I. INTRODUCTION
Molecular targeted therapy (MTT) is a new approach to cancer treatment that resulted from the plethora of molecular and biologic discoveries into the etiology of cancer, which took place over the last quarter of a century. Several agents have already been approved by the U.S. Food and Drug Administration (FDA) for clinical use. Many more are currently being tested in clinical trials, and their widespread integration into the mainstream for cancer treatment is expected to increase at an accelerated pace during the next decade.
Agents in this type of therapy are vastly different from the traditional chemotherapeutic agents that constitute the majority of therapy described throughout the chapters of this book. These new drugs are designed with the intention to specifically target molecules that are uniquely or abnormally expressed within cancer cells while sparing normal cells. Within this chapter, we will discuss
drugs that are already available for clinical use; provide a brief description of the mechanism of action of these agents, the pathways they target, and some of their clinical uses; also address promising agents that are currently in clinical trials and may be coming soon to the clinic.
A. Characteristics of MTT
An ideal molecule for targeted therapy should have the following characteristics:
The molecule is uniquely expressed in cancer cells; hence the therapeutic agent will specifically target the cancer and not the normal cells.
The molecule is important for the maintenance of the malignant phenotype; therefore, once the targeted molecule has been effectively disabled, the cancer cell will not be able to develop resistance against the therapeutic agent by suppressing its function or expelling the targeted molecule from the cell.
The degree to which target molecules do not embody these characteristics coupled with nonspecificity of the therapeutic agent determines, in part, the limitations of current targets and agents.
B. Classification and type of MTT
The classification of MTT is a moving target. In this chapter, we will classify MTT based on the targeting strategy of the molecule. There are two targeting strategies for MTT:
1. Function-directed therapy. This therapeutic strategy is intended to restore the normal function or abrogate the abnormal function of the defective molecule or a pathway in the tumor cell. This is accomplished by:
Reconstituting the normal molecule
Inhibiting the production of a defective molecule
Aborting, altering, or reversing a newly acquired function by targeting the defective molecule, its function, and its downstream effect.
Agents under this category will be classified based on the mechanism of action and subclassified based on the known affected targeted pathway.
2. Phenotype-directed therapy. This is a therapeutic strategy that is intended to target the unique phenotype of the cancer cell where killing the cell is more dependent on nonspecific mechanisms rather than targeting a specific pathway. Such agents include monoclonal antibodies (MoAbs)—including immune conjugates—immunotoxins, and vaccine therapy. Accordingly, agents under this category will be classified based on the type of therapy and subclassified based on the targeted pathway or molecule.
Table 2.1 summarizes the classification and FDA-approved indications of molecular-targeted agents.
TABLE 2.1 Classification and FDA-Approved Indications of Molecular-Targeted Agents
Agent
Target
FDA Approval Cancer Type
Single Agent In Patients
Combined With
In Patients
Blocking of the Ligand-Receptor Binding
Cetuximab
EGFR1
Metastatic colon EGFR+
Did not tolerate irinotecan
Irinotecan
Failed irinotecan
Unresectable head and neck
Failed platinum
Radiation
Failed platinum
Panitumumab
EGFR1
Metastatic colon EGFR+
Failed chemotherapy
Trastuzumab
HER2
Metastatic breast HER2+
Failed at least one chemotherapy or as an adjuvant
Paclitaxel
First-line
Bevacizumab
VEGF
Advanced colon
Fluorouracil
First-line
Locally advanced, recurrent, or metastatic NSCLC
Platinum
First-line
Metastatic RCC
IFNα
Recurrent glioblastomas
Failed chemotherapy
Inhibition of Receptor Tyrosine Kinases
Erlotinib
EGFR
Locally advanced or metastatic NSCLC
As maintenance after four cycles of platinum, or as second- or third-line
Locally advanced or metastatic pancreatic
Gemcitabine
First-line
Gefitinib
EGFR
Locally advanced or metastatic NSCLC
Who demonstrated benefit from the drug
Sunitinib
VEGFR, PDGFR, c-Kit
Advanced RCC
GIST
First-line
Failed or did not tolerate imatinib
Lapatinib
HER2
Advanced, refractory breast HER2+
Failed trastuzumab
Letrozole or capecitabine
Failed trastuzumab
Pazopanib
VEGFR, PDGFR, c-Kit
Advanced RCC
Inhibition of Intracellular Signaling Proteins and Protein Kinases
Imatinib
Bcr-Abl, PDGF, c-Kit
Newly diagnosed, blast crisis, accelerated, or chronic CML Ph+
Failed IFNα or recurrence after stem cell transplant
Unresectable or metastatic GIST c-Kit+
MDS PDGFR+
Chronic eosinophilic leukemia
Dasatinib
Bcr-Abl, c-Kit, PDGFR
Blast, accelerated, or chronic CML Ph+
First-line
ALL Ph+
Failed prior therapy
Nilotinib
Bcr-Abl
Accelerated or chronic CML Ph+
First-line
Sorafenib
Raf/MEK/ERK, VEGFR-2, PDGF
Advanced RCC
Unresectable HCC
First-line
Everolimus
mTOR
Advanced RCC
Failed sunitinib or sorafenib
Temsirolimus
mTOR
Advanced RCC
Protein Degradation Targeted Therapy
Bortezomib
26S proteosome
MM
Refractory
MM
Melphalan and prednisone
First-line
Mantle cell lymphoma
Failed at least one prior therapy
Immune Modulation Targeted Therapy
Lenalidomide
Nonspecific
MM
Dexamethasone
Second-line
MDS with 5q deletion
Transfusion dependent
Phenotype-Directed Targeted Therapy
Rituximab
CD20
