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.

Empirical approaches traditionally used to screen for cytotoxic agents are not optimal for MTAs. Rather, screening for MTAs should be target-based. The increasing number of potential targets and the availability of sophisticated high-throughput screening technology provide tremendous opportunities to screen an enormous set of diverse small molecular compounds for promising therapeutics.¹⁵ Furthermore, the availability of genetically engineered mouse models provide the opportunity to better screen compounds in vivo.¹⁶ A more in-depth discussion of these important drug discovery tools and their implications for the molecularly targeted drug development process is beyond the scope of this chapter.

Optimal development of an MTA requires careful assessment of pharmacokinetic (PK) and pharmacodynamic (PD) effects in relevant nonclinical models before initiating clinical trials. Preclinical in vivo pharmacologic and toxicologic testing is necessary to establish the starting dose and schedule for clinical trials, to evaluate effects on normal host tissue, and to help make predictions about serum and tissue levels required for target modulation, as well as effects on tumor growth. Currently, most in vivo efficacy studies involve human tumor cell murine xenograft models.¹⁷ However, xenograft models have limitations, including the requirement for an immunocompromised host, and they are not ideal for simulating the complex relationship between tumor and microenvironment, such as angiogenesis. Moreover, xenograft models have not been very predictive of drug efficacy in patients with cancer; activity in a particular histology in a xenograft tumor model does not closely correlate with activity in the same human cancer histology.¹⁸ However, agents that have activity against a broad range of tumor types in xenografts have a better chance of clinical activity than do agents that do not have activity against a broad range of tumor types. Major variables to consider in designing xenograft studies include the molecular characteristics of the tumor, site of implantation, size of the tumor at commencement of drug treatment, and dose and schedule of administration. Clearly, future development of MTAs would benefit from more predictive in vivo models. Although limitations exist, prudent use of genetically engineered mouse models in conjunction with traditional xenograft models holds promise for accelerating targeted drug development.¹⁷

Clinical Development of MTAs

Successful development of MTAs may require different strategies than those traditionally used for the development of conventional cytotoxic chemotherapeutic agents (Table 28-3).¹⁹ Consequently, the discovery of an increasing number of molecularly targeted compounds has created new challenges in drug development, both for dose determination and efficacy evaluation. In animal models, some of these newer agents are cytostatic in that they exhibit growth inhibitory and antimetastatic effects without causing impressive tumor regression. Although the specific effects of each class are dependent on the target or targets inhibited, in patients, compared with cytotoxic agents, MTAs are more likely to result in tumor growth inhibition than tumor regression. Pivotal clinical trials of sorafenib in patients with renal cell and hepatocellular carcinoma, for example, substantiate the cytostatic properties of this small-molecule VEGFR inhibitor, with results showing marked improvement in progression-free survival (PFS) with minimal objective tumor response by response evaluation criteria in solid tumors (RECIST) criteria.^12,20

Dose Determination

The primary objective of phase 1 trials of conventional cytotoxic agents ordinarily is to define maximum tolerated dose (MTD), under the assumption that the higher the dose, the greater the antitumor activity (Fig. 28-3, A). Thus the dose recommended for phase 2 efficacy trials is typically the MTD. However, MTAs are generally less toxic and, because of their selectivity, may be effective at doses much lower than the MTD (Fig. 28-3, B). MTAs act on specific targets differentially expressed or activated in cancer cells, and thus they tend to have a wider therapeutic index than traditional cytotoxics. Therefore increasing the dose in a traditional phase 1 trial to the point of normal tissue tolerance (MTD) may be an irrelevant or nonachievable end point with an MTA. Rather, target inhibition may be a better end point, with the primary objective of clinical trials being the determination of an “optimal biological dose,” the lowest dose that maximally inhibits the relevant target or pathway.^19,21

