Introduction

Improved knowledge of cancer biology and synthetic chemistry along with advances in biotechnology have generated extraordinary opportunities for the development of molecularly targeted cancer therapeutics. Molecularly targeted anticancer agents (MTAs) are defined here as agents that selectively target specific molecular features of cancer cells such as aberrations in genes, proteins, or pathways that regulate tumor growth, progression, and survival. By identifying ways that cancer cells differ from normal healthy cells at the molecular level, scientists can exploit these differences to develop drugs that selectively target cancer cells while sparing normal cells. Consequently, an increasing number of MTAs are being developed with the goal of producing more effective and minimally toxic anticancer therapeutics. Furthermore, progress in the development of MTAs can shape cancer therapeutics into a more individualized form of cancer medicine. This chapter will review the principles of molecularly targeted therapy, including strategies for preclinical and clinical development.

Molecular Targets

The increasing number and assortment of molecular targets can be broadly categorized according to genetic or functional properties, including products of activating gene mutations and translocations; growth factors and receptors; aberrant signal transduction and apoptotic pathways; factors that control tumor angiogenesis and microenvironment; dysregulated proteins; DNA repair machinery; and aberrant epigenetic mechanisms (Tables 28-1 and 28-2).

The most promising molecular targets are those solely responsible for sustaining tumor growth and survival because agents that potently and selectively inhibit these critical targets are likely to have a major clinical impact. Probably the best example of a critical target is BCR-ABL in patients with chronic myelogenous leukemia (CML). BCR-ABL is a fusion protein formed by the reciprocal translocation of chromosomes 9 and 22. Knowledge that this dysregulated tyrosine kinase played a causal role in the pathogenesis of essentially all cases of CML spurred preclinical studies, which led to the development of a potent and selective ABL tyrosine kinase inhibitor (TKI), imatinib mesylate (previously known as STI571).¹ Subsequent clinical trials established imatinib mesylate as the first highly effective molecularly targeted therapy for CML and a prototype for the development of others in the class. Imatinib mesylate is also a potent inhibitor of other tyrosine kinases including PDGFR and KIT, and it is highly effective in the treatment of gastrointestinal stromal tumors (GISTs) bearing activating c-KIT mutations and in some GISTs bearing activating PDGFR mutations.^1,2

Unfortunately, most human tumors, including the most common types, are genetically complex and do not have a single critical target, and the relative critical importance of a target in different tumors may vary. Most tumor types have various genetic and molecular abnormalities driving their growth and survival. The existence of multiple abnormalities in one or more molecular pathways helps explain resistance to molecularly targeted therapy and provides a rationale for treatment strategies combining two or more targeted agents.3,4 However, cancer cells may become “addicted” or physiologically dependent on the sustained activity of specific oncogenes for maintenance of a malignant phenotype and for survival. This dependence mechanism, termed oncogene addiction^7–7 (Fig. 28-1), is associated with differential attenuation rates of prosurvival and proapoptotic signals stemming from the oncoprotein, with predominant apoptotic signals resulting in cell killing. The latter process, termed “oncogenic shock,”⁸ could explain the remarkably rapid clinical responses to TKIs in some patients with solid tumors, including those typically having complex molecular abnormalities. Other possible factors controlling sensitivity or resistance to molecularly targeted therapy include increased expression of the target due to gene amplification or transcription, emergence of resistant target gene mutations, and overexpression of multidrug transporter membrane proteins.^4,7

Interest in molecular therapy directed at factors controlling angiogenesis has increased since the United States Food and Drug Administration (FDA) approved several agents that target vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF pathway, involving the VEGF family of proteins and their receptors, is an important regulator of both physiological and pathological angiogenesis. Through its signaling pathways, VEGF/VEGFR activation contributes to increased vascular permeability, mobilization of bone marrow–derived endothelial cell precursors, degradation of the extracellular matrix, and endothelial cell division, differentiation, migration, and survival.9,10 VEGF overexpression occurs in most types of cancers, including colorectal, renal, gastric, pancreatic, liver, lung, breast, thyroid, and genitourinary; it also occurs in glioma and other intracranial tumors, as well as in hematologic malignancies, and it is associated with tumor growth and a worse clinical outcome in a number of these tumor types.^10,11

Potential therapeutic strategies to inhibit signaling through VEGF and VEGFR pathway activation include monoclonal antibodies directed against VEGF or VEGFR, TKIs, and antisense strategies (antisense oligodeoxynucleotides, antisense RNA, and small interfering RNAs). In 2004, the FDA approved bevacizumab, a humanized murine monoclonal antibody directed against VEGF, for treating metastatic colorectal cancer in combination with fluorouracil-based chemotherapy. The FDA subsequently approved sunitinib, sorafenib, and axitinib, three small-molecule TKIs with activity against VEGFR, for the treatment of advanced renal cancer.¹¹ In addition, sorafenib is effective for treating hepatocellular carcinoma, a tumor against which standard cytotoxic chemotherapy has little or no activity.^11,12 The experience with these agents has established the VEGF/VEGFR pathway as a valid target for cancer therapeutics.¹¹

Mammalian target of rapamycin (mTOR) has also emerged as a validated target with the demonstration that the small-molecule mammalian target of rapamycin inhibitors temsirolimus and everolimus are effective in the treatment of renal cell carcinoma.¹³ This activity of temsirolimus is attributed to the downregulation of factors that control cell growth and angiogenesis.¹³

Preclinical Development of MTAs

The discovery and development of molecularly targeted therapies requires closely aligned laboratory and clinical research, integrating drug discovery, development, and clinical investigation. In such a cooperative setting, researchers can effectively take rational and iterative steps from target identification to clinical evaluation (Box 28-1) (Fig. 28-2). A crucial early step in developing a molecularly targeted therapy is target validation, defined as experimental evaluation of the role of a given gene or protein.^14,15 The target validation process involves a variety of preclinical approaches, including genetic, cell-based, and animal models.¹⁶ Validation and prioritization of molecular targets for therapeutic development depends on a variety of criteria, taking into consideration chemical, biological, clinical, and practical factors¹⁵ (Box 28-2). The fundamental goal is to provide evidence that the target is valid (i.e., that affecting the target inhibits tumor growth, progression, or survival) and that making drugs that hit the target is feasible. The next major step in the development of molecularly targeted therapy is finding/synthesizing compounds directed against that target.