Diffuse, large B-cell NHL CD20+
Refractory or relapsed
CHOP, or CVP
First-line
CLL CD20+
Refractory or relapsed
Alemtuzumab
CD52
B-cell CLL
Failed fludarabine
Ofatumumab
CD20
CLL
Refractory
Gemtuzumab
CD33
Myeloid leukemia CD33+
Older patients after the first relapse who are not candidates for chemotherapy
Ibritumomab
CD20
B-cell follicular NHL CD20+
Refractory to rituximab
Tositumomab
CD20
Low-grade or transformed low-grade NHL CD20+
Refractory to chemotherapy and rituximab
Denileukin
CD25
CTCL CD25+
Persistent or recurrent
Cancer Vaccine
Sipuleucel-T
PAP
Metastatic prostate
Asymptomatic or minimally symptomatic hormone refractory
ALL, acute lymphocytic leukemia; CHOP, Cytoxan, hydroxydoxorubicin, hydroxydaunorubicin, and prednisone; CML, chronic myelogenous leukemia; CTCL, cutaneous T-cell lymphoma; CVP, Cytoxan, vincristine, and prednisone; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; IFNα, interferon-alpha; MDS, myelodysplastic syndrome; MM, multiple myeloma; mTOR, mammalian target of rapamycin; NHL, non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; PAP, prostatic acid phosphatase; PDGFR, platelet-derived growth factor receptor; Ph+, Philadelphia chromosome-positive; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
II. FUNCTION-DIRECTED THERAPY
Agents under this category target specific cellular pathways (e.g., signal transduction pathways, angiogenesis, protein degradation, and immune modulators).
A. Cell signaling targeted therapy
Signal transduction pathways are crucial for delivering messages from the extracellular environment into the nucleus and enabling the cell to carry on cellular processes including survival, cell proliferation, and differentiation. These signals are initiated from the cell surface by the interaction of molecules (ligands) such as hormones, cytokines, and growth factors with cell receptors. Cell receptors, in turn, transfer the signal through a network of molecules to the nucleus, which leads to the transcription of new molecules responsible for engineering the desired outcome.
In cancer cells, these pathways are found to be altered through the mutation of some of their components. This leads to the functional dysregulation of the affected pathways resulting in uncontrolled proliferation and inhibition of apoptosis. Accordingly, targeting the components of these pathways is a prime goal for the development of MTT. The components of these pathways include the following:
The ligand
The receptors for these ligands—the majority of which are kinase receptors
The cascade of proteins that form these pathways, which are mainly protein kinases; other classes of proteins are also involved.
Accordingly, strategies targeting signal transduction pathways include the following:
Blocking of the ligand-receptor binding. This leads to the prevention of the initiation of the signal and can be accomplished by either blocking circulating ligands or blocking ligand binding to the extracellular domain of the cellular receptor.
Inhibition of receptor protein kinases. This leads to the prevention of phosphorylation of the intracellular kinase domain of the receptor, hence, aborting the cascade of proteins reactions in the cell signaling pathways. Blocking adenosine triphosphate (ATP) binding to the receptor is one example to achieve this inhibition.
Inhibition of intracellular signaling proteins.
1. Blocking of the ligand-receptor binding. Blocking receptors and ligand-receptor interaction is currently achieved by utilizing specific MoAbs directed against the ligand or the receptor. MoAbs are biologic agents designed with the intention to specifically target soluble proteins or membrane proteins with an extracellular domain. The MoAbs can exert their antitumor effect through multiple potential mechanisms including blocking the targeted receptor or ligand and preventing its function in transmitting
signals to the nucleus, activating antibody-dependent cellular cytotoxicity, or helping to internalize the receptor and hence deliver toxic agents into the cells. The MoAb technology has been very much improved in the last decade by humanizing these agents partially in chimeric or fully humanized constructs. Substituting the murine Fc portion of the MoAb with a human equivalent leads to a significant decrease in the generation of a human antimouse antibody (HAMA) immune reaction. Although generation of human antichimera antibodies (HACAs) may still occur for those MoAbs, it does not occur with fully humanized MoAbs. This technology to humanize MoAbs has made these molecules more usable in the treatment of cancer, particularly when repetitive dosing is required. In this section, we will discuss MoAbs generated against specific membrane receptors. MoAbs that are generated against membrane nonreceptor antigens will be discussed later in the chapter (Section III.A).
a. Epidermal growth factor receptor (EGFR) family. The EGFRs are a small family of proteins belonging to the larger receptor tyrosine kinase (RTK) family. The EGFR family includes at least four described receptors: EGFR1, Her-2-neu (erbB2), Her3 (erbB3), and Her4 (erbB4). These receptors are glycoproteins consisting of three domains: an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a tyrosine kinase activity. Binding of the ligands to the receptor leads to the activation of the intracellular tyrosine kinase and the phosphorylation of the receptor, which in turn leads to activation of the downstream signal transduction pathway. The activation of this pathway promotes cell activation, proliferation, and enhanced survival. Agents have been developed against the receptors EGFR1 and Her-2-neu.
