cancers

Conference Report
Innovative Technologies Changing Cancer Treatment
Sara Charmsaz 1,† ID , Maria Prencipe 2,† , Maeve Kiely 3,† , Graham P. Pidgeon 4 and
Denis M. Collins 5, *
1 RCSI Surgery, Royal College of Surgeons in Ireland, 31A York Street, Dublin 2, Ireland; saracharmsaz@rcsi.ie
2 School of Biomolecular and Biomedical Research, UCD Conway Institute of Biomolecular and Biomedical
Research, University College Dublin, Belfield, Dublin 4, Ireland; maria.prencipe@ucd.ie
3 Graduate Entry Medical School, University of Limerick, Limerick, Ireland; maeve.kiely@ul.ie
4 Trinity Translational Medicine Institute (TTMI), St. James’s Hospital and Trinity College Dublin,
Dublin 2, Ireland; PIDGEONG@tcd.ie
5 Cancer Biotherapeutics, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin,
Dublin 9, Ireland
* Correspondence: denis.collins@dcu.ie; Tel.: +353-1-700-5647
† These authors contributed equally to this work.




Received: 17 May 2018; Accepted: 14 June 2018; Published: 19 June 2018


Abstract: Conventional therapies for cancer such as chemotherapy and radiotherapy remain a
mainstay in treatment, but in many cases a targeted approach is lacking, and patients can be
vulnerable to drug resistance. In recent years, novel concepts have been emerging to improve
the traditional therapeutic options in cancers with poor survival outcomes. New therapeutic
strategies involving areas like energy metabolism and extracellular vesicles along with advances
in immunotherapy and nanotechnology are driving the next generation of cancer treatments.
The development of fields such as theranostics in nanomedicine is also opening new doors for targeted
drug delivery and nano-imaging. Here we discuss the use of innovative technologies presented at
the Irish Association for Cancer Research (IACR) Annual Meeting, highlighting examples of where
new approaches may lead to promising new treatment options for a range of cancer types.

Keywords: cancer therapeutics; emerging technologies; nanomedicine; computational imaging;

cellular stress; radiosensitizing; exosomes

1. Introduction
The transformative impact of technological advances on cancer research featured prominently at
the 54th annual meeting of the Irish Association for Cancer Research (IACR). Translational research is
advancing its enormous potential at breakneck speed, as mature applied technologies meet with the
innovations of multi-disciplinary research groups. High-throughput omics studies (e.g., genomics,
proteomics, metabolomics, transcriptomics) utilize new technologies to generate enormous datasets
that are being mined with ever-more specificity and value [1]. The potential of routine diagnostic
technologies, including magnetic resonance imaging (MRI), computed tomography (CT), positron
emission tomography (PET) imaging, and immunohistochemical analysis of tissues is being fully
understood through the development of the fields of radiomics and pathomics [2,3]. Nanomedicine
is harnessing the power of nanotechnology to improve drug delivery, pharmaceutical properties,
imaging, and diagnosis, establishing the area of theranostics [4,5]. The ability to isolate, characterise,
and functionally phenotype nanometer-scale extracellular vesicles is opening up new possibilities
for the therapeutic and diagnostic use of these intercellular RNA, DNA, and protein carriers [6].
Tissue processing and high-throughput fluorimetry underpins novel tools like BH3 profiling to
predict cellular response to chemotherapeutic agents [7]. The concept of sensitizing cancer cells

Cancers 2018, 10, 208; doi:10.3390/cancers10060208 www.mdpi.com/journal/cancers

Cancers 2018, 10, 208 2 of 9

to radiotherapy has been investigated for close to 50 years but new advances are seeing more effective
small molecule (oxygen/oxygen mimics), macromolecule (miRNA, siRNA, peptide), and engineered
nanomaterial-based radiosensitisers emerge [8]. Here we discuss novel studies presented at the 2018
IACR Annual Meeting, which showcased these cutting-edge technologies and their applications in the
cancer research arena.

