Rationale for the epidermal growth factor receptor as a target for cancer therapy

S e m i n a r s in Oneology Nursittg, Vol 18, No 4, Suppl 4 (November), 2002: pp 3-10

:: To p ~ :informo2ion regardi~ ::::: :i:: tunurr-s~ec'/ficme/ecul~sands/g-

targeted therapies d~t can block the e-phlernml growth f ~ t o r receptor (EGFR) at biologically active and less to~xio chases c~nnparext with standard chenmtl~rap~. i

DATA SOURCES: Research articles.

C ONCLUSIONS: The id~wification and mu/erstanding of novel molecular targets has led to the d~oeloprr~t of therapeut/c agc,nts sToeeifie to these targets. Clinical investigations involvi'ng EGFR inhibito~ agents are being completed. Studies have slu)v_rn s'ingle-~ent cfllec~, m ~ cfiqc.ae~ in eombinatitm with chcnmtheral~, a ~ r r radiation therapy.

IMPLICATIONS FOR NURSING PRACTICE: Nurses are involved in the ~utministration of targeted therapies. They serve to e~sure effective patient edtlcation, compliancy, and early intervention fi~r toxicqties. Kru)wlexlge regarding the impact of signaling pathways amt the goals of targeted theralo, will nu_avimize ereatment oute~mtes fi)r cancer patients.

From the Cleveland Clinic Fomutation, Cleveland, OIL Address reprint requests to Lmtra S. Wood, RN, MSN, OCN~, Cleveland Clinic Foundation, 9500 Euclid Ave, R-33, Cleveland, OH 44195.

Copyright 2002, Elsevier Science (USA). All r(~hts *eserved. 0749-2081/02/1804-0402535. 00/0 doi:l O.1053/son u.2002.37406

RATIONALE FOR THE EPIDERMAL GROWTH FACTOR RECEPTOR AS A TARGET FOR CANCER THERAPY LAURA S. WOOD

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ESEARCI[ over the past 1(I years has expanded the available arsenal in our war against eallcer. New agents, more effeetive eombination strategies, and improved supportive therapies aid ontology professionals in the fight to improve survival rates and maximize quality of life for patients diagnosed with cancer (Fig 1). Chemotherapy agents available in oral preparntions, including cyclophosphamide, etoposide, and eapeeitabine, provide constant eytotoxie therapy administration without the need for continuous infusion pumps or frequent visits to the clinic. Oral targeted therapy with agents such as imatinib mesylate, which inhibits the Bcr-Abl tyrosine kinase, has provided new hope for patients with chronic myeloeytie leukemia. Monoclonal antibodies such as rituximab and trastuzumab have a signifieant role in the treatment of selected CD20-positive non-lIodgkin's lymphomas and HER2-positive metastatic breast cancers, respeetively. Combination strategies involving chemotherapy, biologie response modifiers, and radiation therapy are improving surgical outcomes for a variety of malignancies. Results of clinical trials assist physicians, patients, and others in understanding the various treatment options that must be considered, including the type of treatment, timing of treatment, and possible duration of therapy (Table 11). Goals of neoadjnvant therapy include decrease in tumor size, reduction in the need for extensive surgical procedures, ~md preservation

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F I G U R E 1. Current multimodality approach to cancer therapy involves the combined use of a variety of treatments including surgery, radiation therapy (XRT), chemotherapy (chemo), biologic response modifiers (BRMs), and supportive care therapies.

