Hitting cancer where it hurts: How have targeted therapies improved... Karin Purshouse, Newcastle University

Hitting cancer where it hurts: How have targeted therapies improved our approach.
Karin Purshouse, Newcastle University
‘Will we ever cure cancer?’
Having completed a breast cancer research project, this is a question I am often asked.
Honestly, I say? The more we know about cancer, the less convinced I am that we will
ever find a cure. However, we are learning more about what makes cancer ‘tic’, and
targeted therapies have paved the way for a more elegant approach compared the hit-andhope alternatives of surgery, chemotherapy and radiotherapy. Having spent four months
collecting and analysing blood samples from breast cancer patients, looking particularly
at bone metastasis, it is clear to me that targeted therapy could revolutionise care –
however, there are significant biological and financial stumbling blocks that must first be
overcome.
The problem
Cancer will affect around 1 in 3 people, and 1 in 4 will die from it. Breast cancer will
affect 1 in 9 women, with rates increasing particularly in the developing world due to the
oestrogen-promoting lifestyle choices seen for decades in the developed world such as
obesity, later childbirth, early menarche, oral contraceptive use and a reduction in those
breast feeding.(1,2) In addition, screening is becoming more widespread. Overall,
incidence is increasing, and although mortality rates are decreasing, it remains that some
1.38 million women are diagnosed worldwide every year.(3) (Figure 1)
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Figure 1: Breast cancer incidence in the UK (Source – see figure references)
Current options
Conflict has given us many medical breakthroughs, and cancer is no different. The
realisation that mustard gas was an alkylating agent triggered the development of
chemotherapeutics broadly categorised as alkylating/pseudoalkylating agents, antimetabolites, anthracyclines, vinka alkaloids and taxanes, and topoisomerase inhibitors.
Chemotherapy is used in breast cancer, with radiotherapy and surgery also mainstays.
Targeted therapies have revolutionised breast cancer treatment already. Hormone
therapies such as tamoxifen and aromatase inhibitors are utilised in hormone (estrogen
(ER) and progesterone (PR)) receptor positive patients and increasingly, trastuzumab
(aka Herceptin) and lapatanib are used for HER2 positive patients.
Before treatment is given, breast cancer tissue is analysed. Traditionally, a core biopsy is
stained by immunohistochemistry to identify the ER, PR and HER2 status (with
additional analysis if necessary). However, Sorlie and colleagues identified alternative
subtypes: basal, HER2, luminal A/B and normal, and genetic signatures for these
subtypes indicate a completely different selection of potential targets.(4) Perhaps we are
missing the mark with our existing diagnostic methods and the resulting treatment.
The Hallmarks of Cancer
It had been clear for a decade before Sorlie’s paper that the treatment methods were also
failing to strike a fatal blow to cancer. The six Hallmarks of Cancer described by
Hanahan and Weinberg illustrated cancer’s cure-evading qualities: self sufficiency,
insensitivity to anti-growth signals, anti-apoptotic, invasive, pro-angiogenic and antisenescent.(5) (Figure 2)
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Figure 2: Hallmarks of Cancer
Ultimately, genetic mutations give rise to these attributes, as well as epigenetic and RNA
interference mechanisms contributing to the initiation, propagation and metastasis of
cancer cells. Targeting the genome and related components may be an area for the
future, but for now, limitations include the lack of a suitable vector, toxic side effects or
immunoregulation. Further, our understanding of these mutations and alterations remains
limited. For example, microRNAs involved in the initiation of breast cancer include
microRNA 125b but antisense oligonucleotides, microRNA sponges and mimics remain
very much at their therapeutic infancy.(6) To target the genome would only target that
specific mutation – yes, at its origin, but with the limitation that many thousands of
agents would need to be designed to target the genetic mutations involved in cancer.
Consequently, targeted agents have sought to address the Hallmarks of Cancer, thereby
tackling the qualities that make cancer so destructive.
