Targeting oncogenic drivers.

Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 1–14 (DOI: 10.1159/000355895)

Targeting Oncogenic Drivers Yujie Zhao · Alex A. Adjei Department of Medicine, Roswell Park Cancer Institute, Buffalo, N.Y., USA

Abstract

Cancer is the most common human genetic disease, developing after a series of gene alterations that lead to uncontrolled growth of cells. While a small number of hereditary cancer syndromes are directly caused by germline mutations, the vast majority of human cancers are driven by sequentially accumulated somatic genetic and epigenetic changes. These genetic alterations ultimately lead to acquisition of the hallmarks of malignancy comprising resistance to cell death, sustained proliferative signaling, activation of invasion and metastasis mechanisms, angiogenesis induction and replicative immortality [1]. Additionally, inheritable genetic variations also contribute to cancer development by influencing the susceptibility to malignancy transformation [2, 3].

Downloaded by: Univ. of California Davis 128.120.194.195 - 1/10/2015 12:31:46 AM

Cancer is a genetic disease caused by a series of somatic and/or germline mutations. The roles of oncogenes and tumor suppressors in cancer molecular origin have been well established. Targeting oncogene products has become an attractive therapeutic strategy with great clinical success, whereas tumor suppressors are considered ‘undruggable’ because current technology is not able to restore tumor suppressor function in metastatic disease. Although systematic approaches to discover genetic alterations have become available to individual patients, differentiating driver from passenger mutations and identifying and validating drug targets remain challenging. Protein tyrosine kinases play crucial roles in virtually all cellular processes and possess structural features that render them ‘druggable’. Monoclonal antibodies and small-molecule inhibitors represent two major classes of targeted therapeutic agents, each possessing its own strength and weakness. Although initial successes have been achieved, targeted therapy faces many challenges that need to be addressed and © 2014 S. Karger AG, Basel hurdles to overcome.

Genetic alterations may promote cancer development through either constitutive activation of proto-oncogenes or loss of function of tumor suppressor genes [4, 5]. Proto-oncogenes are normal cellular genes that encode proteins involved in cell proliferation and cell-death protection. When deregulation occurs, either through changes in the protein-coding segment or by alteration of their expression levels, proto-oncogenes are converted to oncogenes, which promote cancer development. The first oncogene isolated was from a cancer-inducing retrovirus, the Rous sarcoma virus, which transmits sarcomas to infected chicks through incorporation of the v-src oncogene to host genomes [6]. Since the discovery of v-src, numerous other proto-oncogenes have been identified. They can be converted to oncogenes through various genetic alterations such as point mutations, deletions, duplication/amplification and chromosome translocations, as well as epigenetic alterations. Following the understanding of oncogenes, a second group of genes in tumor development, the tumor suppressor genes, also entered the center stage of research in the molecular origin of cancer. In contrast to oncogenes, tumor suppressor genes encode proteins that prevent tumor development or progression [4]. This is usually accomplished through maintaining genome integrity and constraining cell proliferation by regulating the cell cycle, promoting apoptosis and facilitating DNA repair. The first gene recognized as a tumor suppressor gene was a gene involved in cell cycle control, the retinoblastoma (RB) gene [7–9]. Loss of RB was found to be the cause of hereditary as well as sporadic retinoblastoma. Since in general one copy of a tumor suppressor gene is sufficient to control cell proliferation, both alleles of a tumor suppressor gene have to be lost or inactivated in order to promote tumor development. This may occur through alterations such as point mutations, deletions, chromosome deletions and translocations, and epigenetic silencing [10, 11]. In addition to oncogenes and tumor suppressors, genetic materials acquired from viruses, including human papilloma virus, Epstein-Barr virus, hepatitis B virus, human T lymphotropic virus 1 and human herpes virus 8, can also promote tumor development. This usually occurs through mechanisms such as inactivation of cellular tumor suppressors or alteration of the transcription of the neighboring genes after integration into the host genome, although viral genes may function as oncogenes themselves as well [12, 13]. The understanding of the molecular origin of cancer development has led to investigations of new therapeutic agents [14]. While strategies to restore tumor suppressor gene functions have been hindered by technical hurdles of ineffective gene delivery, numerous new therapeutics targeting oncoproteins have been evaluated in clinical studies with many approved for clinical use.

