Therapeutic Targeting of Cancer Cells: Era of Molecularly Targeted Agents

Summary of Key Points

Molecularly targeted anticancer agents (MTAs) are designed to target specific molecular features that are either uniquely or differentially expressed in cancer cells compared with normal host cells.
Molecular targets include the following: products of activating 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.
Successful development of an MTA depends largely on the importance of the target in controlling tumor cell proliferation and survival and effective modulation of the target in the tumor at clinically achievable concentrations.
The development of MTAs requires innovative strategies that differ from those traditionally applied to conventional chemotherapy. An important objective in phase I trials of MTAs should be to determine a phase II dose based on optimal target modulation (i.e., a biologically effective dose) rather than solely on a toxicity-driven endpoint, such as the maximum tolerated dose. In addition, objective tumor response may not be an adequate end point for efficacy evaluations of some MTAs that have a primarily cytostatic effect. Alternate end points, such as progression-free survival, may be more appropriate.
Functional and molecular imaging will play an increasingly important role in the development of MTAs.
Patient selection is critical for trials with MTAs.

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 less toxic anticancer therapeutics. Furthermore, progress in understanding cancer biology and in the development of MTAs can shape cancer therapeutics into a more individualized form of cancer medicine. This chapter reviews 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 ( Table 26.1 ).