Phase 1 trials intended primarily to determine a dose that optimally inhibits a target in tumor tissue usually involve pre- and posttreatment tumor tissue acquisition. However, the requirement for tissue biopsies is costly and hampers clinical trial enrollment because only patients with tumors accessible for biopsy are eligible, and not all otherwise eligible patients consent to the procedure. Therefore in lieu of tumor biopsies, one strategy for evaluating target modulation and determining a biologically active dose is to use less-invasive procedures involving target or biomarker assessment in surrogate tissues expressing the target, such as circulating tumor cells (CTCs).22,23 For example, demonstrating a “biologically effective dose” in CTCs may serve as a guide in dose-finding trials. However, before an effect on target in surrogate tissue can be used for dose determination, it must be established that it is a true surrogate for drug effects in patients’ tumors. This need was exemplified in trials conducted with O⁶-benzylguanine, an inhibitor of O⁶-alkylguanine DNA alkyltransferase (AGT), as a modulator of resistance, in combination with bis-chloroethylnitrosourea in melanoma and other malignancies.²⁴ No difference was found in the efficacy of the combination compared with single-agent bis-chloroethylnitrosourea, although inhibition of AGT levels was demonstrated in peripheral blood mononuclear cells at the doses tested; however, tumor samples were not obtained to show that AGT was actually inhibited at the dose and schedule of O⁶-benzylguanine tested. The differential effect of O⁶-benzylguanine on AGT levels in tumor versus peripheral blood mononuclear cells was only established in a separate trial.²⁵

To define a biologically effective dose, it is essential to have a validated target (defined previously) and a reliable, reproducible assay to evaluate target inhibition. This requires having a clear understanding of the dynamics and consequences of target inhibition—specifically, the degree of target effect required for tumor growth inhibition, whether the target needs to be inhibited continuously or intermittently, and the target’s function in normal cells. Thus, optimal clinical development of MTAs requires extensive preclinical studies, including animal models that are predictive of eventual clinical effect and are applicable to thorough assay interrogation.²⁶ After the appropriate preclinical development of a reliable pharmacodynamic assay, the drug and its effect on tumor (as evaluated by the assay) should optimally be evaluated in first-in-human pre–phase 1 or “phase 0” studies before definitive phase 1 trials are initiated.^19,21,27

In addition to having the potential to start substantially earlier than traditional phase 1 trials, phase 0 trials provide a better opportunity to establish feasibility and qualify target assay methodology in limited numbers of human subjects before embarking on studies that involve larger numbers of patients who will receive higher and potentially toxic doses of the study agent. Phase 0 trials characteristically involve rigorous preclinical development of assays for target modulation and pharmacokinetic analysis in advance of clinical investigation, along with the use of real-time analysis of patient samples incorporated into the clinical trial.

Because these pilot pre–phase 1 studies involve a limited number of subjects and very limited drug exposure with no therapeutic intent, they may require less than the usual amount of preclinical toxicity data in accordance with the FDA guidance for Exploratory Investigational New Drug (IND) studies.²⁸ Several types of studies can potentially be conducted under the purview of an Exploratory IND designation, including:

1. Studies that provide important PK information (e.g., oral bioavailability);

2. Studies designed to select the most promising lead agent from several candidates;

3. Studies to determine whether a mechanism of action (e.g., target inhibition) observed in animal models can be observed in humans; and

4. Studies to evaluate in vivo binding properties of novel imaging agents using extremely small doses of the test agent (“microdosing”).

Another approach to determine an optimal dose of an MTA is to conduct a randomized phase 2 trial with a clinical response end point comparing two or more doses. This approach may be necessary if dose selection cannot rely on a biological marker. However, for this design to be effective, the agent must have some degree of clinical activity, yielding objective responses or affecting PFS. Under these circumstances, the randomized phase 2 design is useful in selecting a maximally efficacious dose with the least amount of toxicity that is applicable to subsequent phase 3 trials.²⁹

Rational Use of Functional and Molecular Imaging

Interest in utilizing novel imaging technologies for the development of MTAs is increasing.40,43 Molecular imaging has the potential to monitor both normal and abnormal biochemical and physiological parameters in individual patients. Unlike anatomic imaging, molecular imaging displays biochemical and physiological abnormalities underlying disease, rather than the structural consequences of these abnormalities. Functional and molecular imaging can be helpful in phase 1 studies for dose determination, as discussed earlier, and may be applicable as noninvasive tools to detect drug-target effect, as well as to provide early evidence of efficacy. It may also prove useful in patient selection.