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of organ function. Adjuvant therapy is given to augment the curative potential of surgery by killing any residual cancer cells and delaying or preventing the development of metastatic disease_ The effectiveness of cancer treatment for patients with metastatic disease is based on response rate, overall survival rate, time to progression, symptom relief, and quality of life. Patients who respond to systemic treatment may undergo surgical excision of residual tumor masses, rendering them disease-free for a period of time. Although high-dose monotherapy regimens are used to treat some malignancies, most chemotherapy treatment plans involve combinations of several different cytotoxic agents. Improvements in eytotoxicity and clinical outcome have resulted from the use of combination regimens that use various chemotherapy drugs with demonstrated efficacy but without overlapping toxicities. Drugs are chosen based on the mechanism of action, potential synergism in cytotoxic activity, and optimal dose and schedule of each agent. In certain malignancies, such as melanoma, biochcmotherapy provides both immunomodulatory and cytotoxic effects_ In esophageal and rectal cancer, the combination of chemotherapy and radiation therapy has improved surgical outcome, response rates, overall survival rates, and quality of life for m a n y patients, yet further increases in antitumor activity may require novel approaches distinct from that of traditional chemotherapy.

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TARGETED THERAPIES IN CANCER xtensive efforts in basic and translational research have led to the development and clinE ical investigations of novel strategies for the treatment of cancer, including targeted, vaccine, and gene therapies. The goal in the development of targeted therapies is to identify antitumor agents directed against tumor-expressed molecules while sparing normal cells. This therapeutic approach leads to increased specificity and efficacy while

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RATIONALE

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F I G U R E 2. Role of the epidermal growth factor receptor (EGFR) in the transmission of signals regulating tumor growth and metastasis. Ligands such as EGF and transforming growth factor alpha (TGF-~) bind to the extracellular domain of the EGFR. This results in activation of the receptor tyrosine kinase, which phosphorylates the EGFR and other proteins in the signal transduction pathway. These lead to activation of genes that regulate cell proliferation, angiogenesis, motility, and metastasis. Modulation of EGFR function may also affect cellular response to antitumor therapies such as radiation or chemotherapy. (Reprinted with permission. 2 )

decreasing the toxieities associated with treatment. Ideal drug targets include tumor-specific molecules that drive cancer growth and activate key mechanisms regulating c a n c e r progression but are dispensable in noncritieal cells. One such class of targets consists of moleeules that regulate the signal transduetion process. Cellular signaling is crucial to the life and biological function of all cells, and is critically important in governing proliferation and differentiation. 1 Intracellular signaling pathways are extremely complex and diverse (Fig 2)2 Receptors along the cell surface bind their cognate ligands, resulting in receptor activation. Ligand binding induces the formation of receptor homodimers and heterodimers, initiating a cascade of messages along the signaling pathways that result in a myriad of effects within the nucleus. For example, binding of a specific set of ligands to the extraeellular domain promotes epidermal growth factor receptor (EGFR) dimerization and receptor activation, which in turn increases the receptor tyrosine kinase activity. The net result of this process is that various extraeellular signals are transmitted to the eell nucleus_ -~ Tyrosine kinase reeeptors are involved in path-

ways that receive external or internal signals regulating n u m e r o u s cellular processes, and play a role in transmitting this information from the cell m e m b r a n e to the nucleus. These proteins are involved in both normal cell growth as well as malignant transformation. Increased tyrosine kinase activity in neoplastic cells correlates with a higher degree of malignant transformation, resulting in more aggressive cancer and a worse prognosis. In m a n y different cancer cell types, the tyrosine kinase pathway becomes hyperaetivated or dysregulated because of a range of external or internal mechanisms. These mechanisms inelude the overproduction of ligands or receptors, and the presence of m u t a n t reeeptors that are capable of self-activation.-~-6 One family of tyrosine kinase receptors is known as the ErbB family, consisting of four types of receptors: ErbB1, ErbB2, ErbB3, and ErbB4 (Fig 3). Signaling by the ErbB receptor network serves a erueial role in epithelial development, proliferation, and organogenesis. ErbB1 is known as ttER1 or E G F R ErbB2 is c o m m o n l y known as HER2/neu. Overexpression of HER2/neu in eertain breast cancers is associated with more aggressive growth, c h e m o t h e r a p e u t i c drug resistance,

