Science and Mechanism of Action of Targeted Therapies in Cancer Treatment

Seminars in Oncology Nursing, Vol 30, No 3 (August), 2014: pp 139-146

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SCIENCE AND MECHANISM OF ACTION OF TARGETED THERAPIES IN CANCER TREATMENT DEBRA WUJCIK OBJECTIVES: To identify common signaling pathways that control cancer growth and discuss the mechanism of action of cancer targeted therapies. DATA SOURCES: Medical and nursing literature, research articles, published clinical guidelines.

CONCLUSION: Understanding the signaling pathways and genetic mutations that control cancer cell growth elucidates an understanding of the mechanism of targeted therapies.

IMPLICATIONS

FOR NURSING PRACTICE: To understand the mechanism of action of targeted therapies, oncology nurses must first be familiar with the most common signaling pathways. Adding to this foundation, the nurse can easily learn about the classes of targeted therapies and the strategies to minimize and manage common side effects.

KEY WORDS: Signaling pathways, targeted therapy, monoclonal antibodies, tyrosine kinase inhibitors

Debra Wujcik, PhD, RN, FAAN, AOCNÒ; Director, Clinical Trials Shared Resource, Vanderbilt Ingram Cancer Center, Nashville, TN. Address correspondence to Debra Wujcik, PhD, RN, FAAN, AOCNÒ, Director, Clinical Trials Shared Resource, Vanderbilt Ingram Cancer Center, 2141 Blakemore Ave, Nashville, TN 37208. e-mail: debbie. [email protected] Ó 2014 Elsevier Inc. All rights reserved. 0749-2081/3003-$36.00/0. http://dx.doi.org/10.1016/j.soncn.2014.05.002

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N the past half century, the treatment of cancer has evolved from a single, highly toxic, chemotherapeutic drug such as nitrogen mustard, to targeted therapies that disrupt specific signaling pathways and are more easily tolerated than traditional anti-cancer drugs. In between, cancer treatments have included combinations of drugs, combinations of modalities such as concurrent chemotherapy and radiation or sequential neoadjuvant chemotherapy, surgery, then adjuvant chemotherapy, and finally biotherapy and immunotherapy.

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Targeted therapies are designed to attack a specific target in the cell that subsequently interferes with a growth pathway. Advances in molecular biology and genomic sequencing technology have led to the identification of many therapeutic targets within cancer cells and the design of treatments to interfere with them. These new therapies have fewer and less toxic side effects because they act with precision on specific targets in the growth pathways with little collateral damage to healthy cells and tissue. This article provides an overview of signaling pathways that influence the growth of cancer cells and the mechanism of action of the common targeted therapies used in cancer treatment.

MECHANISMS OF ACTION The growth, death, and differentiation of normal and cancer cells alike are controlled by the action of signaling molecules and pathways. Normal cells are protected with safeguards that are altered in cancer cells. Cancer cells are characterized by uncontrolled growth, absence of apoptosis (programmed cell death), increased blood vessel formation, and local invasion into surrounding tissue or distant metastases. The normal cell processes are activated when an extracellular ligand (growth factor) binds to a receptor on the cell surface. The activation, called dimerization, sends a signal across the cell membrane to the intracellular domain where tyrosine kinase activation occurs. Like the ripple effect of a pebble tossed in the pond, this activating signal causes a cascade of intracellular signaling that may go as far as the DNA in the nucleus. The signals can either promote cell division or cause cells to stop growing; the balance of the two types of signals determines the rate of cell growth. Signal transduction pathways are the mechanisms by which extracellular activation signals are carried into the cell’s cytoplasm and nucleus. The proteins involved are growth factors, growth factor receptors, signal transduction proteins, cell-cycle control proteins, and DNA repair proteins.1 Kinases are proteins that perform phosphorylation, that is, carry phosphates from one stop in the signaling pathway to the next.2 Upstream signaling events occur near the cell membrane and those occurring closer to the nucleus are considered to be downstream.3 Cancer cells often make more growth factor receptors than normal cells. This overexpression al-

