PI3 kinase/AKT pathway is activated by mutation of Ras or pathway components, and by deregulated growth factor receptor signalling to Ras. The activation of Ras signalling increases the survival of tumor cells exposed to agents that cause DNA damage. mTOR is a critical downstream effector of the PI3K/Akt pathway. In xenograft models of human NSCLC, everolimus plus radiotherapy produces significant tumor growth suppression by increasing the antitumor activity of radiation (32). Sirolimus has been tested with thoracic radiation therapy (60 Gy) and weekly cisplatin in a phase I trial and has demonstrated a safe profile (33).

Bortezomib

Bortezomib, a proteasome inhibitor, disrupts homeostatic mechanisms within the cell and leads to cell death. The ubiquitin-proteasome pathway is essential in the degradation of intracellular proteins and regulates the cell cycle, neoplastic growth, and metastasis. Bortezomib has demonstrated in vitro chemotherapy- and RT-sensitizing properties (34), but a phase I (35) trial with carboplatin and paclitaxel with concurrent radiotherapy was halted because of postoperative deaths in patients who underwent right pneumonectomy.

Heat shock protein 90 (Hsp90) inhibition

Hsp90 is a molecular chaperone that mediates the refolding of denatured proteins, such as AKT, HER2, Bcr-Abl, c-KIT, EGFR and PDGFR-α (36). Hsp90 inhibition results in substantial cell death in both chemosensitive and chemoresistant small-cell lung cancer cell lines. Clinically, the geldanamycin compounds are the most mature with manageable toxic effects (37). Celastrol inhibits the ATP-binding activity of Hsp90, and it is considered an effective radiosensitizer acting as a Hsp90 inhibitor and a p53 activator in lung cancer cell lines (38).

Histone deacetylase inhibitors (HDACS)

HDACS play a role in cell motility and are involved in the regulation of many transcription factors. Vorinostat and other HDACs have shown successful results in a wide range of cancers, including NSCLC (39).

Aurora kinases

Aurora kinases are a family of serine-threonine kinases that control chromosome assembly and segregation during mitosis and are expressed in a broad range of cancers (40,41). Most Aurora-selective small-molecule inhibitors are currently undergoing preclinical assessment (42-46).

Mitogen activated protein kinase (MARK) 1/2 inhibitor

The MAPK/extracellular signal-regulated kinase (ERK) signalling pathway is involved in proliferation and survival of tumor cells.

Selumetinib, a selective inhibitor of MAPK1/2 (MEK1/2), inhibits tumor hypoxia in human lung and colon carcinoma xenograft models (47) and is currently in an ongoing phase I trial in combination with RT (48).

Parp inhibitors

Poly (ADP-ribose) polymerases are critical in the repair of DNA strand breaks. Ionizing radiation induces DNA strand breaks, and PARP-1 inhibition may sensitize tumor cells to radiation. Veliparib (ABT-888), a PARP-1 inhibitor, with radiation in lung cancer models is effective in enhancing tumor sensitivity to radiation (49), and is being tested in a phase I trial with chemoradiotherapy (50). A trial with another PARP-1 inhibitor, olaparib, in combination with high dose radiotherapy with or without daily dose cisplatin in locally advanced NSCLC, is ongoing (51).

Conclusions

In the development of novel targeted radiation enhancers, some recommendations have to be followed in relation to the determination of agent activity, preclinical testing of radiation enhancement effects, prioritizing agents when biomarker-based patient selection is available, understanding the proper sequencing of combining targeted agents with radiation together with determining early and late safety of the combination in phase I studies as well as regulatory issues. Angiogenic therapies have been shown to enhance radiotherapy in preclinical models. Antiangiogenics reduce vascular density, but improve tumor oxygenation, therefore, it is reasonable to suppose that a combination of antiangiogenic therapy and radiotherapy may improve tumor control. Radiation activates EGFR signalling, leading to radioresistance by inducing cell proliferation and enhanced DNA repair. Numerous clinical trials are currently exploring this combination.