2. Nanomedicine in Cancer Treatment

In recent years, the development of nanomedicine has shown great promise for both advanced
imaging and therapeutic capabilities against cancer. Nanomedicine is a form of nanotechnology
applied to the biomedical field, in which engineered nanoparticles (NPs) with dimensions of less
than 100 nm are used to treat disease, primarily cancer. With respect to traditional cancer therapies,
such smart and highly engineered NPs provide advantages in passively or actively targeting drugs,
with high solubility, bioavailability, biocompatibility, and multifunctionality. These NPs can be used in
multimodal therapies. Several kinds of smart NPs have thus been developed for targeted drug delivery,
as multi-target inhibitors, and as nano-imaging tools. Only recently, the combination of both therapy
and diagnosis was proposed to operate using the same nanoparticle, thus introducing the concept of
theranostics to the field of nanomedicine field [9]. The core concept is thus to have a multi-functional
NP able to perform imaging and diagnosis at the site of work, i.e., cancer cells, and also treat them.
The therapy would possibly be delivered in a multi-modal approach, for example, combining drug
or gene delivery with external stimuli, like hyperthermal, photothermal, or photodynamic (PDT)
treatments, thus attacking the cancer cells with different mechanisms. Moreover, high colloidal
stability in biological fluids, selective targeting capabilities, and final biodegradation are other features
included in these highly engineered theranostics nanoplatforms. In this way, nanomedicine applied
with theranostic nanoparticles shows promise and may potentially be able to overcome the common
disadvantages of conventional therapies against cancer, i.e., lack of high selectivity and discrimination
among healthy and cancer cells, adverse effects towards normal cells, acquired drug resistance, and
lack of early diagnosis and methods of molecular imaging.
Prof. Valentina Cauda and her group (Department of Applied Science and Technology (DISAT) of
Politecnico di Torino, Turin, Italy) have reported some recent results on smart nanoparticles that are
able to successfully visualize and kill cancer cells in vitro. At first, insights on silica nanoparticles with a
highly porous structures and tiny nanopores of around 3–4 nm in diameter were given, i.e., mesoporous
silica nanoparticles (MSNs). These MSNs can be easily chemically functionalized [10] to show colloidal
and anti-thrombogenic behaviour in biological fluids [11], preventing unwanted aggregation or early
biodegradation [12], and targeting cancer cells [13]. Moreover, these MSNs are able to incorporate
anticancer drugs [14] and/or fluorescent molecule reporters [15] for both drug delivery and molecular
imaging at the desired site of interest.
Particular attention was given to a novel and multifunctional nanoparticle based on a dense
nanocrystalline metal oxide core (zinc oxide) shielded with a lipidic bilayer able to be highly stable
in biological media, even for long-term applications, with the intention of rendering it injectable
into the blood stream [16]. Moreover, its therapeutic capabilities were reported to be dependent
not on drug delivery but on a stimuli-responsive mechanism. Ultraviolet light stimulation for few
seconds (photodynamic therapy—PDT) is able to excite the nanocrystalline particles and generate,
intracellularly, highly toxic reactive oxygen species (ROS) [17]. The first cytotoxicity tests on Hela cancer
cells showed a cell killing rate of 65–80% when the nanoparticles were stimuli-activated. There was
no effect on tumour cell viability following UV stimulation on its own or using the nanoparticles
without stimulation.
These results show the promising role of highly engineered and functionalized nanoparticles for
cancer treatment and molecular imaging. However, global success in cancer therapies based on such
nanomedicine tools can be achieved only with a profound knowledge of tumour biology, markers,
and microenvironment.
Cancers 2018, 10, 208 3 of 9