lows continuous activation of signaling pathways. Other cancer cells have genetic mutations that allow dysfunctional receptors to remain in the ‘‘on’’ position for growth, even in the absence of the growth factor.2 Other ways that normal signaling processes are bypassed occur when there are increased levels of proteins in the pathways or if genetic mutations alter the proteins in the pathway. Altered proteins may then transmit signals on their own to promote growth or interfere with the signals that should tell the cell to stop growing. A number of growth-promoting proteins and signaling pathways have been identified and are being studied in cancer laboratories and in clinical trials. These proteins are activated by gene amplification or genetic alterations, such as point mutations or driver mutations, that cause continuous activation of signaling.4 Examples of these growth promoting proteins are KRAS, EGFR, BRAF, MEKo-1, HER-2, MET, ALK, and RET.5 The clinical significance of studying these genetic mutations is realized in the actionable genes identified in non– small cell lung cancer (NSCLC) and melanoma tumors. The identification of the presence of these mutations and gene rearrangements in these two diseases now directs standard of care treatments.6 Targeted therapies are designed to interfere with dysfunctional signaling of cells to stop the growth of cancer cells.2 Specifically, the growth factor receptors can be blocked or turned off, receptors can be blocked from interacting with other receptors, and signals can be blocked inside the cell. Targeted therapies interfere with the signaling pathways by both extracellular and intracellular events. Binding of the ligand (growth factor) and receptor overexpression resulting in receptor activation are extracellular processes. Intracellular pathways that activate signaling include binding of intracellular proteins, cross talk, receptor mutations, and loss of regulatory mechanisms.7

SIGNALING PATHWAYS To understand the mechanism of action of targeted therapies, oncology nurses must first be familiar with the most common signaling pathways (Fig. 1).7 Adding to this foundation, the nurse can easily learn about the classes of targeted therapies and the strategies to minimize and manage common side effects. Table 1 lists the type and

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FIGURE 1. Cellular signaling pathways. Depicted are the cellular signaling pathways involved in the proliferation, angiogenesis, and differentiation in neoplasm with the targets amendable to therapeutic interventions in cancer therapy. Membranebound human epidermal growth factor receptors (HERs), c-MET, and insulin-like growth factor I receptor (IGF-IR) mediate mitogenic signals from extracellular ligands, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), and insulin growth factor (IGF), respectively. The Ras/Raf/MEK/erk (mitogen–activated protein kinase, MAPK) and PI3k/Akt/mTOR pathways are major intracellular axes that regulate intracellular signaling traffic. The class and agents targeting the signaling proteins are indicated in boxes. (Reprinted from Wujcik D. Targeted therapy in cancer nursing: principles and practice; 2011; Jones & Bartlett Learning; Burlington, MA. www.jblearning.com. With permission.) class of the US Food and Drug Administration (FDA)-approved targeted therapies. EGFR/HER The epidermal growth factor receptor (EGFR) pathway is the first signaling pathway to have clinical application. Human epidermal growth factor receptors (HERs) are part of a family of receptor kinase pathways and a subfamily of the protein tyrosine kinases. These receptors are transmembrane proteins that have a receptor on the cell surface able to bind with a ligand and an intracellular tryrosine kinase domain that, when activated, starts multiple signaling pathways. HER/EGFR family members include EGFR (erbB1), HER2/neu (erbB2), HER3 (erbB3), and HER4 (erbB4). All of the family members are structurally related and all, except HER2, are activated by extracellular ligands.7

The most common HER1/EGFR-inhibitors are the monoclonal antibodies (MoAbs) cetuximab and panitumumab and the tyrosine kinase inhibitors (TKIs) erlotinib, afatinib, and gefitinib. The HER2-inhibitors are the MoAbs trastuzumab, ado-trastuzumabemtansine, and pertuzumab, and the TKI lapatinib. There are currently no FDA-approved drugs that target HER3 and HER4. One of the first targeted therapies designed to target a cell surface receptor was trastuzumab, a monoclonal antibody that interacts with the growth factor receptor HER2.8 Overexpression of HER2 is found in 20% of breast cancers and these breast cancers are among the most aggressive types.9 HER2 dimerizes with receptors on the cell surface to activate signaling pathways that cause cellular proliferation. Trastuzumab binds