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FIGURE 3. Homology among members of the ErbB family, which consists of ErbB1 (HER1, EGFR), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). All four receptor proteins are similar in structure but have different ligands, except for ErbB2 for which no ligand has been identified. The receptors consist of an extracellular ligand-binding domain, and an intracellular domain with tyrosine kinase activity that is critical for signal transduction. (Figure courtesy of Josd Baselga,)

and a worse prognosis. The role of ErbB3 (HER3) and ErbB4 (HER4) are yet to be dearly understood. Binding of ligands to the ErbB receptor results in the formation of ErbB homodimers and heterodimers, phosphorylation of the intrinsic tyrosine kinase domain, and initiation of downstream signaling pathways_ 1 The EGFR, which is expressed in many types of solid tumors (Table 2), plays a critical role in the growth, repair, and survival of tumor cells. This receptor is a 170-kd membrane-spanning glyeoprotein that consists of three regions or domains: the amino-terminal extraeellular domain containing the ligand-binding site, the transmembrane lipophilie region, and the earboxy-terminal intracellular region containing the catalytic tyrosine kinase domain_ The tyrosine kinase domain is responsible for generation and regulation of intracellular signaling. Phosphorylation of the EGFR occurs within the intraeellular domain and is the first step in communicating a growth-promoting stimulus to the nucleus. The phosphorylated tyrosine residues serve as docking sites for downstream signaling molecules and messenger proteins, which initiate a cascade of signals that travel from the cytoplasm to the nucleus. 2 In many tumor cells, the EGFR tyrosine kinase

signal is inappropriately activated, driving uncontrolled cancer cell growth and tumor metastasis (Fig 4).7, s Excessive stimulation of the GGFR by means of receptor mutation or overexpression or

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FIGURE 4. The tyrosine kinase associated with the EGFR plays a pivotal role in regulating the activity of this receptor and its role in tumorigenesis. Activation of this tyrosine kinase via ligand binding to the EGFR can result in tumor cell proliferation, angiogenesis, metastasis, and a reduction in apoptosis (programmed cell death).

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F I G U R E 5. Dual approaches for inhibiting EGFR function. (A) Monoclonal antibodies directed against the EGFR bind to the extracellular domain, blocking ligand binding and subsequent receptor activation. (B) Small-molecule inhibitors bind directly to the EGFR tyrosine kinase domain and inhibit its activation. Both approaches result in pleiotropic effects that serve to inhibit tumor growth and metastasis. (From Leserer M, Gschwind A, UIIrich A: Epidermal growth factor receptor signal transactivation. IUBMB Life 49:405-409, 2000 and Baselga J: New therapeutic agents targeting the epidermal growth factor receptor. J Clin Oncol 18:54s-59s, 2000 [suppl].)

overproduction of ligands aetiwlte the tyrosine kinase pathway, stimulating a variety of malignant processes ineluding cellular proliferation, metastasis, inhibition of apoptosis, and promotion of angiogenesis. The EGFR and its li~ands, particularly transforming growth factor alpha (TGF-c0, play major roles in regulating malignant angiogenesis. TGF-c~ promotes the expression of vascular endothelial growth factor, whieh induees proliferation and permeability of blood vessels. Co-expression of TGF-~ and EGFR is highly correlated with increased microvessel density, a pivotal proeess in angiogenesis and tumor growth promotion_ ErhB signaling also regulates the expression of cell adhesion molecules. These molecules promote penetration of tumor cells into the surrounding tissue, leading to tumor invasion and metastasis. ') Moreover, although there is a high degree of variability in the expression of EGFR within some tumor sties, EGFR expression may serve as a predictor of response to chemotherapy. Ongoing clinical trials are investigating the potential of EGFR expression as a predictive factor in several tumor types. Understanding these signaling pathways has provided researchers with opportunities to develop strategies to block or interfere with the

