DOI 10.

7603/s40681-015-0019-4
BioMedicine (ISSN 2211-8039)
December 2015, Vol. 5, No. 4, Article 1, Pages 1-6

Review article

An overview of targeted cancer therapy

Viswanadha Vijaya Padmaa,b
a
Department of Biotechnology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
b
Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan

Received 30th of August 2015 Accepted 23rd of October 2015

© Author(s) 2015. This article is published with open access by China Medical University

Keywords: ABSTRACT
Chemotherapy;
Multidrug resistance; Cancer is a multifactorial disease and is one of the leading causes of death worldwide. The contributing fac-
Targeted therapy; tors include specific genetic background, chronic exposure to various environmental stresses and improper
Prodrug; diet. All these risk factors lead to the accumulation of molecular changes or mutations in some important
Small molecule proteins in cells which contributes to the initiation of carcinogenesis. Chemotherapy is an effective treat-
inhibitors;
ment against cancer but undesirable chemotherapy reactions and the development of resistance to drugs
Nano-particulate
which results in multi-drug resistance (MDR) are the major obstacles in cancer chemotherapy. Strategies
antibody conjugates
which are in practice with limited success include alternative formulations e.g., liposomes, resistance modu-
lation e.g., PSC833, antidotes/toxicity modifiers e.g., ICRF-187 and gene therapy. Targeted therapy is
gaining importance due to its specificity towards cancer cells while sparing toxicity to off-target cells. The
scope of this review involves the various strategies involved in targeted therapy like-monoclonal antibodies,
prodrug, small molecule inhibitors and nano-particulate antibody conjugates.

1. Introduction Monoclonal antibodies are the focus of intense research in the

field of cancer therapeutics since mid 1970s when the customized
Cancer is the second leading cause of deaths all over the world. monoclonal antibody production was reported. Monoclonal anti-
Globally 7.6 million deaths are caused by cancer which represents body production, antibody engineering with display and screening
13% of all global deaths [1]. Surgery, chemotherapy, and irradia- innovations such as phage display meant the binding of antibody
tion are the mainstream therapeutic approaches for cancer, che- to a wide range of targeted antigens with exceptional specificity.
motherapy being an important component of treatment for cancer Cancer immunotherapy involves the use of gemtuzumab (Mylotarg®;
patients. However, its success is limited due to lack of selectivity Wyeth, CT, USA), a CD-33 specific monoclonal antibody conju-
for tumor cells over normal cells resulting in insufficient drug gated to a calicheamicin used for the treatment of acute myeloid
concentrations in tumors, systemic toxicity and the appearance leukemia [7]. On a similar note, radioisotope conjugated target-
of drug-resistant tumor cells [2]. Several strategies have been ing antibodies have been developed for imaging (immunoscin-
proposed which include alternative formulations e.g., liposomes tigraphy) and radioimmunotherapy strategies. 90Y metal isotope
[3], resistance modulation e.g., PSC833 [4], antidotes/toxicity based anti-CD20 ibritumomabtiuxetan (Zevalin®; Spectrum Phar-
modifiers e.g., ICRF-187 [5] and gene therapy. Recently targeted maceuticals, CA, USA) has been developed for use in clinical
therapy is gaining importance due to its specificity towards cancer therapy [8, 9].
cells while sparing toxicity to off-target cells. Moreover, apart from being used as therapeutic agents anti-
Targeted therapy aims at delivering drugs to particular genes bodies also serve as targeting agents. They are used in targeted
or proteins that are specific to cancer cells or the tissue environ- therapy for the delivery of active therapeutics [10], prodrug
ment that promotes cancer growth. Effectiveness of the therapy activation enzymes [11, 12] and chemotherapy toxins [13-15].
lies in targeted release of therapeutics at the disease site while Monoclonal antibodies block a specific target on the outside of
minimizing the off-target side effects caused to normal tissues. cancer cells or in the tissue surrounding it. Monoclonal antibod-
It is often used in conjunction with chemotherapy and other ies are used to deliver chemotherapeutic drugs and radioactive
cancer treatments. Targeted therapy involves developing drugs substances, directly to cancer cells. Being large compounds these
that block cancer cell proliferation, promote cell cycle regulation drugs are usually given intravenously.
or induce apoptosis or autophagy and targeted delivery of toxic Prodrug cancer therapy involves selective activation of
substances specifically to cancer cells to destroy them. Targeted prodrug(s) in tumor tissues by exogenous enzyme(s) which can
therapy involves the use of monoclonal antibodies or oral small be accomplished by several methods which include: gene-directed
drugs [6]. enzyme prodrug therapy (GDEPT), virus-directed enzyme prod-

* Corresponding author. Department of Biotechnology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India.
E-mail address: padma.vijaya@gmail.com (V. V. Padma).