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TABLE 1. First FDA Approval of Targeted Agents for Cancer Treatment Generic

Trade Name

Trastuzumab Rituximab Imatinib mesylate Gefitinib Cetuximab Erlotinib Sorafenib Sunitinib Dasatinib Bevacizumab Panitumumab Lapatinib Temsirolimus Nilotinib Everolimus Pazopdinib Ofatumumab Ipilmumab Vendetanib Vemurafenib Brentuximab Vedotin Crizotinib Axitinib Pertuzumab Bosutinib Cabozantinib Ponatinib Ado trastuzumab entansine Dabrafenib Trametinib Afatinib Pertuzumab Obinutuzumab Ibrutinib

Herceptin Rituxan Gleevec Iressa Erbitux Tarceva Nexavar Sutent Sprycel Avastin Vectibix Tykerb Torisel Tasigna Afinitor Votrienttm Arzera Yervoy Vendetanib Zeloraf Adcetris

Pharmaceutical

1st Approval

Indication

Class

Type

Genentech Genentech Novartis Astra Zeneca Bristol Myers Squibb Genentech Bayer Healthcare Pfizer BMSO Genentech Amgen GlaxoSmithKline Wyeth Novartis Novartis Glaxo-Smith-Kline Glaxo-Smith-Kline BMSO Astra Zeneca Hoffman-LaRoche Seattle Genetics

September 1997 December 1997 April 2003 May 2003 February 2004 November 2004 December 2005 January 2006 June 2006 September 2006 September 2006 March 2007 May 2007 October 2007 Mar 2009 October 2009 October 2009 March 2011 April 2011 August 2011 August 2011

Breast NHL CML, GIST NSCLC mCRC, SCCHN NSCLC, Pancreas RCC, HCC RCC, GIST CML CRC, NSCLC, RCC mCRC Breast RCC CML RCC RCC CLL Melanoma Thyroid Myeloma Hodgkin’s Lymphoma

MoAb MoAb Small Molecule Small Molecule MoAb Small Molecule Small Molecule Small Molecule Small Molecule MoAb MoAb Small Molecule Small Molecule Small Molecule Small Molecule Small Molecule MoAb MoAb Small Molecule Small Molecule MoAb

Humanized Chimeric TKI TKI Chimeric TKI Multi TKI Multi TKI Multi TKI Humanized Fully human Multi TKI mTOR TKI mTOR Multi TKI Fully human Fully human Multi TkI BRAF Chimeric

Xalkori Inlyta Perjeta Bosulif Cometriz Iclusig Kadcyla

Pfizer Pfizer Genentech Pfizer Exelixis, Inc Ariad Pharmaceuticals Genentech

August 2011 January 2012 June 2012 September 2012 November 2012 December 2012 February 2013

NCLC RCC Breast CML Thyroid ALL Breast

Small Molecule Small Molecule MoAb Small Molecule Small Molecule Small Molecule MoAb

ALK Multi TKI Humanized TKI Multi TKI TKI Humanized

Tafinlar Mekinist Gilotrif Perjeta Gazyva Imbruvica

GlaxoSmithKline GlaxoSmithKline Boehringer Ingelhiem Genentech Genentech Pharmacyclics