3. Radiomics and Pathomics

Traditional biology generally attempts to molecularly dissect diseases and study them part
by part with the idea that the sum of knowledge of the parts will help explain the disease as a
whole. This strategy has only rarely been successful when trying to understand the causes and
cures for complex diseases. Therefore, a systems-based approach seems a better strategy to study and
understand this complexity. Specifically, this approach takes into account a large number of interrelated
variables such as gene expression profile, tumour cellular architecture, and microenvironment
(seen through histological image features), three-dimensional tissue architecture and vascularization
(seen through dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI)), and metabolic
features (seen through magnetic resonance spectroscopy (MRS) or PET), to identify a specific disease
phenotype. Prof. Anant Madabhushi (Director of the Center for Computational Imaging and
Personalized Diagnostics (CCIPD) at Case Western Reserve University, Cleveland, OH, USA) presented
some of the tools that they have developed to integrate and correlate heterogeneous biological data
spanning different spatial and temporal scales, modalities, and functionalities. These tools include
computerized feature analysis methods for extracting sub-visual attributes for characterizing disease
appearance and behaviour on radiographic (radiomics) and digitized pathology images (pathomics).
At the IACR meeting, Prof. Madabhushi presented a number of examples of the application of
radiomics and pathomics to predict disease outcome, recurrence, progression, and response to therapy
which are reported below.
(1) Computational imaging of digital pathology for risk stratification of cancers: Prof. Madabhushi’s
group has been developing powerful computerized image-based risk assessment tools for the mining
of digital pathology images for outcome prediction and risk stratification of prostate cancers [18],
breast cancers [19], and p16+ oropharyngeal cancers [20]. Specifically, Prof Madabhushi’s group
showed that image-derived biomarkers from digitized tissue images of oestrogen receptor-positive
(ER+) breast cancers were highly correlated with Oncotype DX, a USD $4000 21-gene expression panel
for risk stratification of breast cancer [19]. This approach thus has the potential to complement—and
in some cases obviate—the need for more expensive molecular-based assays for personalizing
treatment strategies.
(2) New radiomic approaches for diagnosis and prognosis of disease on radiologic imaging:
Prof. Madabhushi’s group has developed a new image-based descriptor called CoLlAGe
(Co-occurrence of Local Anisotropic Gradient orientations) [21] which allows for quantification of
entropy associated with pixel-level image gradients. The CoLlAGe descriptor has been successfully
used to distinguish between radiation necrosis (a benign effect of radiation therapy) and cancer
recurrence from a routine MRI scan. Currently radiologists are unable to tell these two pathologies
apart using an MRI scan. As a result, thousands of patients with radiation necrosis have to undergo
unnecessary cranial biopsies to confirm absence of cancer.
(3) Fused imaging-molecular predictors of treatment outcome: Prof. Madabhushi presented a
new computational image and bioinformatic algorithm [22] to combine disease patterns (as identified
through histologic imaging) with proteomic data. This leads to better predictors of disease risk
stratification and treatment response. These methods have recently been successfully applied to
predicting disease recurrence in the context of men with prostate cancer where the combined imaging
and omics predictor was shown to be more accurate compared to just imaging or “omics” alone.

4. Enhancing Radiotherapy Treatment

Radiotherapy is a main treatment modality for approximately 50% of cancer patients and second
only to surgery in curative ability. However, the biological mechanisms conferring radioresistance in
inter- and intra-cell types are poorly understood. The importance of the mitochondria and its links
with radiation resistance are topical in the literature. During the last decade, numerous approaches
that selectively target cancer cells by virtue of their mitochondrial defects have been shown to exert
anti-tumour effects [23]. Hypothetically, the most efficient mitochondrial therapies would be those
Cancers 2018, 10, 208 4 of 9

that affect processes in mitochondria linked to key features of the neoplastic phenotype. Damage to
the mitochondria is at the crossroad between normal metabolism and the regulation of cell death,
and represents an important direction for the development of new therapies. Those targets that can
regulate mitochondria function and metabolism and simultaneously increase sensitivity to induction
of apoptosis may be the most effective anti-cancer agents.
Prof. O’Sullivan’s group (Trinity Translational Medicine Institute, Trinity College Dublin) has
a particular focus on understanding the role of the mitochondria and energy metabolism in models
of oesophageal cancer (OAC) radiation resistance. In Ireland, incidence of OAC has increased
by 48% over the past 15 years and the overall cure rate is less than 20% [18]. Consequently, a
multi-modal approach to treating this disease involves neoadjuvant treatment (treatment prior to
surgery) with either chemotherapy alone or combination chemoradiotherapy (neo-CRT) for locally
advanced tumours [24,25]. Unfortunately, only ~30% of patients show a beneficial response with ~70%
of patients receiving a toxic treatment with no benefit. These patients also experience a delay to surgery
which may significantly affect overall patient survival.
Using an isogenic model of OAC radioresistance, Prof. O’Sullivan’s group has shown
that radioresistance is associated with altered mitochondria structure and size. The levels of
random mitochondrial mutations and altered metabolic profiles demonstrated metabolic plasticity,
efficiently switching between glycolysis and oxidative phosphorylation energy metabolism pathways
accompanied by enhanced clonogenic survival [26]. In vivo using patient samples, energy metabolism
as measured by the levels of ATP synthase F1 subunit beta (ATP5B) can significantly segregate
responders and non-responders to neoadjuvant chemoradiation treatment [26].
Through a gastrointestinal drug discovery programme, Prof. O’Sullivan’s group has identified
and patented a novel radiosensitiser with dual anti-metabolic and anti-angiogenic activity. Using
an in vivo zebrafish model and human ex vivo OAC explant models, they have shown this small
molecule inhibitor can significantly reduce both metabolic and anti-angiogenic activity in real time
and in parallel with increasing radiosensitivity in an isogenic model of radioresistance. Importantly,
the action of this novel small molecule is also effective under hypoxic conditions. Prof. O’Sullivan’s
group is building further pre-clinical data on the use of this novel radiosensitiser in the neoadjuvant
treatment setting for gastrointestinal malignancies.