One of the most exciting developments in biomedical research over the past decade has been the technological advances in genome sequencing. The availability of nextgeneration sequencing (NGS) has revolutionized cancer genome sequencing. Com-

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Zhao · Adjei Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 1–14 (DOI: 10.1159/000355895)


Identification of Cancer Therapy Targets

Targeting Oncogenic Drivers Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 1–14 (DOI: 10.1159/000355895)

3


pared with previous sequencing methods, NGS executes reactions in a massively parallel fashion, and thus millions of short sequence fragments are read simultaneously, and the reaction steps occur in parallel with the detection steps. This not only allows rapid sequence reading, but also provides improved coverage and increased accuracy since the same segment of a DNA sequence is read repeatedly [15]. The dramatically reduced cost and turnaround time of NGS makes sequencing of entire cancer genomes for each individual patient technologically and financially possible [16, 17]. With the availability of this new technology on the horizon for clinical care, the pressing question now is how to identify mutations that play causal roles in cancer. Genetic alterations described in tumors include single-base substitutions, small insertions and deletions (indels), amplifications, homozygous deletions, and translocations. These alterations can be compiled into two categories, “drivers” and “passengers”; while the former confer growth advantage on cancer cells carrying them and are required to sustain proliferation of cancer cell, the latter are not. While more than one driver is likely required to sustain tumor growth, the number of driver mutations required in each tumor type has not been well established [13]. Since cancer is genetically unstable, a cancer cell often bears numerous genetic alterations. The ultimate assay to distinguish drivers from passengers is the transformation assay, which however is often not feasible due to the sheer volume of mutations existing in cancer cells. Alternatively, predictions can be made based on other factors. Whether a mutation can lead to potential functional impact due to protein coding sequence alterations may be predicated using computational tools. Mutations in genes that have been previously identified as cancer related or involved in cellular signal transduction pathways that play significant roles in malignancy transformation are more likely to be driver mutations [16, 18, 19]. Since passenger mutations are assumed to occur randomly throughout the genome, whereas driver mutations occur frequently in cancerrelated genes, a gene that exhibits higher prevalence of somatic mutations than expected by chance is considered more likely to be a driver mutation, even though it has been recognized that passenger mutations may occur in clusters, and driver mutations can exist at low frequency in cancer cells [18, 19]. Since cancer is an evolutionary process with continuous acquisition of new genetic alterations, additional driver mutations can be acquired after cancer development, and clones harboring these mutations will expand under positive selection due to enhanced growth potential and/or treatment resistance [20–23]. Moreover, a preexisting passenger mutation may become a driver mutation by contributing to treatment resistance and clonal expansion [24]. In addition to identifying drivers, cancer genome profiling-based therapy selection faces other hurdles. The discordance between primary tumor and recurrent/metastatic lesions and intra-tumor heterogeneity raise the question of whether a single biopsy sample can be used to determine the genomic landscape of the entire disease [25]. Whether the driver mutations discovered are actionable, and how to design clinical studies to match patients with targeted agents are also among the challenges remaining to be addressed [26].

Approaches to Inhibit Driver Genetic Alterations

Therapeutic targeting of driver genetic alterations has become a major focus of oncology. The development of new therapies is often based on inhibition of disease-associated molecular interactions. Modern biology has facilitated the search for new small molecules that potently and selectively modulate the functions of molecular targets via this approach. Additionally, monoclonal antibodies, which exert their antitumor activity through neutralizing and/or depleting targeted molecules or target positive cancer cells, have also become a vital drug class in targeting cancer-related molecular pathways [27, 28]. Other types of targeted therapeutic agents such as peptide mimetics and siRNAs have also emerged and are being evaluated in clinical studies [29, 30].