BioMedicine | http://biomedicine.cmu.edu.tw/ 1 December 2015 | Volume 5 | Issue 4 | e46

rugtherapy (VDEPT), and antibody-directed enzyme prodrug ferences between normal and tumor cells [33, 34]. Several tumor-
therapy (ADEPT). The important aspect of prodrug cancer specific Transription responsive elements (TREs) have been used,
therapy is to deliver drug-activating enzyme or gene or functional which include genes that are either tumor specific or tumor as-
protein to tumor tissues, followed by systemic administration of a sociated antigens, such as CEA for colorectal cancer or N-myc for
prodrug [2]. neuroblastoma [2].
Prodrug cancer therapy is a two step process, the first step Antibody directed enzyme prodrug therapy (ADEPT) uses a
involves, targeting the drug-activating enzyme and its expression conjugate which consists of tumor specific antibody linked to a
in tumors followed by the systemic administration of the nontoxic drug-activating enzyme which when administered systemically
prodrug, which is the substrate for the exogenous enzyme that is targets tumor tissues. This targeted enzyme which is localized on
targeted and expressed in tumors [16-18]. This in turn helps in the tumor surface, converts the systemically administered nontox-
localization of activated anticancer drug (toxic drug) in high con- ic prodrug into a toxic drug resulting in cytotoxic effects in tumor
centration in tumors. The success of the prodrug therapy requires cells [12, 35-40]. The ideal drugs for ADEPT include diffusible
that both enzymes and prodrugs should meet certain criteria: the small molecules, which can diffuse in to both antigen-positive and
enzyme should be of nonhuman origin or a human protein either antigen-negative tumor cells, and cause a bystander effect [35-37].
absent or has low expression levels in normal tissues [19, 20] but The interval between enzyme and prodrug administrations should
should find sufficient expression in tumors with high catalytic be optimized to enhance the conjugate accumulation in tumors
activity [21]. The prodrug should not be activated by the en- and avoid their leakage to blood and normal tissues, to avoid sys-
dogenous enzymes in non-tumor tissues but must be a good sub- temic toxicity.
strate for the expressed enzyme in tumors. The prodrug should The important criteria for ADEPT include: the target antigen
be highly diffusible and be activated in the tumor cell with high should be accessible, therefore it should preferably be a mem-
cytotoxic potential. Further, it must exhibit ‘bystander’ killing ef- brane bound antigen associated with the tumor cell membrane or
fect by being actively taken up by the nonexpressing neighboring secreted into the extracellular matrix of the tumor [41], and the
cancer cells. The half life of the prodrug should be long enough antibody should be a monoclonal antibody with high affinity [35].
to exhibit bystander effect but should not permit drug leakage to The enzyme should have optimal activity at a pH close to that of
systemic ciruculation [22]. The targeting strategies for enzyme/ the tumor extracellular fluid.
prodrug can be divided into two major classes: (a) delivery of The interval between enzyme and prodrug administrations is
genes that encode prodrug-activating enzymes to tumor tissues important for ADEPT, studies carried out in animals regarding
(GDEPT, VDEPT, GPAT etc.); and (b) delivery of active enzymes the optimal interval showed that with the enzyme CPG2 linked to
onto tumor tissues (ADEPT). the anti-CEA antibody A5B7, the prodrug CMDA can be safely
Gene directed enzyme prodrug therapy, is a technique that in- given 48 h or 72 h after antibody-enzyme administration [36]. In
volves delivery of a gene that encodes a foreign enzyme to tumor human subjects, the prodrug can be administered safely after 7