Detecting and monitoring responsiveness to a cytostatic agent using functional imaging, such as [¹⁸F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), has been evaluated in detail. Uptake of the glucose analogue FDG by tumor cells is a marker of glucose metabolism, number of viable cells, and the level of cell proliferation in a tumor mass. Thus treatment that causes metabolic changes associated with inhibition of tumor cell proliferation or death should have a relatively rapid effect on the degree of FDG uptake. Decrease in the maximum standardized uptake value on FDG-PET was found to be an early predictor of response to imatinib therapy for patients with advanced GIST.⁴⁴ These changes can occur as early as 24 to 48 hours after initiating imatinib and predict for objective response or stabilization of disease as determined subsequently by computed tomography scanning. Conversely, failure to achieve a decrease in FDG-PET uptake after treatment with imatinib is predictive of a poor clinical response for patients with GIST.

Another area of mounting interest is the use of PET and novel imaging probes to visualize cancer targets and processes in vivo.⁴¹ These probes include a wide variety of small molecules, peptides, and antibodies to image processes, including cell proliferation, angiogenesis, apoptosis, hypoxia, PK, and multidrug resistance. In addition, probes exist or are in development to image tumor cell receptors such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2, and bombesin, to name a few.⁴⁵ The investigational radiopharmaceutical agent 16 alpha-[¹⁸F]-fluoro-17 beta-estradiol (FES), which is synthesized by adding the radioactive element, ¹⁸F, in the D ring of estradiol, has been used to assess the pharmacodynamic effect of tamoxifen, fulvestrant, and aromatase inhibitors,⁴⁶ and the level of uptake of FES has been correlated with tumor response to tamoxifen.⁴⁷

3′-[¹⁸F]Fluoro-3′-deoxythymidine PET is particularly useful as an in vivo marker of tumor cell proliferation and for monitoring response to antiproliferative therapy.⁴⁸ Finally, interest in the use of optical imaging by spectral fluorescence enhancement is increasing because of its sensitivity and ability to detect very small clusters of cancer cells.⁴⁹ However, optical imaging has the disadvantage of being limited to settings where direct imaging is possible (e.g., intraoperative or endoscopic), because whole-body imaging is not yet feasible. Progress in the clinical application of molecular imaging depends on the development of probes that have better sensitivity and specificity, as well as increases in the signal-to-noise or spatial resolution of molecular imaging devices. Unquestionably, noninvasive imaging will play an increasingly important role in the development and application of molecularly targeted therapy.

Patient Selection

An important consideration in the enrollment of patients on exploratory efficacy trials of MTAs is the use of patient selection to optimize the chance of a positive effect. This optimization is not feasible unless the patients enrolled have tumors that express or have a high probability of expressing the target. Until recently, essentially all phase 2 trials have evaluated a drug in a specific histologic type (e.g., breast cancer or NSCLC) on the presumption that a given histologic type represents a relatively uniform disease entity. However, an increasing amount of evidence shows that tumors are heterogeneous at the molecular level within any given histologic type and that genetic variations in the tumor may significantly affect drug sensitivity. Clearly, patient selection beyond histologic type is becoming increasingly important in drug development, especially for agents likely to benefit specific patient subsets. For example, the efficacy of crizotinib in patients with advanced NSCLC whose tumors harbor a specific type of alteration in the anaplastic lymphoma receptor tyrosine kinase (ALK) gene,⁵⁰ and the efficacy of vemurafenib in patients with metastatic melanoma carrying the V600E BRAF mutation,⁵¹ might have been overlooked in trials of these agents in larger, unselected groups of patients with NSCLC or melanoma.