processing of signaling messages. These novel classes of agents include small-molecule tyrosine Mnase inhibitors, antibodies against growth factor receptors (eg, EGFR) and their ligands, Ras farnesylation inhibitors, and antisense oligonueleotides. Combinations of these agents with chemotherapy and/or radiation therapy may enhance cytotoxieity, induce cell cycle arrest, promote apoptosis, and inhibit DNA damage repair within cancer cells, lo-12 EGFR-TARGETING AGENTS hc EGFR family provides promising targets for therapies directed against internal and external domains of these receptors. Interruption in the activation of the EGFR can be accomplished through the use of monoelonal antibodies or small-molecule inhibitors. Anti-EGFR nlonoclonal antibodies bind to the external domain of the EGFR and block binding of endogenous ligands to the EGFR, thus preventing initiation of the tyrosine kinase signal (Fig 5A). Clinical trials of monoelonal antibodies directed against the extraeellular receptor domain, sueh as IMC-C225 and ABX-EGF, are ongoing, ineluding

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6. Inhibition of xenograft tumor regrowth with the combination of ZD1839 (Iressa) and paclitaxel. Human LX-1 or PC-3 prostate (right) tumors were grown as xenografts in mice, then treated with either ZD1839 alone, alone, or the combination. Growth inhibition was significantly enhanced when ZD1839 was combined with compared with either agent alone. (Reprinted with permission. 14 )

single-agent trials and combination strategies involving chemotherapy and radiation therapy (see below). The EGFR pathway can also be blocked by the use of pharmacologic agents that inhibit specific downstream components including the EGFRassociated tyrosine kinase. 13 Small-molecule tyrosine kinase inhibitors (SMTKIs) cross the cell membrane and bind to the tyrosine kinase enzyme, directly blocking the downstream signal. The signaling pathway is completely blocked, regardless of the external or internal triggering event, eliminating downstream processes including cellular proliferation, angiogenesis, and metastasis (Fig 5B). The SMTKIs act by interfering with ATP binding to the receptor, thus preventing receptor activation and downstream signaling. The preelinieal antitumor activity of SMTKIs has been shown in a wide variety of tumors, both as single agents and in combination with chemotherapy. For example, Sirotnak et a114 demonstrated inhibition of xenograft lung and hormone-resistant prostate cancer cell lines using ZD1839 (Iressa; AstraZeneea Pharmaceuticals LP, Wilmington, DE) as monotherapy, with increased inhibition when ZD1839 was combined with paelitaxel (Fig 6). Clinical investigations involving EGFR inhibitory agents are being completed at cancer centers throughout the United Sates and Europe. IMC-

C225 and ABX-EGF are monoelonal antibodies that bind to the extraeellular domain of the EGFR and inhibit its function. ZD1839, OSI-774, and PKI-166 bind to the intracellular domain of the EGFR tyrosine kinase, preventing activation and signal transduetion. Maximal benefit of EGFR inhibition may result from prolonged suppression of the tyrosine kinase pathway, suggesting that irreversible inhibitors may be advantageous in permanently eliminating existing tyrosine kinase activity. 1 Examples include CI-1033 and EKB-569, which bind irreversibly to all intracellular ErbB tyrosine kinases. It is important to differentiate between the targets and thus the mechanisms of action of the various EGFR inhibitors because drug administration, nursing care, and patient education will vary according to the type of EGFR inhibitory agent chosen. It has been suggested that continuous exposure of cancer cells to an EGFR tyrosine kinase inhibitor may provide maximal benefit. ~ Thus, these agents may be administered in a chronic fashion, emphasizing the need for effective patient education to ensure compliance and early intervention for toxicities. Schedule and frequency of administration may vary depending on whether they are used as monotherapy or in combination with chemotherapy and/or radiation therapy. Small-molecule tyrosine kinase inhibitors may be orally administered, lessening the