cells where it finds expression and activates a systemically ad- days to avoid systemic toxicity due to the activation of prodrug in
ministered nontoxic prodrug [16, 23, 24]. The enzyme/prodrug plasma, as it takes 7 days for the adequate clearance of antibody-
systems applied in GDEPT include: HSV-TK/GCV, Escherichia enzyme conjugate from the plasma [35]. The Phase I clinical
coli CD/5-FC and E. coli NTR/CB1954 which act intracellularly trials carried out with CMDA/CPG2 prodrug/ enzyme system in
by converting prodrugsinto active drugs within cancer. Cell-cell colorectal carcinoma patients has revealed promising results. The
contact is essential for this mode of action for effective killing. bacterial enzyme CPG2 was conjugated to the F(ab)2 fragment of
An extra-cellular cytotoxic effector system includes the conver- murine A5B7 monoclonal Ab, and a galactosylated second clear-
sion of an inactive glucuronidated derivative of doxorubicin ing Ab against CPG2 was also used to lower levels of conjugate
(HMR 1826) to the cytotoxic doxorubicin in the tumor cells by in the circulation and other nontumor tissues. The plasma levels
the secreted form of lysosomal human glucuronidase. In the ex- of the prodrug CMDA and active drug CJS11, a bifunctional
tracellular system the hydrophilic prodrug gets converted into a alkylating agent, released from prodrug by the action of CPG2
lipophilic, cell-permeable cytotoxic drug outside cells and hence localized in tumors were measured. The results showed that after
targets both transduced and nontransduced cells. It exhibits en- applying the clearing agent, CPG2 activity was found in meta-
hanced cytotoxic potential as cell-cell contact is not required for a static tumor biopsies, but not found in normal tissues. Further, a
bystander effect [16]. rapid appearance of the active drug with half-life of 36 ± 14 min
Virus directed enzyme prodrug therapy (VDEPT) uses viral in plasma was encouraging [42].
vectors to deliver a gene that encodes an enzyme that can convert The limitations of ADEPT include: restricted delivery of the
a systemically administrated nontoxic prodrug into a cytotoxic large conjugate in poorly vascularized tumors, therefore it is not
agent within tumor cells. The NTR/CB1954 combination is used possible to deliver antibody/enzyme conjugate to all of the tumor
against colorectal and pancreatic cancer cells to sensitize them cells [43]. With low levels of the enzyme, adequate quantities
to CB1954 after retro-viral transduction and expression of the E. of active drug to reach the cytotoxic concentration cannot be
coli NTR gene [25, 26]. achieved. The antigen heterogeneity does not permit the bind-
The viruses used for VDEPT include: retroviruses, adenovi- ing of the conjugate to the cell surface. Other disadvantages of
ruses, HSV [27], adeno-associated virus [28-30], lentivirus and ADEPT include cost and availability of purified antibodies, im-
EBV [31]. Over the years, many drug-activating enzyme gene/ munogenicity of antibodies, accessibility of tumor to the enzyme/
prodrug combinations have been delivered into tumors in vitro or antibody conjugate, and the conversion of prodrugs in nontumor
in vivo by VDEPT, the majority using CD/5-FC or HSV-TK/GCV tissues [41]. The main problem being the immunogenicity of
with the involvement of retroviral and adenoviral vectors [32]. the antibody-enzyme conjugate, which limits multiple cycles of
Genetic prodrug activation therapy (GPAT) induces the selec- its application this can be overcome with the use of humanized
tive expression of a drug-metabolizing enzyme for activation of proteins and concomitant administration of immunosuppression
prodrug into a toxic moiety using the known transcriptional dif- [35].