Some mutations may confer sensitivity to a particular agent, whereas other mutations confer resistance, such as exon 11 mutations of c-Kit in GIST⁵² and T315I BCR-ABL mutations in CML, respectively, in the case of imatinib. On the other hand, the effect of inhibiting the same mutation may be context dependent based on disease histology, as evidenced by the >50% overall response rate to vemurafenib in patients with advanced melanoma who carried the BRAF^V600E mutation as opposed to a <5% overall response rate in patients with advanced colorectal carrying the same mutation.^53,54 It has been shown that vemurafenib treatment, with inhibition of the BRAF^V600E oncoprotein, results in feedback activation of EGFR, which is present on a majority of colorectal cancer cells, resulting in resistance.⁵⁴ This finding might explain the poor response of patients with colorectal cancer to vemurafenib treatment. In addition, targeting BRAF mutation in tumors bearing other types of mutations such as in RAS or wild-type BRAF can lead to excessive signaling of the RAF-MEK-ERK pathway with unintended clinical consequences, such as the development of keratoacanthomas and squamous cell carcinomas.⁵⁵

The development and FDA approval of vemurafenib for the treatment of melanoma is limited to patients with BRAF^V600-mutation–positive tumors. To select patients for vemurafenib treatment, the FDA concurrently approved the Cobas 4800 BRAF^V600 mutation test. The approved indication for vemurafenib specifically includes the limitation that treatment of patients with wild-type melanoma is not recommended because essentially no safety or efficacy data are available for these patients. The decision to limit the development of vemurafenib for melanoma to patients with BRAF mutations was reasonable given what was known about the drug’s mechanism of action and existing nonclinical data. However, in general, it is useful to obtain at least some information about how a drug affects target (test)-negative as well as target (test)-positive patients; the data may be important for the validation of the biomarker assay and to make certain the drug is not effective in test-negative patients. Crizotinib was approved by the FDA for the treatment of patients with ALK-rearrangement–positive NSCLC based on two single-arm trials demonstrating unprecedented overall response rates of 50% to 60%. However, preliminary data from a small cohort of ALK-negative patients revealed a potentially promising response rate of about 20%, suggesting that further evaluation of crizotinib in patients with ALK-negative tumors is warranted.⁵⁶ The response in ALK-test–negative patients could be due to activity against other crizotinib targets such as MET or ROS1, independent of the drug’s effect on ALK.

Thus development of MTAs requires a detailed understanding of the target in a disease-specific context, the consequences of target inhibition, and the relationship of target inhibition to the observed antitumor effect. In light of the importance for MTA development of determining the presence of the target or specific molecular aberration in the tumor, it is essential to have validated assays available for use in clinical practice to allow appropriate patient selection.

Rational Approaches to Combination Therapy

An increasing number of MTAs in development have some clinical activity against selected types of cancer. However, with few exceptions, such as imatinib for the treatment of CML and GIST, MTAs have limited effectiveness as single agents, and any clinical benefit is restricted to a relatively small proportion of patients. Because molecular abnormalities in cancer are usually complex, and multiple processes and pathways are responsible for tumor proliferation and survival, the likelihood that engaging any one specific target will have a major antitumor impact is relatively low. Consequently, there is considerable interest in combining MTAs that affect two or more critical targets with the expectation that such regimens will have more pronounced antitumor activity.³ Because of the large number of targets and MTAs in development, the number of potential combinations is almost limitless. Thus the design of clinical trials evaluating MTAs in combination should not be empirical but based on a sound scientific rationale. Various strategies are being used to devise rational drug combinations that optimize antitumor efficacy while limiting toxicity³ (Table 28-4).