Targeted agents
In understanding the significance of targeted therapies, their limitations and future
directions, we should consider the hallmarks they attack and their mode of action,
looking particularly at their role in breast cancer therapy.

Self Sufficiency and insensitivity to antigrowth signals
o In contrast to normal cells, cancer cells enhance the manner in which
growth factors induce their activation and proliferation. Growth Factor
receptors on cells, such as fibroblast growth factor (FGF) and vascular
endothelial growth factor (VEGF), are transmembrane tyrosine kinases.
Their activation by extracellular growth factors leads to receptor
dimerisation and downstream signalling by autophosphorylation.
o Imatinib (Glivec) was the first drug to successfully inhibit this pathway by
blocking phosphorylation via tyrosine kinase inhibition in patients with
Chronic Myeloid Leukaemia (CML) demonstrating the bcr-abl
(Philadelphia chromosome) mutation.
o In breast cancer

•
HER2 and VEGF receptors are often upregulated
•
VEGF expression may be increased
Pro-angiogenic
o An angiogenic ‘switch’ occurs, whereby proangiogenic factors such as
VEGF outweigh anti-angiogenic factors like thrombospondin.

Antiapoptotic
o Apoptosis occurs via intra- and extracellular activation of the common
caspase-3 pathway, leading to cell death. Intracellular regulators of this
are often mutated in various forms of cancer – p53, which acts as a
gatekeeper of correct DNA replication and promotes apoptosis via
mitochondrial signalling, is mutated in over 50% of cancers. Decoy FAS
ligands prevent extracellular apoptosis activation.
o Kinases, including MAPK and P13K/AKT, are key regulators of
apoptosis.

Antisenescent
o The Hayflick factors which regulate senescence (Telomere shortening,
accumulation of DNA damage and activation of the ARF/INK4a/INK4b
locus) also act as tumour suppressors. In cancer cells, telomerase is
upregulated and gene mutations lead to a faulty senescence mechanism.

Invasive
o Arguably the area where targeted therapies could have the most important
role, metastasis is the commonest cause of cancer death. Cancer cells
break free from their neighbouring cells and extracellular matrix and enter
the blood and lymphatic systems.
o In breast cancer, bone metastases affect 69% of those with advanced
disease, with bone a particularly vulnerable site given its well-vascularised
red marrow.(7)
Existing therapies have, by design or by accident, addressed some of these qualities. For
example, the antimetabolite chemotherapeutic methotrexate acts as a dihydrofolate
reductase inhibitor, inhibiting synthesis of nucleotides and therefore proliferation and
growth. Radiotherapy also prevents the survival and proliferation of cancer cells via
ionising radiation. Surgery simply removes the tumour bulk, which may be curative in
some cancers either alone or in combination with prior or subsequent treatments, or
provide symptomatic relief. In some cancer types, these methods are becoming
increasingly sophisticated. For example, in liver carcinoma, targeted radiofrequency
ablation, direct radiotherapy via yttrium microspheres and arterial embolisation are
revolutionising treatment of patients with moderate to palliative disease. However,
cancer is still outwitting these approaches, and in my view, many research centres are
focussing on new technology and crude methods of blocking the cancer waterfall
ignoring the biological basis of cancer, which is in itself still being explored. As such,
targeted therapies seem a far more logical approach to not just blocking the waterfall, but
sealing it off for good.
Breast cancer and targeted therapies
The National Cancer Institute in the United States identifies hormonal therapies such as
estrogen receptor modulators (e.g. tamoxifen, fulvestrant) and aromatase inhibitors (e.g.
letrozole, exemestane) as the first targeted therapies.(8) These have revolutionised breast
cancer therapy, although really they should be considered separately to novel targeted
therapies.
Targeted therapies can be broadly divided into monoclonal antibodies and small molecule
inhibitors.