The modern era of monoclonal antibody therapy began after the development of hybridoma technology in 1975, which enabled the continuous supply of specific monoclonal antibodies [31]. Among all antibody isotypes, immunoglobulin G (IgG) is the most frequently used monoclonal antibody in cancer therapy. Structurally, it comprises an antigen binding (Fab) and a constant fragment (Fc) region. While Fab binds specific antigen, Fc interacts with IgG receptors (FcγRs) and complement, mediating antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). Fc also interacts with neonatal FcR, which is responsible for the long serum half-life of IgG. Since murine antibodies are immunogenic, lack effector functions, and have a short half-life when used in humans, chimerization and humanization are required in order to achieve adequate efficacy [32]. Additionally, fully human antibodies obtained by screening phage display libraries expressing human antibody fragments or expressed by mice genetically engineered with human immunoglobulin gene sequences have also become available for clinical use [27, 33]. The antitumor activities of monoclonal antibodies are exerted through both immune and nonimmune mechanisms, including binding and depletion of growth factors, blockade of ligand and receptor interactions and signaling, and cellular depletion through ADCC, ADCP and CDC [27]. In addition to the antitumor effect medicated by naked antibodies, antibody-drug conjugates carrying drugs, toxins or radionucleotides have also been developed and gained approval for clinical use [34]. Since the approval of the first therapeutic monoclonal antibody rituximab in November 1997, thirteen monoclonal antibodies have been introduced to clinic for treatment of solid tumors and hematological malignancies (table 1). Currently, there are about 300 monoclonal antibodies at various stages of clinical development. Among them, 10 are undergoing evaluation in phase 2/3 or phase 3 clinical studies [35]. In general, treatments with currently approved monoclonal antibodies are better toler-

4



Therapeutic Monoclonal Antibody

Molecular target(s)

Mechanism of action

Treatment indications

Cetuximab

EGFR/ErbB1

mouse/human chimeric IgG1

squamous cell carcinoma of the head and neck, KRAS wild-type colorectal cancer

Panitumumab

EGFR/ErbB1

human IgG2

KRAS wild-type colorectal cancer

Trastuzumab

ErbB2/HER2/Neu

humanized IgG1

HER2-overexpressing breast cancer, gastric or gastroesophageal junction adenocarcinoma

Pertuzumab

ErbB2/HER2/Neu

humanized IgG1

HER2-overexpressing breast cancer

Bevacizumab

Vascular endothelial growth factor A

humanized IgG1

glioblastoma, colorectal cancer, non-small cell lung, renal cell cancer

Rituximab

CD20

mouse/human chimeric IgG1

follicular, CD-20-positive, B-cell non-Hodgkin lymphoma

Ofatumumab

CD20

human IgG1

chronic lymphocytic leukemia

Alemtuzumab

CD52

humanized IgG4

chronic lymphocytic leukemia

Ipilimumab

cytotoxic T lymphocyteassociated antigen 4 (CTLA-4)

human IgG1

melanoma

Tremelimumab

anti-CTLA-4

human IgG2

melanoma

Tositumomab and iodine I131 tositumomab

CD-20

murine IgG2 iodine-131 conjugate

non-Hodgkin’s lymphoma

90Yttrium-ibritumomab

CD20

murine IgG1 chelator tiuxetan conjugate

non-Hodgkin’s lymphoma

CD30

chimeric IgG1-monomethyl auristatin E conjugate

Hodgkin lymphoma, systemic anaplastic large-cell lymphoma

tiuxetan Brentuximab vedotin

ated compared with conventional chemotherapeutic agents, although toxicity profiles may vary depending on the therapeutic targets, with the exception of infusion reactions, which have been reported across all agents. Skin rash and cardiac dysfunction were observed with epidermal growth factor receptor (EGFR)- and HER2-targeted agents, respectively; hypertension, thrombosis, hemorrhage and delayed wound healing were observed with vascular endothelial growth factor-targeted agents; infection and cytopenia are more commonly associated with monoclonal antibodies targeting hematological malignancies, while immune-related adverse events have been reported with immune-modulating agents. Most of the monoclonal antibodies approved for


