Therapeutic Targeting of Cancer Cells: Era of Molecularly Targeted Agents



Therapeutic Targeting of Cancer Cells


Era of Molecularly Targeted Agents


Shivaani Kummar, Anthony J. Murgo, Joseph E. Tomaszewski and James H. Doroshow



Summary of Key Points



• Molecularly targeted anticancer agents (MTAs) are those that selectively target specific molecular features of cancer cells such as aberrations in genes, proteins, or pathways that regulate tumor growth, progression, and survival.


• 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.


• The development of MTAs requires innovative strategies that differ from those traditionally applied to nontargeted conventional chemotherapy.


• 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.


• Primary objectives of clinical trials of MTAs differ from those used in trials of conventional chemotherapy. An important objective in phase 1 trials of MTAs should be to determine a phase 2 dose based on optimal target modulation (i.e., a biologically effective dose) rather than on maximum tolerated dose. In addition, objective tumor response may not be an adequate end point for efficacy evaluations of MTAs that have a primarily cytostatic effect. Alternate end points, such as progression-free survival, may be more appropriate.


• Functional and molecular imaging plays an increasingly important role in the development of MTAs.


• Patient selection is critical for trials with MTAs.



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).



Table 28-1


U.S. Food and Drug Administration–Approved Molecularly Targeted Agents



































































































































FDA Approved Agents(s) Target Disease Indication
Imatinib mesylate BCR-ABL, KIT, PDGFR-β Ph+ CML, Ph+ ALL, chronic monomyelocytic leukemia, dermatofibrosarcoma protuberans
Dasatinib BCR-ABL, Src family kinases Ph+ CML
Nilotinib hydrochloride monohydrate BCR-ABL Ph+ CML
All-trans retinoic acid PML-RAR Acute promyelocytic leukemia
Sunitinib malate VEGFR, KIT, PDGFR-α GIST, pancreatic neuroendocrine tumors, kidney cancer
Vemurafenib BRAFV600E mutation BRAFV600E-positive melanoma
Crizotinib ALK tyrosine kinase ALK-positive non–small cell lung cancer
Erlotinib EGFR Non–small cell lung cancer
Panitumumab EGFR Colorectal cancer
Cetuximab EGFR Head and neck cancer, colorectal cancer
Trastuzumab ErbB-2 HER2 overexpressing breast cancer
Lapatinib ErbB-2 HER2 overexpressing breast cancer
Vismodegib Hedgehog pathway Advanced/metastatic basal cell carcinoma
Brentuximab vedotin CD30 Hodgkin lymphoma, anaplastic large cell lymphoma
Ofatumumab CD20 CLL
Ibritumomab Non-Hodgkin lymphoma
Rituximab B-cell non-Hodgkin lymphoma
Alemtuzumab CD52 B-cell chronic lymphocytic leukemia
Bevacizumab VEGF Colorectal cancer, non–small cell lung cancer, renal cell carcinoma
Vandetanib VEGFR Medullary thyroid cancer
Sorafenib VEGFR, B-Raf kinase Kidney cancer, hepatocellular cancer
Pazopanib VEGFR Soft tissue sarcomas, kidney cancer
Axitinib VEGFR Kidney cancer
Temsirolimus mTOR Renal cell carcinoma
Everolimus mTOR Renal cell carcinoma, advanced pancreatic neuroendocrine tumors
Azacitidine DNA methyltransferase Myelodysplastic syndrome
Decitabine DNA methyltransferase Myelodysplastic syndrome
Vorinostat Histone deacetylase Cutaneous T-cell lymphoma
Romidepsin Histone deacetylase Cutaneous T-cell lymphoma
Bortezomib Proteosome Multiple myeloma
Ipilimumab Cytotoxic T-lymphocyte–associated antigen 4 Metastatic melanoma


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ALK, Anaplastic lymphoma receptor tyrosine kinase; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; HER2, human epidermal growth factor receptor-2; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.