BioMedicine | http://biomedicine.cmu.edu.tw/ 2 December 2015 | Volume 5 | Issue 4 | e46

 next challenge is that of selecting and validating the best targets.
2. Small molecule inhibitors in cancer therapy This requires establishing a causal linkage of the proposed target
and target modulation to deliver a therapeutically meaningful
Small drugs constitute a pill that a patient takes orally. As they biological effect in relevant experimental models. ‘Druggability
are smaller chemical components than monoclonal antibodies, the gap’ is the main concern in the drug discovery for medicinal
body absorbs them better. The small drugs usually are targeted chemists using small molecules. Frequently, the promising tar-
against specific molecular targets which are important for cancer gets are regarded as technically undruggable as they cannot be
cell proliferation or metastasis or angiogenesis. The current targeted with small molecules which is referred to as ‘druggability
state of cancer drug discovery and development focuses on small gap’ e.g., RAS proteins, c-MYC or hypoxia inducible factor (HIF)
molecule inhibitors which act against new molecular targets that [61]. Unfortunately, sometimes, cancer cells develop resistance
determine therapeutic outcome. The molecularly targeted cancer for drugs with therapeutic efficacy as proved by the successful
therapies have resulted in improving the lives of a large number completion of clinical trials as shown recently by crizotinib [62]
of cancer patients. The successful treatment of patients with and vemurafenib [63]. This could be due to the mutation of the
acute promyelocytic leukaemia harbouring translocations in the target gene [64], or activation of feedback loops [65] or develop-
RARα retinoic acid receptor gene with all-trans retinoic acid [44] ment of alternative oncogenic pathways [66, 67]. In such cases
and chronic myeloid leukaemia in which the malignancy is driven combinatorial regimen helps to overcome such problems [68].
by the BCR-ABL translocation with the ABL inhibitor imatinib [45,
46] serve as the proof of the concept of molecular targeting of
pathogenetic driver abnormalities with a small molecule in the clini- 3. Antibody-conjugated Nanoparticles for targeted
cal setting. The other small molecule inhibitors of cancer targets Cancer Therapy
include, e.g. the gefitinib - inhibitor of epidermal growth factor re-
ceptor (EGFR) kinase and erlotinib- the inhibitor of EGFR in non Recently research in nanoparticle based targeted therapy has
small cell lung cancer (NSCLC) patients; the lapatinib- inhibitor gained momentum which saw the use of a full spectrum of nano-
of EGFR/ERBB2 for ERBB2-positive breast cancer; and the particles in diagnostic and therapeutic applications of cancer
sorafenib- inhibitor of vascular epidermal growth factor receptor [69]. Antibody-NP conjugates are being used for targeted de-
(VEGFR) kinase, in renal cancer [47]. The recent addition to the livery of chemotherapeutics and are considered as better thera-
list is, abiraterone- the CYP171A1 inhibitor which blocks andro- peutic agents compared to NP conjugates due to their ability to
gen synthesis, approved for treatment of late stage, castration- circumvent some of the problems associated with direct conju-
resistant prostate cancer [48], crizotinib -inhibitor of the protein gates, such as possible inactivation of the drug and the release of
kinase ALK approved for the treatment of NSCLC patients with a the drug in nonspecific areas once internalized into endosomal/
pathogenic rearrangement of the ALK gene [49] and vemurafenib – lysosomal vesicles through pH labile or reducible linkers [70,
inhibitor of BRAF kinase [50] for metastatic melanoma with 71]. Moreover, the limitation with respect to the amount of drug
the BRAF V600E mutation. The progress with small molecule that can be delivered to targeted area with direct antibody con-
drugs is mirrored by the successful introduction of protein-based jugated drug can be overcome by the use of antibody-NP com-
therapeutics, particularly antibodies, as exemplified by the anti- plexes, which maximize the concentration of drug that can be
ERBB2 monoclonal antibody trastuzumab in ERBB2-positive targeted to the disease site. Recent studies focused on the de-
breast cancer [51, 52]. These examples provide ample evidence velopment of antibody-coated lipid and non-lipid based nanopar-
of the success in targeting the pathogenic drivers to which cancer ticulates for antitumor research. The nanoparticulate antibody-
cells are ‘addicted’ [53, 54]. targeting research is focused on antitumor strategies, where the
Despite the considerable progress in cancer therapy with the antibody is used to target cell-surface markers of disease which
advent of new molecularly targeted therapies, therapeutic options are frequently upregulated or are specifically expressed in tumor
are still limited for many patients and the process of new drug cells [70-72].
development is frustratingly slow with high failure rates [52, 55], Thus, the cancer drug discovery involves genome wide se-
The reasons for slow progress is that, frequently, a patient with quencing, understanding molecular pathology through bioinfor-
a particular anatomically and histologically defined solid tumor matics and systems biology approaches for understanding how
respond to the treatment with a particular class of kinase inhibi- cancer cells can be targeted through single agents or on several
tor that matches the predominant pathogenic driver mutation e.g., fronts through drug combinations [73-75]. Although targeted
NSCLC patients with EGFR mutations respond to EGFR inhibitors treatment is considered a breakthrough in cancer treatment, latest
while those with ALK translocations respond to ALK inhibitors research findings show that tumor heterogeneity with respect
[47, 56]. Which necessitates understanding the value of specific to molecular targets cause failure in many cases. This lead to
gene targeting and selection of patient specific companion bio- evolution of concept of matching a patient to treatment which in
markers on cancer drug discovery. other words is known as personalized medicine. In order to find
Another important task is identification of specific molecular the most effective treatment, the patient will be screened for the
targets through the sequencing of various cancer genomes which genes, proteins, and other factors unique to your tumor. After
revealed extraordinary complexity with several genetic alterations identifying the appropriate molecular targets the best suitable
and considerable genetic heterogeneity, not only between different treatment will be recommended. Personalized medicine is gain-
tumours but also within an individual cancer [57-59]. Further, the ing importance which ensures that the right drug is given to the
heterogeneous population of tumors also include drug-resistant right patient at the right time whereby maximum therapeutic ben-
stem [60] and other host cells which aid in tumour progression efit to patients is achieved. Pharmacologists and basic researchers
[47]. This heterogeneity leads to drug resistance and the need for are working together towards the discovery of effective and safe
combinatorial therapy. clinical candidates against the new targets trying to bridge the gap
After identification of a potential novel therapeutic target, the frequently referred to as technically druggable.

BioMedicine | http://biomedicine.cmu.edu.tw/ 3 December 2015 | Volume 5 | Issue 4 | e46

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