Combining new drugs and concomitant chemoradiation has become an attractive therapeutic option for locally advanced NSCLC, but the addition of targeted therapies to concomitant chemoradiotherapy is still under investigation. Caution has to be exercised with respect to compliance with treatments as this is not always reported in clinical trials. Furthermore, large volume radiotherapy plus targeted drugs should be avoided and especially in hypo-fractionated regimens where high toxicities have been observed (52).

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Pfister DG, Johnson DH, Azzoli CG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330-53. [PubMed]
2. Vokes EE, Herndon JE 2nd, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007;25:1698-704. [PubMed]
3. Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:5565-70. [PubMed]
4. Abdollahi A, Lipson KE, Han X, et al. SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. Cancer Res 2003;63:3755-63. [PubMed]
5. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003;300:1155-9. [PubMed]
6. Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 2004;14:198-206. [PubMed]
7. O’Reilly MS. Radiation combined with antiangiogenic and antivascular agents. Semin Radiat Oncol 2006;16:45-50. [PubMed]
8. Shibuya K, Komaki R, Shintani T, et al. Targeted therapy against VEGFR and EGFR with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2007;69:1534-43. [PubMed]
9. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010;28:43-8. [PubMed]
10. Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J Clin Oncol 2012;30:3953-9. [PubMed]
11. Hoang T, Dahlberg SE, Schiller JH, et al. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol 2012;30:616-22. [PubMed]
12. Ma S, Xu Y, Sun X, et al. Endostar in combination with radiotherapy and paclitaxel/carboplatin in patients with unresectable non-small cell lung cancer of stage III: preliminary results of a phase II study. J Clin Oncol 2011;29:abstr 7043.
13. Citrin D, Ménard C, Camphausen K. Combining radiotherapy and angiogenesis inhibitors: clinical trial design. Int J Radiat Oncol Biol Phys 2006;64:15-25. [PubMed]
14. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366:2-16. [PubMed]
15. Das AK, Sato M, Story MD, et al. Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 2006;66:9601-8. [PubMed]
16. Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 2000;6:2166-74. [PubMed]
17. Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol 2011;29:3120-5. [PubMed]
18. Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. J Clin Oncol 2013;31:abstr 7501.
19. Hughes S, Liong J, Miah A, et al. A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. J Thorac Oncol 2008;3:648-51. [PubMed]
20. Jensen AD, Münter MW, Bischoff HG, et al. Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: the NEAR trial. Cancer 2011;117:2986-94. [PubMed]
21. Chemotherapy and Radiation Therapy With or Without Panitumumab in Treating Patients With Stage IIIA Non-Small Cell Lung Cancer (Cetuximab Closed as of 05/14/10). Available online: http://www.cancer.gov/clinicaltrials/search/view?cdrid=654690&version=HealthProfessional
22. Qu YY, Hu SL, Xu XY, et al. Nimotuzumab enhances the radiosensitivity of cancer cells in vitro by inhibiting radiation-induced DNA damage repair. PLoS One 2013;8:e70727. [PubMed]
23. Bebb G, Smith C, Rorke S, et al. Phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab with concurrent external thoracic radiotherapy in Canadian patients diagnosed with stage IIb, III or IV non-small cell lung cancer unsuitable for radical therapy. Cancer Chemother Pharmacol 2011;67:837-45. [PubMed]
24. Choi HJ, Sohn JH, Lee CG, et al. A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung Cancer 2011;71:55-9. [PubMed]
25. Qi D, Wang Q, Huang C, et al. P57 Nimotuzumab in combination with docetaxel and carboplatin as treatment for advanced non-small-cell-lung-cancer. Eur J Cancer 2011;47:2491.