5


Table 1. Monoclonal antibodies approved for clinical use

clinical use have been shown to improve overall survival. Some agents are restricted to selected patients based on predictive biomarkers. For example, overexpression of the targeted protein HER2 is required for treatment with trastuzumab and pertuzumab, and in colon cancer patients, cetuximab and panitumumab only demonstrate activity in KRAS wild-type tumors. Consistent with other targeted therapeutics, intrinsic and acquired resistance to therapeutic monoclonal antibodies have been noted. Resistance mechanisms such as inadequate expression of targeted antigen, compensatory activation of related pathways, lack of penetration of tumor tissue by monoclonal antibodies, receptor saturation and immune escape have been proposed [36–40]. Research addressing the resistance mechanisms as well as other challenges such as identifying true tumor-specific antigen targets, optimizing antibody design for better efficacy, and decreasing the costs of industrial production are ongoing.

Small molecule-targeted therapies represent another major class of anticancer therapies with around 20 agents currently approved for various tumor types. The process of discovering new small molecule therapeutics generally begins with screening diverse libraries of compounds to identify ‘hits’ that bind noncovalently to a target protein. Hits will be further transformed to leads, which are compounds suitable for further development and eventually clinical use [41]. The leads undergo more extensive optimization before finally entering preclinical drug development. In addition to high throughput small molecule library screening, hits can also be generated by other methods such as virtual screening or based on existing knowledge of therapeutic targets, endogenous ligands or structure information [42, 43]. Due to their small size which requires proper binding surface, the most suitable targets of small-molecule drugs in cancer therapy are often enzymes. Since protein kinases are involved in virtually all cellular signal transduction processes, they have become the most intensively investigated targets in small-molecule cancer drug development. The feasibility of developing highly selective small-molecule inhibitors with favorable pharmaceutical properties and the successful experience in targeting kinases for cancer therapy also endorsed interest in the development of this drug category [44, 45]. Protein kinases constitute a large gene family with diverse function (fig. 1). A total of 518 putative protein kinases have been identified based on genomic, complementary DNA, and expressed sequence tag sequences [46]. Structurally, protein kinase possesses a conserved catalytic domain with an adenosine triphosphate (ATP)-binding pocket as well as less conserved surrounding pockets, both of which have been targeted in the development of selective kinase inhibitors [47]. Through catalyzing the transfer of the terminal phosphoryl group of ATP to specific hydroxyl groups of serine, threonine or tyrosine residues, protein kinases alter the activity, subcellular localization, protein turnover, and ability of interacting with cellular partners of their sub-

6



Small-Molecule Inhibitors


7


Fig. 1. Phylogenetic tree of the complete superfamily of human protein kinases.