Table 26.1

US Food and Drug Administration (FDA)–Approved Molecularly Targeted Agents

FDA-Approved Agent	Target	Disease Indication(s)
Alemtuzumab	CD52	B-cell CLL
Atezolizumab	PD-1	1. Locally advanced or metastatic urothelial carcinoma with disease progression after platinum-containing chemotherapy 2. Metastatic NSCLC with disease progression after platinum-containing chemotherapy
Bevacizumab	VEGF	1. Metastatic CRC 2. Nonsquamous NSCLC 3. GBM 4. Metastatic RCC 5. Cervical cancer 6. Platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer
Blinatumomab	Bispecific CD19-directed CD13 T-cell engager	Ph− relapsed or refractory B-cell precursor ALL ^a
Cetuximab	EGFR	1. KRAS wt+, EGFR-expressing CRC 2. Advanced, recurrent, of metastatic HNSCC
Dinutuximab	Glycolipid GD2-binding monoclonal antibody	Pediatric patients with high-risk neuroblastoma who have achieved a PR to first-line multiagent, multimodality therapy
Ibritumomab tiuxetan	CD20	Relapsed or refractory, low-grade follicular B-cell NHL
Ipilimumab	CTLA4	1. Unresectable or metastatic melanoma 2. Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy
Obinutuzumab	CD20	1. Untreated CLL 2. Follicular lymphoma relapsed after or refractory to a rituximab-containing regimen
Olaratumab	PDGFRα	Soft tissue sarcoma ^a
Nivolumab	PD-1	1. BRAF V600 wt+ unresectable or metastatic melanoma 2. BRAF V600 mutation unresectable or metastatic melanoma ^a 3. Unresectable or metastatic melanoma in combination with ipilimumab ^a 4. Metastatic NSCLC and progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations with disease progression on FDA-approved therapy for these aberrations 5. Advanced RCC after prior antiangiogenic therapy 6. Classical HL relapsed or progressed after HSCT and posttransplantation brentuximab vedotin ^a
Ofatumumab	CD20	CLL
Panitumumab	EGFR	KRAS wt+ metastatic CRC
Pembrolizumab	PD-1	1. Unresectable or metastatic melanoma 2. Metastatic NSCLC with tumors expressing PD-L1 and disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations with disease progression on targeted therapy ^a 3. Recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy ^a
Pertuzumab	HER2	1. HER2+ metastatic breast cancer 2. HER2+ locally advanced, inflammatory, or early-stage breast cancer
Ramucirumab	VEGFR2	1. Gastric cancer 2. NSCLC 3. Colorectal cancer
Rituximab	CD20	1. NHL 2. CLL 3. Rheumatoid arthritis 4. Granulomatosis with polyangiitis and microscopic polyangiitis
Siltuximab	IL-6	Patients with multicentric Castleman disease who are HIV and HHV-8 negative
Ziv-aflibercept	VEGF, PlGF	Metastatic colorectal cancer resistant to or progressed following an oxaliplatin-containing regimen
Erwinia l -asparaginase	Asparaginase	ALL with hypersensitivity to Escherichia coli– derived asparaginase
Ado-trastuzumab emtansine	HER2+	HER2+ metastatic breast cancer
Brentuximab	CD30	1. Classical HL after failure of auto-HSCT or after failure of at least two prior multiagent chemotherapy regimens in patients who are not candidates for auto-HSCT 2. Patients with classical HL at high risk for relapse or progression as post–auto-HSCT consolidation 3. Systemic anaplastic large cell lymphoma after one prior multiagent chemotherapy regimen ^a
Afatinib	EGFR	1. Metastatic NSCLC with EGFR exon 19 deletion of exon 21 (L858R) substitution 2. Metastatic squamous NSCLC progressed after platinum-based chemotherapy
Alectinib	ALK	ALK+ NSCLC ^a
Axitinib	VEGFR	Advanced RCC after failure of systemic therapy
Bosutinib	BCR-ABL, Src	Chronic, accelerated, or blast phase Ph+ CML
Cabozantinib	VEGFR2, c-MET	Patients with advanced RCC who have received prior antiangiogenic therapy
Ceritinib	ALK	Patients with ALK+ metastatic NSCLC that progressed or who are intolerant of crizotinib ^a
Crizotinib	ALK	1. ALK+ metastatic NSCLC 2. ROS1+ metastatic NSCLC
Dabrafenib	RAF	Unresectable or metastatic melanoma with BRAF V600E mutation
Dasatinib	BCR-ABL, Src	1. Ph+ CML in chronic phase 2. Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML after prior imatinib 3. Ph+ ALL
Erlotinib	EGFR	1. Metastatic NSCLC with EGFR exon 19 deletion of exon 21 (L858R) substitution 2. Locally advanced or metastatic NSCLC progressed after first-line platinum-based chemotherapy 3. Locally advanced, unresectable, or metastatic pancreatic cancer
Everolimus	mTOR	1. Hormone receptor–positive HER2− breast cancer 2. Progressive neuroendocrine tumors of pancreatic origin, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin 3. Advanced RCC 4. Renal angiomyolipoma and tuberous sclerosis complex
Ibrutinib	BTK	1. Mantle cell lymphoma ^a 2. CLL/SLL with or without 17p deletion 3. Waldenström macroglobulinemia
Idelalisib	PI3K	1. CLL 2. Relapsed follicular B-cell NHL 3. SLL
Imatinib	BCR-ABL, KIT, PDGFRβ	1. Ph+ CML 2. Ph+ ALL 3. MDS or myeloproliferative diseases with PDGFR gene rearrangements 4. Aggressive systemic mastocytosis with D816V c-kit mutation 5. Hypereosinophilic syndrome chronic monomyelocytic leukemia, dermatofibrosarcoma protuberans
Lapatinib	HER-2, EGFR	1. HER2-overexpressing advanced or metastatic breast cancer progressed through trastuzumab 2. HER2-overexpressing hormone receptor–positive metastatic breast cancer
Lenvatinib	VEGFR1, VEGFR2, VEGFR3 FGFR PDGFRα	1. Locally recurrent or metastatic, progressive, radioactive iodine–refractory DTC 2. RCC following prior antiangiogenic therapy
Nilotinib	BCR-ABL	Ph+ CML progressed on imatinib
Osimertinib	EGFR T790M	NSCLC with EGFR T790M mutation progressed on EGFR TKI ^a
Palbociclib	CDK 4/6 inhibitor	Hormone receptor–positive, HER2− advanced or metastatic breast cancer ^a
Pazopanib	VEGFR, PDGFR, FGFR, c-KIT	1. RCC 2. Soft tissue sarcoma
Ponatinib	BCR-ABL	1. T315I+ CML or T315I+ Ph+ ALL 2. Ph+ ALL or CML progressed on prior TKI
Regorafenib	VEGFR2, TIE2	1. Metastatic CRC 2. GIST progressed on imatinib and sunitinib
Ruxolitinib	JAK	1. Intermediate- or high-risk myelofibrosis 2. Polycythemia vera with inadequate response or intolerance of hydroxyurea
Sorafenib	VEGFR, PDGFR, RAF	1. Unresectable HCC 2. RCC 3. Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment
Sunitinib	PDGFR, VEGFR, c-KIT, RET, CD114, CD135	1. GIST progressed on imatinib 2. Advanced RCC 3. Pancreatic neuroendocrine tumors
Trametinib	MEK	Unresectable or metastatic melanoma with BRAF V600E or V600K mutation
Vandetanib	VEGFR, EGFR, RET	Medullary thyroid cancer
Vemurafenib	BRAF	Unresectable or metastatic melanoma with BRAF V600E mutation
Abiraterone acetate	CYP17 inhibitor	Metastatic castrate-resistant prostate cancer
Azacitidine	DNMT	Myelodysplastic syndrome
Belinostat	HDAC	Relapsed refractory peripheral T-cell lymphoma ^a
Bortezomib	Proteosome inhibitor	MM, mantle cell lymphoma
Carfilzomib	Proteosome inhibitor	MM
Decitabine	DNMT	Myelodysplastic syndrome
Enzalutamide	AR	Metastatic castrate-resistant prostate cancer
Omacetaxine Mepesuccinate	A-site cleft of ribosomes	Chronic or accelerated phase CML with resistance to two or more TKIs ^a
Olaparib	PARP	BRCA mutated ovarian cancer after three or more prior lines of chemotherapy
Panobinostat	HDAC	MM after two prior regimens, including bortezomib and an immunomodulatory agent
Romidepsin	HDAC	1. Cutaneous T-cell lymphoma 2. Peripheral T-cell lymphoma
Temsirolimus	mTOR	RCC
Vismodegib	Hedgehog	Basal cell carcinoma
Vorinostat	HDAC	Cutaneous T-cell lymphoma
Radium-223 dichloride	Alpha particle–emitting radioactive agent	Hormone-refractory prostate cancer with symptomatic bone metastases and no known visceral metastatic disease