As noted previously, the use of MTAs in combination with standard chemotherapy has met with mixed success. Among the successes are trials demonstrating improved survival with the addition of trastuzumab in persons with breast cancer³⁴ and bevacizumab in persons with colorectal cancer^35,36 and NSCLC.⁵⁷ Among the failures are randomized trials of gefitinib and erlotinib combined with chemotherapy in persons with NSCLC.^37,38 The reasons these latter combination trials failed to show superiority over chemotherapy alone are not clear, but they include the possibility of suboptimal dosing (as may have been the case for gefitinib), antagonism with the chemotherapy agents, or dilution of the study population with patients harboring insensitive tumors.³⁹ Combining MTAs can also cause chronic toxicities that limit dosing and compromise efficacy. Consequently, there is a need to better elucidate these variables by using reliable predictive preclinical models for efficacy and toxicity and appropriately designing early-phase clinical trials to address PK, PD, efficacy, and toxicity considerations in advance of large phase 2 and phase 3 clinical trials.

Rational combinations of MTAs that have been evaluated clinically maximize inhibition of a single target or pathway, inhibit two or more parallel cellular processes or pathways, inhibit tumor cell processes and the microenvironment in concert, and use epigenetic remodeling agents to increase the expression of a target (Table 28-4). For example, inhibitors of DNA methyltransferase and histone deacetylase are being studied alone and in combination to restore the expression of tumor suppressor genes and other genes silenced by DNA methylation, such as hormone receptors and tumor antigens, to make tumor cells more sensitive to targeted hormonal and vaccine therapy, respectively.^58,59

The potential advantages of using two or more MTAs in combination are clear. Another approach is to design a single agent with specificity against multiple targets of interest. One successful example is the small-molecule human epidermal growth factor receptor-2/EGFR inhibitor lapatinib, which recently received FDA approval for the treatment of advanced breast cancer.⁶⁰ Avoiding the complex trial designs that may be necessary to isolate the effects of each agent, as well as the potentially complicated intellectual property negotiations with another company needed to perform combination MTA trials, are incentives for pharmaceutical companies to take this approach. Regardless of whether developing single agents with multiple targets or combinations of agents that focus on a limited number of targets is the drug development strategy employed, it is important to minimize the risk of clinical toxicity by avoiding overlapping or off-target toxicities.

Conclusions and Future Directions

Recent advances in cancer genetics, biology, and drug discovery, as well as an enhanced capacity to characterize tumors at the molecular level, have created many opportunities for improved treatment of malignancy and have accelerated the development of new molecularly targeted therapeutics. The development of MTAs with greater selectivity and less toxicity than conventional chemotherapeutics during the past decade has been remarkable. However, this paradigm shift has presented new challenges.

The development of MTAs requires different strategies than those traditionally applied to conventional, nontargeted chemotherapy. Empirical methods for the development of standard agents are mostly inadequate for the development of MTAs. Rather, optimal MTA development from discovery through clinical testing requires the integration of innovative methods that are primarily target-based. Furthermore, novel clinical trial designs have evolved with the introduction of MTAs. Most phase 1 trials of MTAs should have as a primary objective the determination of a recommended phase 2 dose based on optimal target modulation, because escalation to MTD may not be needed or feasible; however, accomplishing this goal successfully requires reliable procedures for tissue acquisition and handling in conjunction with authenticated assay methodologies to measure target modulation. These target assay procedures are best developed and performed in preclinical in vitro and in vivo models and, if feasible, in phase 0 clinical studies in a limited number of patients in advance of large, more definitive trials.²¹

The development of MTAs has moved cancer therapeutics rapidly along the road toward individualized cancer care. Advancements in genomics, proteomics, and other platforms for identifying potential new therapeutic targets and drugs, along with the effective integration of PD assessment of drug effects on tumor targets using tissues or molecular imaging in clinical trials, will result in continuing major strides toward the more selective treatment of cancer.