(1) EGFR1-targeted therapy. EGFR1 is the first member of the EGFR family to be identified. It is activated by binding to epidermal growth factor (EGF) and to transforming growth factor alpha (TGF-α). EGFR1 is found to be overexpressed in many cancers including 50% to 70% of colon, lung, and breast cancers. Several antibodies targeting EGFR have been approved by the FDA for clinical use in patients with cancer:
Cetuximab (Erbitux) is a humanized immunoglobulin-G (IgG1) chimeric MoAb that binds to the external ligand-binding domain of EGFR1. It also binds with much lower affinity to EGF and TGF-α. The combination of cetuximab and irinotecan can improve disease response and progression-free survival (PFS) over the use of cetuximab alone in patients with advanced colorectal carcinoma who express EGFR on their tumors and have previously
failed irinotecan therapy. Recent studies have suggested that better PFS and overall survival (OS) can be achieved when cetuximab is combined with FOLFIRI (a combination made up of folinic acid, fluorouracil, and irinotecan) or FOLFOX-4 (a combination made up of folinic acid, fluorouracil, and oxaliplatin) in advanced colon cancer (see Chapter 7 for a definition of these regimens and further discussion). The increased response rate as a result of adding cetuximab was higher in patients with tumors expressing the wild type KRAS gene. Currently, cetuximab in combination with irinotecan is approved by the FDA to treat patients with advanced colon cancer expressing EGFR who failed irinotecan treatment or as a single agent in patients who cannot tolerate irinotecan. It is also approved in combination with radiation or as monotherapy in patients who failed prior platinum-based therapy in unresectable head and neck cancers. Recently, a phase III trial demonstrated that patients with advanced EGFR-positive non-small-cell lung cancer (NSCLC) treated with cetuximab combined with cisplatin/vinorelbine had superior survival compared to chemotherapy alone. It has also been found that, in this group of patients, KRAS mutation correlates with progressive disease and shorter median time to progression, but not with survival. Similar to other antibodies, common side effects include rash and diarrhea, and, although very uncommon, cardiac arrest and myocardial infarction (MI) were reported among the serious side effects.
Panitumumab (Vectibix) is a fully humanized MoAb that has been developed against EGFR. Panitumumab binds to EGFR1 with higher affinity than cetuximab. A randomized phase III study demonstrated that patients with refractory EGFR-expressing metastatic colorectal cancer treated with panitumumab plus best supportive care had a better PFS compared to patients who received best supportive care alone. The patients who benefit from the treatment were those with tumors that did not contain KRAS mutations. Therefore, panitumumab was approved by the FDA as monotherapy for chemotherapy-refractory EGFR-expressing metastatic colon cancer. Other diseases with promising results using panitumumab include NSCLC and renal cancer. Common adverse effects include rash, peripheral edema, fatigue, and diarrhea. Serious toxicity, including bronchospasm, has been reported only rarely, and as a consequence does not require premedication for human use.
Other anti-EGFR MoAbs currently being evaluated in phase II trials include the following:
Matuzumab is a humanized anti-EGFR IgG1 MoAb. The agent has been tested in a phase I trial followed by paclitaxel in EGFR-expressing advanced NSCLC with a partial response achieved in 3 of 18 patients and a complete response reported in 1 treated patient. An ongoing trial is evaluating matuzumab in combination with pemetrexed in advanced NSCLC.
Nimotuzumab is a recombinant humanized IgG1 MoAb against EGFR that is approved for squamous cell carcinoma in head and neck in other countries and has been granted orphan drug status for glioma in the United States. Currently, it is being tested in combination with external radiotherapy in patients with NSCLC.
(2) Her-2-neu (HER2, erbB2)-targeted therapy. HER2 is the second member of the EGFR family. This receptor has the same basic structure as the other family members; however, no conjugate ligand has been identified for HER2. There have been no mutations identified in the HER2 gene in human cancers, yet it is overexpressed in many epithelial cancers including colon, pancreas, genitourinary, and breast cancers. HER2 signals via the phosphoinositide-3 kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase pathways, and HER2 overexpression leads to inhibition of apoptosis and increase in cell proliferation.Related posts:
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Biologic Basis of Molecular Targeted Therapy
Biologic Basis of Molecular Targeted Therapy
Osama E. Rahma
Samir N. Khleif