ALK, Anaplastic lymphoma receptor tyrosine kinase; ALL, acute lymphocytic leukemia; AR, androgen receptor; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CRC, colorectal cancer; CTLA4, cytotoxic T-lymphocyte antigen 4; DNMT, DNA methyltransferase; DTC, differentiated thyroid cancer; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GBM, glioblastoma multiforme; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HCST, hematopoietic stem cell transplantation; HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; HHV, human herpesvirus; HL, Hodgkin lymphoma; HNSCC, head and neck squamous cell carcinoma; JAK, Janus kinase; MDS, myelodysplastic syndrome; MM, multiple myeloma; mTOR, mammalian target of rapamycin; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; PARP, poly (ADP-ribose) polymerase; PDGFR, platelet derived growth factor receptor; PD-1, programmed death receptor 1; Ph+, Philadelphia chromosome positive; PR, partial response; RCC, renal cell carcinoma; RET, rearranged during transfection; SLL, small lymphocytic lymphoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; wt, wild-type.

a Indication approved under accelerated approval.

The most promising molecular targets are those solely responsible for sustaining tumor growth and survival without playing a significant role in normal cells—providing the therapeutic window that allows highly efficacious doses to be administered safely. One of the best examples 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). 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 platelet-derived growth factor receptor (PDGFR) and KIT, and is highly effective in the treatment of gastrointestinal stromal tumors (GISTs) bearing activating c-KIT mutations and in some GISTs bearing activating PDGFR mutations.

Unfortunately, most human tumors are genetically complex and do not have a single critical target, and the relative importance of a target in different tumors may vary. The existence of multiple abnormalities in one or more molecular pathways driving growth and survival contributes to resistance and provides a rationale for treatment strategies combining two or more targeted agents. 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 ( Fig. 26.1 ), 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, 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.

