Cancer Pharmacology

Principles of Cancer Drug Action

Genetics is a fundamental part of the study of cancer research (see Chapter 1 ). The range of applications for genetics in cancer includes hereditary predisposition and interactions of heredity with nonhereditary factors (see Chapter 13 ).

In cancer pharmacology, molecular targets that could be relevant to therapy have received the most intense emphasis of pharmacogenomics. This focus includes unique proteins coded by translocations, differences in gene expression between tumors and host tissues, and mutations in sequences. The identification of the most attractive molecular targets and the ability to monitor target engagement during therapy are cornerstones for customized treatment.

As described in Chapter 26 and elsewhere (e.g., Chapter 8 ), our understanding of the physiology and molecular biology of tumors has provided a wealth of potential targets for anticancer therapy. Although the relative intensity has magnified, the concept of molecular targeting and linkage to diagnostics for selection and monitoring of individual patients has a long history. The selection of hormonal therapies for patients whose tumors express the estrogen receptor was among the first successful uses of molecular targeting.

The current era of targeting began with approval of trastuzumab (1998) only in patients with Her2-positive tumors and approval of imatinib (2001) only in patients with chronic myelogenous leukemia (CML) that is Philadelphia chromosome positive. These early successes fueled emphasis on other targets. ALK and BRAF are among the many descendants of the approach. In 2017, the target became more pivotal with the approval for pembrolizumab for treatment of tumors with tumors that demonstrate mismatch repair or microsatellite instability, regardless of tumor's site of origin.

In addition to the obvious attraction of matching drugs to the molecular characteristics of the tumor, the therapeutic index can also be improved by examining host tissues. In his last major research publication, Dr. Abeloff was a leader in a large multicenter study of the pharmacogenetics of cyclophosphamide. The goal was to determine whether the germline DNA of patients altered the toxicity profile of cyclophosphamide. The researchers found a subgroup of women who had variant GSTP1 alleles that were associated with less susceptibility to adverse hematologic toxicity in regimens containing cyclophosphamide. Subsequent work by large cooperative groups in the United Kingdom for paclitaxel in breast cancer and in the United States for docetaxel in prostate cancer found other links between germline DNA and sensory neuropathy.

Although these studies were only hypothesis generating, the examples illustrate the possible ways that the therapeutic index for a drug can be improved with examination of host tissues. Later in this chapter, in the discussion of drug delivery, the pharmacogenetics of metabolism and cellular membrane transporter cell membranes in host tissues are discussed.

Combinations of Drugs

As described in the various chapters relating to specific malignancies in Part III of this book, it is rare for a drug to be used as a single agent. The development of combinations would be an extensive topic in itself. Box 25.1 provides a set of points to consider for combinations. Within a combination chemotherapy regimen, the drugs are intended to interact at the pharmacodynamic level. Originally, a major strategy was to combine cancer drugs with nonoverlapping toxicities. Increasingly, more detailed knowledge regarding pathways for cancer drugs permits the design and evaluation of combination strategies that target parallel and/or sequential pathways.

Most combinations are based on a preexisting scientific rationale or by addition of a new agent to an established regimen. However, it would be presumptuous to assume that all possibilities are already understood. One tool to expand the scope of hypothesis generation is the systematic study of all cancer drugs in combination with one another or in combination with approved agents outside oncology, or the testing of every investigational agent versus all approved cancer drugs. Although this screening approach begins as an empiric exercise, the successful combinations generate challenges for explaining the underlying mechanisms of action. The focus on drugs that are already approved provides a potentially fast route to clinical implementation.

Molecular Imaging of Cancer Drug Action

With the widespread availability of fluorine-18 fluorodeoxyglucose ( ¹⁸ F-FDG), a consensus was building in the late 1990s that positron emission tomography (PET) would emerge as a tool for functional assessment, which would complement anatomic imaging modalities. Since then, FDG has been highly successful as a general probe in many tumor types, providing additional information to help separate malignant from benign lesions and to monitor response to therapy.

FDG is now an approved agent for imaging. Its success has spurred interest in the development of other probes for PET imaging that are currently in the investigational stage of clinical evaluation, including fluorine-18 fluorothymidine ( ¹⁸ F-fluorothymidine; FLT). Liu et al. demonstrated the potential for FLT in a patient with uterine cancer. At baseline, the FLT image shows major uptake by the tumor, indicative of active proliferation. During treatment with sunitinib, uptake of FLT in the tumor decreased, which was interpreted as reduced proliferation. The image following the withdrawal of treatment exhibited a flare—that is, intensity that rebounded above the baseline value. Anatomic imaging by computed tomography (CT) readily identified the tumor and could monitor tumor size over the subsequent weeks or months, but FLT provided the ability to follow molecular pathways in real time.

Cancer Drug Delivery: Systemic Exposure

Once the appropriate drug has been chosen, the most important everyday question in clinical cancer pharmacology is the selection of an appropriate dose. The standard dose determined previously in population studies is a starting point for consideration, but what factors could make this dose too high or too low for individual patients? For many cancer drugs, evidence-based advice is not available. In some cases, guidance for dose adjustment is available based on prior courses of treatment or age.

Increasingly, cancer drugs are approved with information about dosage adjustment based on renal function testing, food intake, and the concurrent use of other drugs. All of these factors can produce variability in systemic exposure. Thus the delivery of drugs to both the tumor and normal tissues is affected. In addition to empiric data from clinical investigations for specific drugs, what are the principles that underlie these decisions based on drug delivery?

Clearance is at the top of the list for drug delivery parameters in Box 25.2 because it is the underlying factor with the greatest impact on dose adjustment in cancer drug delivery. As stated in Box 25.3 , clearance is the summation of all mechanisms for a drug to be removed from the systemic circulation, sometimes called total body clearance. Several specific applications of clearance for dosage adjustment are covered in the next few sections.

Bioavailability, which is the second concept listed in Box 25.2 , is a measure of how much drug enters the systemic circulation. Because of the shift toward oral therapy, bioavailability has risen sharply in importance. This concept is described further in the section Oral Cancer Drugs.

Half-life was previously the most discussed parameter for cancer drug delivery. However, its role is primarily in the development stage, to help explore frequency of administration. Once a drug has been approved for clinical practice, oncologists do not have a frequent need to know the specific value for half-life of a cancer drug. Other drug delivery parameters such as volume of distribution or protein binding can have value in specific situations, but only on rare occasions.