Understanding Novel Molecular Therapies
Understanding Novel Molecular Therapies
Human cells process and respond to diverse stimulatory and inhibitory signals through multifaceted signaling pathways. A tightly regulateed system of signal transduction pathways controls cell metabolism, division, death, differentiation, and movement. Malignant transformation stems from altered regulation of six essential cell behaviors: self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis (programmed cell death), limitless replication potential, sustained angiogenesis, and tissue invasion and metastasis.
Researchers have identified numerous abnormal signal transduction elements that contribute to the development of cancer. These discoveries have led to the creation of pharmacologic agents that target signal transduction elements and cell behavior. Two signal transduction pathways regulate the development, proliferation, and metastasis of solid tumors: the human epidermal growth factor (HER) receptor pathway and the vascular endothelial growth factor (VEGF) receptor pathway. Each of the novel pharmacologic agents that target these pathways has unique indications and means of administration.
Human Epidermal Growth Factor Receptors
The HER family of receptors consists of four structurally related transmembrane receptors: HER1 (epidermal growth factor receptor [EGFR] or cerbB1), HER2 (cerbB2 or HER2/neu), HER3 (cerbB3), and HER4 (cerbB4). HER receptor tyrosine kinases (TKs) have an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase (TK) domain. Research has demonstrated that HER family dysregulation is associated with atypical cell behavior, and current investigations are focused specifically on the role that EGFR signaling pathways play in carcinogenesis.
EGFR is expressed in healthy cells of germ cell derivation, especially those of epithelial origin. EGFR overexpression is associated with cancers of the colon, head and neck, pancreas, lung (non-small cell), breast, kidney, bladder, and gliomas. Alterations in EGFR activity correlate with disease progression, poor prognosis, and the development of resistance to cytotoxic agents.
EGFR activation begins when an extracellular ligand binds to an EGFR monomer (inactive protein). Several stimulatory ligands bind with EGFR, including the epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). The ligand-bound receptor dimerizes or pairs with other monomers on the cell surface. EGFR can pair with another EGFR (homodimerization) or another member of the HER family (heterodimerization). Dimerization promotes transmembrane signal transduction, resulting in intracellular TK activity and phosphorylation. A phosphate group from adenosine triphosphate (ATP) is transferred to the tyrosine residues on the signal transduction molecules. The phosphorylated TK residue becomes a binding site for key signal transducers that activate multiple downstream signaling pathways. Significant downstream pathways include Ras-Raf-Mek-MAPK, which regulates gene transcription and proliferation, and the P13K/Akt signaling pathway, which governs cell survival. The specific binding ligand and the coreceptor to which EGFR is dimerized determine the signaling pathways that EGFR activates. Multiple factors contribute to upregulation of EGFR signaling, including overproduction of ligands by the tumor cell, overexpression of EGFRs on the cell surface, and mutations that initiate EGFR activity independently of ligand binding.
HER2, like EGFR, is a TK receptor that is expressed on a variety of normal cells. The HER2 receptor has no known ligand and participates in signal transduction by forming heterodimers with other HER family receptors. HER2-containing heterodimers exhibit strong ligand binding, which enhances downstream signaling and delivery of proliferative signals to the nucleus. Overexpression of HER2 results in the formation of HER2 homodimers that are also extremely active. Gene amplification (generation of more than the normal two gene copies) and overexpression of HER2 occur in approximately 25% of breast cancers and are associated with aggressive tumor behavior and decreased overall survival.
Activation of HER2 and EGFR receptors triggers multiple signaling pathways that play a critical role in cellular growth and proliferation. Tumor cells express VEGF, a protein responsible for the development of new blood vessels (angiogenesis), as a result of EGFR signaling.
Vascular Endothelial Growth Factor
Like normal cells, cancer cells depend on an adequate blood supply to provide oxygen, nutrients, and other elements essential for survival and growth. Solid tumors can absorb sufficient nutrients and oxygen by diffusion until they measure 2 to 3 mm; further growth requires the formation of new blood vessels or angiogenesis.
Angiogenesis is a normal physiologic response during wound healing, menstruation, and embryonic development. It is a dynamic, complex process regulated by a number of factors. VEGF, a member of the platelet-derived growth factor family, has a well-documented role in tumor angiogenesis. A number of solid tumors express VEGF; among them are glioblastomas and colon, gastric, breast, lung, brain, hepatocellular, and bladder cancers.
Numerous stimuli increase VEGF expression: genetic events, hypoxia, nitric oxide, and growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor (IGF-1). The primary source of VEGF is the tumor itself, but associated stromal and vascular endothelium cells also express VEGF, especially in the presence of hypoxia.
Angiogenesis is a multistep process that begins with VEGF binding to VEGFR1 (FLT1) and VEGFR2 (KDR or Flk-1), which are located on endothelial cells found in blood vessels. Receptor activation leads to TK phosphorylation, inducing multiple downstream pathways and production of proteins that promote angiogenesis. VEGF signaling increases the permeability of surrounding vasculature, proliferation of endothelial cells, and degradation of the extracellular matrix, which promotes endothelial cell migration.
Finally, VEGF inhibits endothelial cell apoptosis by stimulating the expression of antiapoptotic factors Bcl-2 and Bcl-A1. The resulting unstable vasculature is tortuous, dilated, and leaky. Despite the development of new vasculature, the tumor remains hypoxic, and angiogenesis is further stimulated. The unstable characteristic of the tumor vasculature may contribute to ineffective delivery of cytotoxic agents, resulting in poor response.[12,13]