Trastuzumab (or as it is better, known, Herceptin) targets the extracellular domain of
HER-2 (Human epidermal growth factor receptor 2), thereby inhibiting dimerisation and
activation of the receptor.’s downstream pathways HER- 2 is internalized and destroyed.
HER-2 is overexpressed in 25% of breast cancers, which tend to be particularly
aggressive. A classic example of monoclonab antibody therapy, Slamon and colleagues
completed a revolutionary study demonstrating its superiority with chemotherapy over
chemotherapy alone in metastatic breast cancer in terms of time to progression, response
rate and survival.(9) Subsequent work by Piccard-Gebhard and colleagues in a large
international, multicentre trial demonstrated a survival advantage at one year.(10) It is
now recommended by NICE as adjuvant therapy for early breast cancer.
Small molecule inhibitors, include lapatinib, an inhibitor of the intracellular domain of
the receptor’s tyrosine kinase, thereby blocking autophosphorylation via the ATP binding
domain. In 2006, Geyer published a landmark study exploring lapatinib with
capecitabine versus capecitabine alone in advanced HER-2 positive breast cancer that had
progressed despite treatment including anthracyclines, a taxane trastuzumab in terms of
disease progression.(11) In the absence of recommendation by NICE, it is only used in
exceptional cases or in clinical trials such as that recently completed by Coombes and
colleagues at Imperial College London (Clinical Trial no: ISRCTN71165034). Given
that advanced disease and its associated metastases are a more common cause of patient
death than the primary tumour, this is a significant area of progress. Other small
molecule inhibitors include intracellular kinase inhibitors and, notably in breast cancer,
conserved site inhibitors such as Poly(ADP-Ribose) Polymerase (PARP) Inhibitors.
These have a particular role in patients with a BRCA1/2 mutation by inhibiting normal
DNA repair mechanisms and leading cancer cells with a BRCA mutation to expire. Fong
et al demonstrated that Olaparib has few side effects and inhibits tumour activity.(13)
Although this would only benefit a small proportion of patients, Tutt and colleagues
identified in a recent ‘proof-of-concept’ study that showed a ‘favourable therapeutic
index’ for olaparib.(14)
Not all targeted agents have found success, and it is clear that we must take care in
interpreting studies’ findings. Bevacizumab, a VEGF-binding agent, prevents the
interaction between VEGF and various receptors, including VEGFR. Work by Miller
and colleagues, and thereafter Hurwitz’s group (although this was in colorectal cancer),
which explored bevacizumab in combination with various chemotherapeutic regimes,
identified improved progression free survival but no overall increase in survival.(15,16)
As such, NICE does not recommend bevacizumab,. Ongoing trials such as the Artemis
trial in early breast cancer may yield enlightening results.
There are other Hallmarks that these examples do not address – inhibitors of caspase
activation, telomerase inhibitors and metallomatrix proteinase (MMP) inhibitors are other
therapeutic agents under investigation.
Bone metastasis
An area of personal interest is bone metastasis, one of the major causes of morbidity and
mortality among breast cancer patients. A significant cause of morbidity and ultimately
mortality, the diagnostic methods for bone metastasis are predominantly image based,
with no clinical use of potential biomarkers of bone turnover. Further, therapeutic options
remain limited to bisphosphonates and radiotherapy.
During my research in this area, I collected plasma samples from breast cancer patients
attending oncology outpatient clinics. From the obvious difficulties, such as using a
walking stick or a wheelchair, to the ones only understood through conversation, such as
the pain, the psychological difficulty of accepting one’s diagnosis and the worry of how
much worse it will get, it is clear that we need more answers and solutions.
My research was concerned with Endo180, although many other targeted therapies, such
as src kinase inhibitors, are also being developed to treat bone metastasis. Endo180 is a
transmembrane recycling collagen receptor involved in both collagen remodeling and cell
migration and metastasis. By exploring its potential role in bone metastasis in breast
cancer, and observing the work of other research groups into different targets, I
appreciated the difficulties of finding potential targets, characterizing the target and
eventually designing agents to modify its activity. It is also clear that targeting the
interactions between the cells and their microenvironment will be vital for future
therapeutic agents. (Figure 3)
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Figure 3: Cell-cell and cell-microenvironment interactions.