8



strates. Protein kinases play essential roles in signal transduction and orchestration of complex functions such as cell cycle regulation, apoptosis and angiogenesis [46]. A protein kinase may become a therapeutic target due to its direct involvement in tumor development following genetic alterations such as mutations, chromosome translocation or gene amplification. For example, the V600E mutation of BRAF is known to be associated with the development of melanoma [48, 49], BCR-ABL has a causative role in chronic myeloid leukemia, and EGFR mutation and EML4-anaplastic lymphoma kinase (ALK) translocations are implicated in lung cancer development [50–52]. Another group of kinases, although rarely mutated in tumors, are required to sustain tumor cell proliferation and escape cell death mechanisms, therefore are also considered as potential drug targets. Kinases of this category are often the key downstream effectors of driver mutations, or critical players in cycle control or mitosis, such as MEK1/2, cyclin-dependent kinases, aurora kinases and polo-like kinases [53, 54]. Additionally, since host-tumor interaction plays a crucial role in tumor growth and metastasis, kinases involved in host activity that is required for sustaining tumor growth such as angiogenesis are often exploited for therapeutic development as well [44, 55]. Kinases can be inhibited via different mechanisms. Most kinase inhibitors are ATP competitive. They bind to the ATP-binding site by presenting one to three hydrogen bonds which mimic the hydrogen bonds normally formed by ATP [55, 56]. Frequently, this type of kinase inhibitor recognizes the active confirmation of the kinase, occupying the purine-binding site via a heterocyclic ring system which subsequently allows the side chains to occupy adjacent hydrophobic regions [44]. Additionally, kinase inhibitors may also recognize the inactive conformation of the kinase, which offers an additional hydrophobic binding site directly adjacent to the ATP-binding site. Kinase activity can also be modified by allosteric inhibitors, which bind outside the ATP-binding site. This mechanism provides the highest selectivity since it avoids the more conserved ATP-binding site. Furthermore, other mechanisms such as formation of an irreversible, covalent bond of inhibitor to the kinase active site can also be employed by small-molecule kinase inhibitors [44]. Protein tyrosine kinases represent a major group of kinases targeted by cancer therapy. They can be divided into receptor tyrosine kinases and nonreceptor tyrosine kinases. Receptor tyrosine kinases are single-pass transmembrane proteins that contain extracellular domain, lipophilic transmembrane segment, and intracellular domain with tyrosine kinase catalytic site plus additional carboxy-terminal and juxtamembrane regulatory regions [57]. Nonreceptor tyrosine kinases lack transmembrane domains and are found inside the plasma membrane. In the absence of ligand, receptor tyrosine kinases exist as unphosphorylated inactive monomers. Ligand binding invokes oligomerization, typically dimerization of receptor tyrosine kinases, which triggers autophosphorylation of cytoplasmic domains and activation of tyrosine kinase activity. Autophosphorylated intracellular domain then interacts with downstream signaling proteins, recruiting them to the membrane and activating various signaling cascades [58]. The receptor tyrosine kinase family members include

EGFR or ErbB, platelet-derived growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, Met (hepatocyte growth factor/ scatter factor receptor), stem cell factor receptor KIT, ALK, and the insulin receptor. Similar to receptor tyrosine kinases, nonreceptor tyrosine kinases remain in inactive states in the absence of stimuli. Upon stimulation, nonreceptor tyrosine kinases become phosphorylated via either auto- or transphosphorylation [59]. Examples of established nonreceptor tyrosine kinase therapeutic targets are c-ABL and Janus kinase. In addition to protein kinases, other targets, such as enzymes involved in chromatin modulation, protein complexes that mediate protein degradation, and tumor-promoting secreted proteins, have also been successfully exploited for cancer therapy (table 2). For example, DNA methyltransferase and histone deacetylase inhibition are effective treatment strategy for leukemia [60]; Hedgehog pathway-targeted agents have achieved great success in basal cell carcinoma treatment, and proteasome inhibitors represent a key drug class for multiple melanoma.

Although monoclonal antibodies and small-molecule inhibitors represent the major drug classes of targeted therapy, they differ in many ways. The major differences of these two approaches have been reviewed by Imai and Takaoka [61]. Small-molecule inhibitors are frequently administered orally, whereas monoclonal antibodies can only be given intravenously. Small-molecule agents can pass through cell membranes and interact with the cytoplasmic domain of cell surface receptors as well as intracellular targets such as MEK1/2 and RAF, whereas monoclonal antibodies can only have extracellular targets. The small size of small-molecule inhibitors likely allows better tissue penetration and brain distribution than monoclonal antibodies. Greater interpatient variation in drug exposure is more likely to occur with small-molecule inhibitors than monoclonal antibodies due to its oral administration route and degradation system. Immune responses often contribute to the antitumor activity of monoclonal antibody but not small-molecule inhibitors. Monoclonal antibodies have a longer half-life ranging from days to weeks, whereas most small-molecule inhibitors typically have a shorter half-life and require daily dosing. There are fewer concerns of drug interactions with monoclonal antibodies than small-molecule inhibitors, which are usually metabolized by cytochrome P450 enzymes. Monoclonal antibodies may be used as vehicles to deliver drugs, toxins, and radioisotopes specifically to cells carrying the targeted antigens, which cannot be achieved using small-molecule inhibitors. Monoclonal antibodies and small-molecule inhibitors also differ in target specificity and selectivity, with monoclonal antibodies being significantly more specific and small-molecule inhibitors often exhibiting off-target or multi-target effects, which may carry therapeutic advantage by enabling broader antitumor activity and delaying resistance development. The correlation of target mutation status and drug sensitiv-