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F I G U R E 7. Model for using biologic therapy with current treatment modalities in metastatic cancer. Following debulking of the primary tumor with surgery and/or radiation therapy, chemotherapy can be combined with one or more biologic therapies such as monoclonal antibodies or signal transduction inhibitors to prevent or inhibit the growth of metastases. Continued treatment with these targeted agents may be required as maintenance therapy to suppress the formation and progression of micrometastases. (Reprinted with permissionJ 4 )

frequency of clinic appointments. Detailed patient education, written supplemental information, and follow-up telephone contact will therefore bc neecssary to maximize therapeutic outcomes and quality of life for these patients. Frequent clinic visits may occur initially because these agents can be given c o n c u r r e n t l y with c h e m o t h e r a p y or radiation therapy for several months, while treatm e n t with the SMTKIs can be continued for an extended period of time. Synergistic activity with c h e m o t h e r a p y and radiation therapy m a y increase efficacy while minimizing overlapping toxicity because of the unique m e c h a n i s m of action of these agents. Monoclonal antibodies are administered on a weekly basis in treatment centers, allowing for frequent interactions with the nurse or physician.

Ontology research and practice is developing a new paradigm for the use of biologic therapy (Fig 7). The additive and synergistic effects of these new agents, used with other biologics and with more traditional therapeutic modalities such as radiation therapy and c h e m o t h e r a p y , will likely increase the options available for the t r e a t m e n t of caneer in coming years. Ongoing laboratory, translational, and clinical research will improve the ability of oncologists to individualize treatment r e c o m m e n d a t i o n s for patients. The challenge for oneology nurses is to gain knowledge and understanding of these novel agents to ensure effective patient education, support, and side effect m a n a g e m e n t to maximize the potential benefit these new t r e a t m e n t strategies may bring to cancer patients.

REFERENCES 1 Rowinsky EK: Targeting signal transduetion: The erbB receptor family as a target for therapeutic development IIorizons in Cancer Therapeutics, from Bench to Bedside 2:3, 2001 2 IIarari PM, Huang S-M: Modulation of molecular targets to enhance radiation. Clin Cancer P,cs 6:323-325, 2000 3. Raymond E, Faivre S, Armand JP: Epidermal growth factor rceeptor tyrosine Mnase as a target for anticancer therapy Drugs 6{):15-23, 20(}0 (suppl 1) 4. Velu TJ: Structure, function and transforming potential of the epidermal growth factor receptor. Mol Cell Endoerin 70: 205-216, 1990

5. Wells A: Molecules in focus: EGF reeeptor, lnt J Bioehem (Jell Biol 31:637-643, 1999 6 Moghal N, Sternberg PW: Multiple positive and negative regulators of signaling by the EGF-reeeptor. Curr Opin Cell Biol 11:19t)-196, 1999 7 Woodburn JR: The epidermal growth faetor receptor and its inhibition in eancer therapy. Pharmaeol Ther 82:241-250, 1999 S. Ciardicllo F, Caputo R, Bianco R, et al: Inhibition of growth faetor production and angiogenesis in human eancer by ZD1839 (lressa) selective epidermal faetor rceeptor kinasc inhibitor. Clin Canecr Rcs 7:1459-1465, 2001

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9. Prenzel N, Fischer OM, 8treit S, et al: The epidermal growth factor receptor family as a central element for cellular signal transduetion and diversification. Endocr Relat Cancer 8:11-31, 2001 10. Kwok TT, 8utherland RM: Cell cycle dependence of epidermal growth factor induced radiosensitization. Int J Radiat Oncol Biol Phys 22:525-527, 1992 11. Laderoute KR, Ausserer WA, Knapp AM, et al: Epidermal growth factor modifies cell cycle control in A431 human squamous carcinoma cells damaged by ionizing radiation. Cancer Res 54:1407-1411, 1994 12. Wollman R, Yahalom J, Maxy R, et al: Effect of epidermal

growth factor on the growth and radiation sensitivity of human breast cancer cells in vitro. Int J Radiat Oncol Biol Phys 30:91-98, 1994 13. Huang 8M, Harari PM: Epidermal growth factor receptor inhibition in cancer therapy: Biology, rationale and preliminary clinical results. Invest New Drugs 17:259-269, 1999 14. 8irotnak FM, Zakowski MF, Miller VA, et al: Efficacy of eytotoxie agents against human tumor xenografts is markedly enhanced by eoadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6:48854892, 2000