Table 28-2


Classes of Molecularly Targeted Anticancer Agents under Clinical Development










































































































































































Target Role of Target Disease Indication References
FMS-like tyrosine kinase-3 (FLT-3) Regulates cell cycle progression, proliferation, and survival Acute myeloid leukemia 61
Poly (ADP-ribose) polymerase (PARP) Single-strand DNA break repair Various solid tumors, BRCA-positive breast and ovarian cancer 62
O6-Alkylguanine DNA alkyltransferase Prevents intrastrand DNA cross-links   63
Insulin-like growth factor-1 receptor (IGF-1R) Regulates cell proliferation, differentiation and survival Various adult and pediatric tumors 64
Insulin-like growth factor binding protein-3 (IGFBP3) Regulates cell proliferation, differentiation and survival Various adult and pediatric tumors 64
Hypoxia-inducible factor-1α (HIF-1α) Regulates tumor cell response to oxygen deprivation HIF-1α–expressing solid tumors 65
αvβ3 integrin receptor Involved in cell adhesion Glioma and various solid tumors 66, 67
Syk Inhibits differentiation and induces growth factor–independent proliferation of pre–B cells B-cell lymphomas 68
MET Regulates cell growth, anti-apoptosis, altered cytoskeletal function Solid tumors 69
MEK1/2 Regulates tumor cell proliferation and survival Various solid tumors, melanoma 70, 71
RAS Promote cell proliferation and survival Acute myeloid leukemia 72
RAF Regulates tumor cell proliferation and survival Melanoma and other solid tumors 73
RET Regulates tumor cell proliferation and survival Medullary thyroid cancer 74
Akt kinase Regulator of cell cycle and apoptotic pathway Variety of solid and hematologic cancer 75
Clusterin Promotes cell survival Variety of solid tumors 76
HSP-90 Chaperone for several oncogenic proteins and growth factors Myeloid leukemia and solid tumors 77
Bcl-2 Antiapoptotic Lymphomas, solid tumors 78
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) Apoptotic mechanism Various types of cancer 79
Angiopoietin 1 and 2 Reduces blood flow to tumor Solid tumors 80
DNA methyltransferase inhibitors Reexpression of genes silenced by methylation Myelodysplastic syndrome, acute myeloid leukemia, various solid tumors in combination with chemotherapy or radiation 58, 59
Src inhibitors Src family kinases that interact with other growth, proliferation, and angiogenic pathways Solid tumors 81
VEGFR, VEGF Reduces blood flow to tumor Solid tumors 11
CD105 (Endoglin) Reduces blood flow to tumor Solid tumors 82
HDAC Reexpression of silenced genes T-cell lymphoproliferative disorders, adenoid cystic cancer, solid tumors 83
Retinoid receptor Increase in reactive oxygen species and dihyceramide levels resulting in cytotoxicity T-cell lymphoproliferative disorders 84, 85
Wee 1 DNA repair and cell cycle (abrogates the G2 cell cycle checkpoint) Solid tumors 86
BTK inhibitor Bruton tyrosine kinase Lymphoma, chronic lymphocytic leukemia 87
Gamma secretase inhibitor Notch pathway Solid tumor 88
CDK inhibitors Cyclin-dependent kinases (cell cycle, proliferation) Solid tumors 89
CHK1 inhibitors Checkpoint kinases (cell cycle) Solid tumors 90
DNA minor groove DNA damage Solid tumors 91
SMAC mimetic, IAP inhibitor Induction of apoptosis Solid tumors 92


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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 addiction77 (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


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Figure 28-1 Models of oncogene addiction. A, The “genetic streamlining” theory postulates that nonessential pathways (top, light grey) are inactivated during tumor evolution, so that dominant, addictive pathways (red) are not surrogated by compensatory signals. Upon abrogation of dominant signals, a collapse in cellular fitness occurs and cells experience cell-cycle arrest or apoptosis (bottom, red to gray shading). 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 (dashed lines, bottom) 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. (Reprinted with permission from Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 2011;3(11):623–36.)

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.




Box 28-2


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 biological test cascade to support the drug discovery program to allow evaluation of lead compounds and to select a development candidate for preclinical toxicology testing and clinical trials


• Feasibility of establishing, validating, and running an affordable and robust high-throughput screen

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Jun 13, 2016 | Posted by in ONCOLOGY | Comments Off on Therapeutic Targeting of Cancer Cells: Era of Molecularly Targeted Agents

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