9


Comparing Therapeutic Monoclonal Antibody and Small-Molecule Inhibitor

Molecular target(s)

Mechanism of action


Erlotinib

EGFR/ErbB1

ATP-competitive kinase inhibitor

non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, pancreatic carcinoma

Afatinib

EGFR/ErbB1, ErbB2/ HER2, ErbB4/HER4


NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations

Gefitinib

EGFR/ErbB1


NSCLC (with FDA limitations)

Lapatinib

EGFR/ErbB1 and ErbB2/Her2/Neu


HER2-overexpressing breast cancer

Sorafenib

RAF/vascular endothelial ATP-competitive kinase inhibitor growth factor receptor (VEGFR)

hepatocellular carcinoma and renal cell carcinoma

Sunitinib

VEGFR2, platelet-derived ATP-competitive kinase inhibitor growth factor receptor-β (PDGFRβ), and c-KIT

renal cell carcinoma, well-differentiated pancreatic neuroendocrine tumors, gastrointestinal stromal tumors (GIST)

Pazopanib

VEGFR1, -2 and -3, c-KIT and PDGFR


renal cell carcinoma, soft tissue sarcoma

Axitinib

VEGF and PDGF


renal cell carcinoma

Cabozantinib

RET, MET, and VEGF receptor 2


medullary thyroid cancer

Regorafenib

VEGFRs 2 and 3, RET, Kit, PDGFR and RAF


GIST, colorectal cancer

ziv-aflibercept

VEGF

soluble decoy receptor-binding VEGFs

colorectal cancer

Vandetanib

RET, EGFR, VEGFR


medullary thyroid cancer

Crizotinib

ALK


ALK-positive NSCLC

Imatinib mesylate

ABL and c-KIT


Ph+ chronic myelogenous leukemia (CML), GIST, aggressive systemic mastocytosis without D816V c-Kit mutation (or c-Kit mutation status unknown), dermatofibrosarcoma protuberans , hypereosinophilic syndrome and/or chronic eosinophilic leukemia, myelodysplastic (MDS)/myeloproliferative disease associated with PDGFR gene rearrangements, Ph+ acute lymphoblastic leukemia (ALL)

Bosutinib

ABL and SRC


Ph+ CML with resistance or intolerance to prior therapy

Dasatinib

ABL and SRC


Ph+ CML, Ph+ ALL

Nilotinib

ABL


Ph+ CML

Ponatinib

ABL


Ph+ CML and Ph+ ALL resistant or intolerant to prior tyrosine kinase inhibitor therapy

Vemurafenib

BRAF


melanoma with the BRAFV600E mutation

10



Table 2. Small molecule therapeutics approved for clinical use

Table 2. Continued Molecular target(s)

Mechanism of action


Everolimus

mammalian target of rapamycin (mTOR)

inhibits mTOR serine/threonine kinase activity by forming complex with FKBP12

hormone receptor-positive, HER2-negative breast cancer, subependymal giant cell astrocytoma, subependymal giant cell astrocytoma associated with tuberous sclerosis, progressive neuroendocrine tumors of pancreatic origin, renal cell carcinoma, renal angiomyolipoma, associated with tuberous sclerosis complex