Limitations
Biologically, the main target therapies, monoclonal antibodies and small molecule
inhibitors, have several limitations. The former most be administered intravenously, are
expensive, can only reach extracellular targets and are associated with allergic reactions.
Small molecule inhibitors are short acting and can have significant off-target toxic
effects. We must still identify potential targets, and need to modify existing agents to
maximize their effects, such as radioimmunotherapeutic antibodies and immune
response-potentiating agents.
Other problems include communication. To most members of the general public, the
information they receive about targeted therapies is via news reports of patients denied
expensive treatments due to the postcode lottery. Although discussing the health
economics of pharmaceutical agents would be another essay in itself, it cannot be ignored
that these therapies are often expensive and offer two to three extra months of life at best.
Drug companies increasingly determine success by ‘disease free survival’ rather than
overall survival. A classic example of where this has led to misleadingly positive results
is in the case of bevacizumab, where improved disease free survival did not translate into
improved survival. The public is being misled by drug companies, interpreted by the
media, who are keen for a quick fix to The Cancer Problem. The ethics of cancer drug
trials is a further cause for concern. Patients invited to participate in current targeted
cancer trials may participate with false hope of a wonder cure, despite the low rate of
success of cancer trials compared with other pharmaceutical agents.
Future Directions and Challenges
The future for targeted therapies could be an exciting one. We may be on the brink of
truly personalized cancer therapy. If we can identify all the possible targets, and, more
importantly, a means of detecting them clinically, an individual’s cancer could be
characterized and a detailed map generated. A personalized therapeutic strategy could
then be developed. Such a strategy could even eliminate the cancer completely.
But before we get ahead of ourselves, there are still significant challenges ahead.
Research is facing the most difficult financial challenges in recent years, particularly with
renewed government enthusiasm for teaching over research and charitable funding ever
more challenging to obtain. Further, other targeted agents, such as sunitinib, which is
used in renal cell carcinoma, recommended by NICE despite a cost per Quality Adjusted
Life Years (QALY) of £79 000, are occasionally recommended because they fill a
significant treatment gap. Such an argument is unlikely to be won for an expensive
breast cancer targeted agent when so many other therapeutic options exist.
The high quality of patient care, alongside improved understanding and resolving of the
limitations of chemotherapy, radiotherapy and surgery makes it harder for targeted
therapies to show a clear benefit over these widely accepted treatment modalities. It is
far more appealing to improve the devil you know rather than constantly enter the
unknown. The public has high expectations, and it remains a slow process, getting from
the laboratory to the patient – perhaps we should review the processes for getting drugs
through the system and create a more coordinated research effort. Although some cancer
research partnerships exist, it is still a long way off the kind of research consortia that
have been developed to solve other clinical problems, for example, the UK Cystic
Fibrosis Gene Therapy Consortium.
In conclusion, targeted agents have revolutionized how we look at cancer therapeutics
and cancer biology. However we have a long way to go in fully understanding the
mechanisms involved, and significant financial, communication and biological issues
must be overcome before we can not only hit cancer where it hurts, but where it is fatal to
its survival.
References:
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Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N
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M, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or
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Figures:
Figure 1: Breast Cancer incidence in the UK - Office for National Statistics. Breast
Cancer: Incidence rates rise, mortality rates fall. ; 2010. Accessed 29/7/11
Figure 2: Hallmarks of Cancer - Hanahan D, Weinberg RA. The hallmarks of cancer.
Cell. 2000 Jan 7;100(1):57-70.
Figure 3: Cell-cell and cell-microenvironment interactions - Hanahan D, Weinberg RA.,
Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74.