26. Tanaka T, Munshi A, Brooks C, et al. Gefitinib radiosensitizes non-small cell lung cancer cells by suppressing cellular DNA repair capacity. Clin Cancer Res 2008;14:1266-73. [PubMed]
27. Stinchcombe TE, Morris DE, Lee CB, et al. Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer. J Thorac Oncol 2008;3:250-7. [PubMed]
28. Chinnaiyan P, Huang S, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 2005;65:3328-35. [PubMed]
29. Zhuang HQ, Bo QF, Yuan ZY, et al. The different radiosensitivity when combining erlotinib with radiation at different administration schedules might be related to activity variations in c-MET-PI3K-AKT signal transduction. Onco Targets Ther 2013;6:603-8. [PubMed]
30. Komaki R, Blumenschein GR, Wistuba II, et al. Phase II trial of erlotinib and radiotherapy following chemoradiotherapy for patients with stage III non-small cell lung cancer. J Clin Oncol 2011;29:abstr 7020.
31. Martinez E, Martinez M, Viñolas N, et al. Feasibility and tolerability of the addition of erlotinib to 3D thoracic radiotherapy (RT) in patients (p) with unresectable NSCLC: a prospective randomized phase II study. J Clin Oncol 2008;26:7563.
32. Mauceri HJ, Sutton HG, Darga TE, et al. Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer. Oncol Rep 2012;27:1625-9. [PubMed]
33. Sarkaria JN, Schwingler P, Schild SE, et al. Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. J Thorac Oncol 2007;2:751-7. [PubMed]
34. Richardson PG, Mitsiades C, Hideshima T, et al. Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med 2006;57:33-47. [PubMed]
35. Edelman MJ, Burrows W, Krasna MJ, et al. Phase I trial of carboplatin/paclitaxel/bortezomib and concurrent radiotherapy followed by surgical resection in stage III non-small cell lung cancer. Lung Cancer 2010;68:84-8. [PubMed]
36. Neckers L, Kern A, Tsutsumi S. Hsp90 inhibitors disrupt mitochondrial homeostasis in cancer cells. Chem Biol 2007;14:1204-6. [PubMed]
37. Shimamura T, Shapiro GI. Heat shock protein 90 inhibition in lung cancer. J Thorac Oncol 2008;3:S152-9. [PubMed]
38. Lee JH, Choi KJ, Seo WD, et al. Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90. Int J Mol Med 2011;27:441-6. [PubMed]
39. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006;6:38-51. [PubMed]
40. Gautschi O, Heighway J, Mack PC, et al. Aurora kinases as anticancer drug targets. Clin Cancer Res 2008;14:1639-48. [PubMed]
41. Teicher BA. Newer cytotoxic agents: attacking cancer broadly. Clin Cancer Res 2008;14:1610-7. [PubMed]
42. Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004;10:262-7. [PubMed]
43. Soncini C, Carpinelli P, Gianellini L, et al. PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity. Clin Cancer Res 2006;12:4080-9. [PubMed]
44. Wilkinson RW, Odedra R, Heaton SP, et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 2007;13:3682-8. [PubMed]
45. Rubin EH, Shapiro GI, Stein MN, et al. A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients. J Clin Oncol 2006;24:abstr 3009.
46. Hata T, Furukawa T, Sunamura M, et al. RNA interference targeting aurora kinase a suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res 2005;65:2899-905. [PubMed]
47. Shannon AM, Telfer BA, Smith PD, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts. Clin Cancer Res 2009;15:6619-29. [PubMed]
48. MEK Inhibitor and Thoracic Radiotherapy Trial (MEKRT). Available online: http://clinicaltrials.gov/ct2/show/NCT01146756?term=Selumetinib++AND+lung+cancer&rank=7
49. Albert JM, Cao C, Kim KW, et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res 2007;13:3033-42. [PubMed]
50. Veliparib With or Without Radiation Therapy, Carboplatin, and Paclitaxel in Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery. Available online: http://clinicaltrials.gov/ct2/show/NCT01386385?term=veliparib+radiotherapy&rank=4
51. Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC. Available online: http://clinicaltrials.gov/ct2/show/NCT01562210?term=olaparib+lung+radiotherapy&rank=1
52. Niyazi M, Maihoefer C, Krause M, et al. Radiotherapy and “new” drugs-new side effects? Radiat Oncol 2011;6:177. [PubMed]