Temsirolimus

mTOR

inhibits mTOR serine/threonine kinase activity by forming complex with FKBP12

renal cell carcinoma

Decitabine

DNA methyltransferase

inhibits DNA methyltransferase

MDS

Azacitidine

DNA methyltransferase

inhibits DNA methyltransferase

MDS

Romidepsin

histone deacetylases

inhibits histone deacetylases

cutaneous T-cell lymphoma

Vorinostat

histone deacetylases

inhibits histone deacetylases

cutaneous T-cell lymphoma

Vismodegib

Hedgehog signaling pathway

cyclopamine-competitive antagonist of the smoothened receptor

basal cell carcinoma

Thalidomide

multiple

multiple

multiple myeloma

Lenalidomide

multiple

multiple

multiple myeloma

Pomalidomide

multiple

multiple

multiple myeloma

Carfilzomib

proteasome

inhibits proteasome

multiple myeloma

Bortezomib

proteasome

inhibits proteasome

multiple myeloma

ity may differ as indicated by the experience with EGFR-targeted agents in lung, colorectal and head and neck cancers [52, 62, 63]. Monoclonal antibody development requires more complex processes with substantially higher cost compared with smallmolecule inhibitors; therefore, they are more expensive than small-molecule inhibitors. Since small-molecule inhibitor requires suitable surface architecture for binding which may not always be available, whereas antibody is able to bind on relatively large and flat protein surfaces, many of the monoclonal antibody targets may not be ‘druggable’ by small-molecule inhibitors [64].

Although the clinical successes of targeted therapy have established the critical role of the molecular targeting approach in cancer treatment, many issues have arisen and remain to be addressed. With the availability of genomic technology, how to effec-


11


Challenges and Limitations of Targeted Therapy

tively identify and validate new targets, how to identify biomarkers to identify patients most likely to benefit from specific treatments, how to address drug resistance to current therapeutic agents and understand compensatory pathway activation and pathway crosstalk, how to combine targeted therapeutic agents or with conventional chemotherapy in order to achieve maximum clinical benefit and delay resistance development, and how to decrease the cost of drug development and production are all questions that remain to be answered.

Acknowledgements This study was supported by a Drug Development Research Professorship from Conquer Cancer Foundation of the American Society for Clinical Oncology.

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Alex A. Adjei Department of Medicine, Roswell Park Cancer Institute Elm & Carlton Streets Buffalo, NY 14263 (USA) E-Mail [email protected]

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Defining and Targeting the Oncogenic Drivers of Neuroendocrine Prostate Cancer.

Oncogenic drivers and mitochondrial dependency.

Melanoma: oncogenic drivers and the immune system.

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy.

Deciphering oncogenic drivers: from single genes to integrated pathways.

One patient, two lesions, two oncogenic drivers of gastric cancer.

Targeting Oncogenic Mutant p53 for Cancer Therapy.

Targeting drivers of melanoma with synthetic small molecules and phytochemicals.

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer.

Targeting the oncogenic Met receptor by antibodies and gene therapy.

ARF1 promotes prostate tumorigenesis via targeting oncogenic MAPK signaling.

A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors.

CXCR4 in breast cancer: oncogenic role and therapeutic targeting.

Oncogenic and Therapeutic Targeting of PTEN Loss in Bone Malignancies.

Targeting MET Amplification as a New Oncogenic Driver.

Therapeutic potential of targeting the oncogenic SHP2 phosphatase.

Cancer metabolism: strategic diversion from targeting cancer drivers to targeting cancer suppliers.

Do oncogenic drivers exist in squamous cell carcinoma of the lung?

Oncogenic drivers, targeted therapies, and acquired resistance in non-small-cell lung cancer.

Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers.

Former smokers with non-small-cell lung cancers: a comprehensive investigation of clinicopathologic characteristics, oncogenic drivers, and prognosis.

Targeting oncogenic protein kinase Cι for treatment of mutant KRAS LADC.

LncRNA MALAT1 exerts oncogenic functions in lung adenocarcinoma by targeting miR-204.

Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2.