May 2013 May 2013 July 2013 September 2013 November 2013 November 2013

Melanoma Melanoma NSCLC Breast CLL Mantel cell lymphoma

Small Molecule Small Molecule Small Molecule MoAb MoAb Small Molecule

BRAF BRAF TKI Humanized Humanized TKI

Abbreviations: ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CRC, colorectal cancer; GIST, gastrointestinal stromal tumors; HCC, hepatocellular cancer; mCRC, metastatic colorectal cancer; MoAb, monoclonal antibody; NSCLC, non-small cell lung cancer; RCC, renal cell cancer; SCCHN, squamous cell cancer head neck; TKI, tyrosine kinase inhibitor; mTOR, mammalian target of rapamycin. Amgen: Thousand Oakes, CA; Ariad: Cambridge, MA; Astra Zeneca: Wilmington, DE; Bayer Healthcare: Deerfield, IL; Boehringer: Ridgefield, CT; Bristol Myers Squibb Oncology: Princeton, NJ; Exelixis, Inc: San Francisco, CA; Genentech: San Francisco, CA; Glaxo Smith Kline: Philadelphia, PA; Hoffman-LaRoche: San Francisco, CA; Novartis: East Hanover, NJ; Pfizer: New York, NY; Pharmacyclics: Sunnyvale, CA; Seattle Genetics: Seattle, WA.

with HER2, preventing the activation of the signaling pathways. Trastuzumab was first approved by the FDA for treatment of women with HER2-overexpressing metastatic breast tumors who had already received chemotherapy or who had not yet received chemotherapy but would receive paclitaxel along with trastuzumab.10 More recently, trastuzumab has been approved for use as an adjuvant therapy in combination with doxo-

rubicin, cyclophosphamide, and paclitaxel in women with early stage HER2-positive disease.2 ALK Anaplastic lymphoma kinase (ALK) gene rearrangements are present in 2% to 7% of patients with NSCLC.11 EGFR mutations and ALK rearrangements are generally mutually exclusive. A molecular diagnostic test using fluorescence in situ

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hybridization (FISH) has been approved by the FDA for detecting ALK before treatment with crizotinib.12 Crizotinib is an inhibitor of ALK and MNNGHOS transforming gene (MET) proteins and was FDA approved in 2011 for patients with locally advanced or metastatic NSCLC who have the ALK gene rearrangement.13 National Comprehensive Cancer Network (NCCN) guidelines now recommend that patients diagnosed with advanced NSCLC with adenocarcinoma histology be tested for EGFR mutations and ALK rearrangements. For those who test EGFR-positive, first-line therapy includes erlotinib or afatinib. Crizotinib should be considered as first-line therapy for patients who test positive for ALK gene rearrangements.14

BRAF mutation.25 Vemurafenib inhibits the ERK pathway and cell proliferation in cancer cells with the BFAF V600E mutation only, and therefore has an 80% response rate in patients with metastatic melanoma.25 A second BRAF inhibitor, dabrafenib, was approved in 2013.26,27

K-ras K-ras is an oncogene found on the 12p12 chromosome that, when mutated, activates unregulated cellular proliferation and impaired differentiation. K-ras is one the families of rat sarcoma (RAS) proteins and affects more than 10 downstream pathways.15 About 60% of patients with colorectal cancer (CRC) are K-ras wild type and 40% have a K-ras mutation.16 K-ras gene mutations are predictive markers for determining resistance to anti-EGFR MoAbs; cetuximab and panitumumab are not indicated for patients with CRC with K-ras mutation.17,18 However, K-ras wild type is not completely predictive of clinical response and other mutations in the pathway are being explored. The PIK3CA mutation is present in 10% to 20% of CRC19; there is early evidence that PIK3CA mutations may be a predictive biomarker.20Although K-ras mutations are found in 25% of patients with NSCLC, there are no targeted therapies available at this time.11

MTOR The mTOR (mammalian target of rapamycin) pathway is a cross point for external growth factor signaling pathways and internal pathways that regulate nutrient and energy levels in the cell.29 This pathway ‘‘cross talks’’ or activates horizontal pathways such as the MAPK pathway.30 There are two drugs that target this pathway. Temsirolimus binds to the intracellular protein FKBP12 and inhibits mTOR. Temsirolimus was approved for treatment of advanced renal cell cancer in 2007.31Everolimus, another mTOR inhibitor, was approved in 2009 for treatment of advanced renal cell cancer after failure with sunitinib or sorafinib.32