Figure 26.1, Models of oncogene addiction. (A) The “genetic streamlining” theory postulates that nonessential pathways (top; gray) are inactivated during tumor evolution, so the dominant, addictive pathways (red) are not surrogated by compensatory signals. On abrogation of dominant signals, a collapse in cellular fitness occurs and cells experience cell cycle arrest or apoptosis ( bottom; red and gray ). (B) In the “oncogenic shock” model, addictive oncoproteins (e.g., RTKs, red triangle ) trigger at the same time prosurvival and proapoptotic signals ( top; red and blue pathways, respectively). Under normal conditions, the prosurvival outputs dominate over the proapoptotic ones (top), but after blockade of the addictive receptor, the rapid decline in the activity of survival pathways (bottom; dashed lines) subverts this balance in favor of death-inducing signals, which tend to last longer and eventually lead to apoptotic death. (C) Two genes are considered to be in a synthetic lethal relationship when loss of one or the other is still compatible with survival but loss of both is fatal. In the top panel, biochemical inactivation of pathway A (gray) has no effect on cell viability because pathway B (red), which converges at some point on a common substrate or effector (yellow), has compensating activity. When the integrity of pathway B is disrupted (bottom), the common downstream biochemical function is lost, and again cancer cells may experience cell cycle arrest or apoptosis.

Preclinical Development of Molecularly Targeted Anticancer Agents

The discovery and development of molecularly targeted therapies require 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 26.1 and Fig. 26.2 ). 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. The target validation process (i.e., that affecting the target inhibits tumor growth, progression, or survival) involves a variety of preclinical approaches, including genetic, cell-based, and animal models. Validation and prioritization of molecular targets for therapeutic development depend on a variety of criteria, taking into consideration chemical, biologic, clinical, and practical factors ( Box 26.2 ). The next major step is finding or synthesizing compounds directed against that target.

Box 26.1

Steps in Discovery and Preclinical Development of Molecularly Targeted Therapy

Identify molecular target against which an agent will be developed
Validate molecular target—affecting the target inhibits tumor growth or survival
Screen for compounds that “hit” target—high-throughput screening
Optimize compounds—select or modify structure to increase activity and selectivity while maintaining favorable pharmacologic drug properties
Qualify assay methodologic methods for measuring drug levels and drug-target effect, in vitro and in animal models
Evaluate lead drug(s) in vivo for efficacy and safety
Prioritize and select drug candidate(s) for clinical testing
Conduct necessary preclinical animal toxicologic and pharmacokinetic studies to support an investigational new drug application for first-in-human trial

Figure 26.2, Central role of high-throughput screening in the mechanism-based drug discovery process.

Box 26.2

Modified from Aherne GW, McDonald E, Workman P. Finding the needle in the haystack: why high-throughput screening is good for your health. Breast Cancer Res. 2002;4(4):148–154.

Validation Criteria and Prioritization of New Targets for Drug Screening

High frequency of genetic or epigenetic deregulation of the molecular target or pathway in human cancer indicates that the target or pathway is likely important in driving the disease.
Linkage of the deregulation to clinical outcome strengthens the case for causal involvement.
Evidence in a model system that the target pathway causes or contributes to the malignant phenotype demonstrates a direct causal role in malignancy.
Demonstration of reversal of the malignant phenotype provides greater confidence that modulation of the target by a drug will produce an anticancer effect.
Demonstration of “drugability” of the target—for example, enzymes are generally much more “drugable” than are large-domain protein-protein interactions.
Availability of a robust, efficient biologic test cascade to support the drug discovery program to allow evaluation of lead compounds and to select a development candidate for preclinical toxicologic testing and clinical trials.
Feasibility of establishing, validating, and running an affordable and robust high-throughput screen.
Potential for a drug design approach based on structural biology; such an approach, based on an x-ray crystallographic or nuclear magnetic resonance spectroscopy structure, can be highly complementary to a screening strategy.

Empiric 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 technologies have resulted in tremendous opportunities to screen an enormous set of diverse small-molecular compounds for promising therapeutics. Furthermore, the availability of genetically engineered mouse models provides the opportunity to better screen compounds in vivo. 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 initiation of 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. 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. Moreover, xenograft models have not been very predictive of drug efficacy in patients with cancer; activity in a particular histologic type in a xenograft tumor model does not closely correlate with activity in the same human cancer histologic type. However, agents that have activity against a broad range of tumor types in xenografts have a better chance of clinical activity. 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.

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