BRAF BRAF is a protein that is part of the signaling pathway known as the RAS/MAPK pathway, another pathway that helps control proliferation, differentiation, migration, and apoptosis. This protein normally switches on and off in response to growth signals. When mutated, BRAF stays on, activating continued growth of melanoma cells. BRAF is the most commonly mutated oncogene in melanoma (50% to 60%)21 and is also found in CRC (57%)22 and hairy cell leukemia (100%).23 BRAF inhibitors interfere with mutated BRAF proteins.24 In 2011, vemurafenib was the first BRAF inhibitor approved for the treatment of metastatic or unresectable melanoma with the V600

MAPK Kinase MAPK kinase (MEK) is found immediately downstream of BRAF and is the next relay in the signaling pathway. MEK inhibitors suppress ERK signaling in both normal and tumor cells. Trametinib is an MEK inhibitor, approved for the treatment of patients with advanced melanoma containing a BRAF V600E or V600K mutation.28

Src Src is a proto-oncogene found in an intracellular signaling pathway that plays a role in cancer cell mitosis, frame adhesion, invasion, motility, and progression. Src is implicated in the tumorgenesis of breast, CRC, lung, ovarian, and certain hematologic malignancies. Dasatinib is a Src and Abl inhibitor and is approved for Philadelphia positive acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML).33 Bcr-abl The abl protein is located in the nucleus of normal cells. Bcr-abl is a protein tyrosine kinase formed when there is a gene translocation known as the Philadelphia chromosome. The Bcr-abl fusion protein promotes leukemic cell proliferation and inhibits apopotosis.34 The Bcr-abl translocation is found in 95% of patients with chronic myelogenous leukemia (CML) and 14% to 30% of patients with acute lymphocytic leukemia (ALL).34 The mutated tyrosine kinase causes the signaling

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pathway to remain activated. Imatinib inhibits several different proteins, including c-kit and abl.35 When imatinib is given, the proteins are bound so they can no longer transmit phosphorylation signals and cell growth and division is inhibited. Drug resistance develops when the tumor cells develop another pathway for signaling. As previously stated, imatinib targets a mutation within the kinase domain of the protein Bcr-abl in patients with ALL and CML. A multi-kinase inhibitor, dasatinib, has higher affinity for the Bcr-abl kinase than imatinib.36 Patients who develop resistance to imatinib are given dasatinib and 93% again show response. For those patients who then develop resistance to dasatinib, a newer agent, nilotinib, is now available.37 Angiogenesis Angiogenesis is the formation of new blood vessels from existing vessels. The new vasculature is essential for tumors to grow and metastasize. Vascular endothelial growth factor (VEGF) is essential for the vessel growth and therefore is a good target to interfere with tumor growth. There are two main types of VEGF receptors: VEGFR-1 (Flt-1) is most important during embryonic development, but may also be involved in metastasis and other functions; VEGFR-2 (Flk-2, KDR) is the major receptor involved in pathological angiogenesis and lymphangiogenesis in tumors.7 On a cellular level, the process of angiogenesis begins with a signal sent by a cell in need of nutrients or oxygen to a nearby endothelial cell. The cell releases proteins called matrix metalloproteinases (MMPs) that bind to receptors on the surface of endothelial cells that make up blood vessels. These MMPs forge a path that allows endothelial cells to migrate in the direction of the cell in need and form new blood vessels. Because angiogenesis is essential for tumors to grow beyond a certain size, blocking angiogenesis is an ideal strategy for cancer therapy. Targeted therapies bind to either the proteins released from the tumor or receptors on the endothelial cell surface, to prevent the activation of signaling pathways. Other drugs prevent the creation of pathways for blood vessel expansion by blocking the MMPs.2,7 Bevacizumab is a monoclonal antibody that binds to VEGF and keeps it away from receptors on the surface of endothelial cells. It was first approved in 2004 for use in first- and second-line treatment of metastatic CRC and in 2006 for NSCLC and in combination with interferon alfa

for metastatic renal cell carcinoma in 2009.38 Existing blood vessels no longer receive a signal for increased blood flow, so new blood vessels are not formed. This prevents the tumor from continuing to grow. Sorafenib is a small molecule that inhibits multiple kinases (the proteins involved in growth signaling described earlier). These kinases include some cell surface receptors as well as enzymes located within the cell. In addition to blocking the signaling pathways for growth, disrupting kinase signaling also interferes with the tumor’s recruitment of new blood vessels. Sorafenib is FDA-approved for treatment of advanced renal cell cancer.39 Because the kinases targeted by sorafenib are also important to some normal cells, therapies like sorafenib may also affect some normal cells. Sunitinib, a multi-targeted TKI, is approved for the treatment of advanced renal cell cancer, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors.40

TARGETED THERAPIES There are three types of targeted therapies: small molecule protein TKIs, MoAbs, and vaccines.2 Vaccines do not act specifically on pathways in cancer cells, but act broadly to activate the body’s immune system to make it recognize and attack cancer cells. Knowing the name of the targeted therapy can facilitate understanding the mechanism of action and expected side effects of both TKIs and MoAbs. Small molecules are so named because they can cross cell membranes. The small molecule tyrosine kinases all have nib in their name and some form of tinib, anib, or rafenib. Examples of the small molecules are erlotinib, imatinib, pazopanib, sunitinib, and sorafenib. The small molecule drugs are taken orally, which then requires consideration of drug/food and drug/drug interactions. Because patients receive most of their treatment at home, oncology nurses have developed strategies to assure adherence to dose and time requirements as well as side effect management.41 Monoclonal antibodies work outside of the cell, preventing signaling molecules and receptors from interacting. MoAbs can also deliver radioactive molecules or toxins to the cancer cell. Once inside the cell, the cytotoxin is released and causes cell death. MoAbs can also work outside the cell, triggering an immune response that destroys the cell. MoAbs are made from mouse, chimeric, or human antibodies and are administered intravenously.

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Those from human antibodies produce less infusion reactions and are more tolerable. Examples are tositumomab, rituximab, trastuzumab, panitumumab, and bevacizumab. MoAbs are identified with mab at the end of the name. Working backwards from the end, the next part of the name indicates the derivation of the antibody. Mo before mab means mouse derived such as in tositumomab. Xi before mab means chimeric or cross between mouse and human, such as in rituximab. Zu before mab means humanized, as in trastuzumab or bevacizumab, and mu before mab means fully human, as in panitumumab. The more humanized the antibody, the less infusion reactions can be expected. The final key to the MoAb is the target of action. Tu before the type of antibody means that the tumor is the target, such as in trastuzumab or panitumumab. Ci indicates a circulatory target, such as in bevacizumab. Li or l means that the MoAb is an immunomodulator, such as ipilimumab. Using these definitions, erlotinib is a TKI and pertuzumab is a humanized MoAB that targets the tumor cells. Once the oncology nurse understands the naming conventions, mastery of administration and side effect management is more easily accomplished.

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NURSING IMPLICATIONS Cancer treatment previously relied on a pathologic diagnosis and was disease-focused. Today, therapeutic decisions rely on the results of molecular testing and targeted therapies are directed at specific mutations along the signaling pathways. Nurses must understand the signaling pathways and genetic mutations that control cancer cell growth to understand the mechanisms of targeted therapies. Adding to this foundation, the nurse can recognize the type of targeted therapy, the structure of the MoAb, and the target of the agent all found in the name of the agent. This understanding is then applied to the patient education and symptom management that is unique to targeted therapies. As new information about signaling pathways emerges and new actionable targets are identified, additional agents will be tested and approved for clinical use. The sequence of using agents as resistance develops must be explained to patients. When combinations of agents are used, patients must understand and adhere to the regimens for maximum efficacy. Oncology nurses must continue to learn about each development to ensure patient education and safety.

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