5. RNase-Based Transcriptome Interrogation

Cellular stress responses are essential for tumour suppression in healthy cells. Stress responses
mediated by checkpoints in numerous complex signalling pathways allow the cells time to repair the
damage induced by a plethora of potentially dangerous events (including dysregulated proliferation
and nutrient deprivation) [27]. If the damage cannot be repaired, cells can trigger arrest of the cell
cycle or induce cell death mechanisms as a protective measure. Exploitation of these cellular stress
responses in cancer therapeutics has the potential to slow down cancer cell growth but also to induce
the death of the cancer cell.
The endoplasmic reticulum (ER) is a major site for protein folding and quality control. Tumour
cells need to overcome powerful ER stress responses to survive. However, even when it does this,
the tumour cell can still remain vulnerable to therapeutic opportunities [28]. Dr. Eric Chevet and his
group (Centre de Lutte Contre le Cancer Eugène Marquis, Université de Rennes, Rennes, France) have
demonstrated that ER stress and the unfolded protein response (UPR) play an instrumental role in
the development of glioblastoma multiforme (GBM). GBM is the most severe form of primary brain
cancer, representing more than 15% of all brain tumours [29]. Despite aggressive treatment comprised
of surgical resection and radio/chemotherapy, patient survival post-diagnosis of GBM remains short,
with a median of 15 months [30].
Dr. Chevet has found that the ER stress sensor IRE1alpha (referred to as IRE1) contributes to GBM
progression, impacting both tissue invasion and tumour vascularization. IRE1 is an RNase that signals
by catalysing the splicing of mRNA encoding the transcription factor X-box binding protein 1 (XBP1),
Cancers 2018, 10, 208 5 of 9

in addition to regulating the stability of certain miRNAs and mRNAs through a process known as
regulated IRE1-dependent decay (RIDD). Somatic mutations in the IRE1 gene have been identified
in GBM and other forms of cancer. Taking advantage of the specific signalling outputs of the RNase
domain of IRE1 engaged by distinct GBM-related mutations, they defined specific expression signatures
that were then investigated in the context of human GBM transcriptomes. This approach allowed them
to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumour outcomes. As part
of this response, they demonstrated that the IRE1/XBP1 axis ensures the secretion of pro-inflammatory
chemokines by the tumour cells, thereby promoting the recruitment of tumour-associated macrophages,
microglial cells and to some extent, neutrophils. This was demonstrated with cell lines, primary GBM
lines, and using in vivo GBM orthotopic mouse models and patient tumour samples [31].
This study provides the first demonstration of a dual role of IRE1 downstream signalling in cancer
and opens a new therapeutic window to abrogate tumour progression. This study also indicates that
ER stress as well as UPR and IRE1 signalling might represent appealing targets for the development of
therapeutics that could in turn be used either alone or as adjuvant to the current treatments.

6. Dynamic BH3 Profiling

Apoptosis is one of the main mechanisms of response to cellular stress which function through
clearance of dysfunctional cells that pose a risk to the healthy organism [32]. Apoptosis occurs through
two major pathways: the extrinsic (death receptor pathway) and the intrinsic (mitochondrial pathway).
In the intrinsic apoptotic pathway, a subset of BCL-2 family proteins called “BH3-only” play a key role
in promoting apoptosis in response to cellular stress cues [32]. These BH3-only proteins interact with
other pro-apoptotic and anti-apoptotic proteins members of the BCL-2 family to decide cell fate.
Dr. Letai’s group (Dana-Farber Cancer Institute, Boston, MA, USA) takes a different approach
towards precision medicine, based on the belief that the most important outcome of precision medicine
in cancer is to match the right patient to the right drugs. Many studies on precision medicine are
exclusively focused on the study of the cancer genome. While genomic approaches have yielded some
exciting successes, it must be acknowledged that the vast majority of cancer patients do not derive
direct therapeutic benefit from such approaches. Therefore, new avenues must be investigated to
improve the current situation [33].
One characteristic that genomic approaches have in common with most (if not all) omic approaches
is that they are static studies of the cancer cell. In fact, the first step one takes to initiate most of these
studies is to kill the cancer cell. The valuable functional information from the genomic studies
can be lost when the cancer cell is reduced to a bag of molecules. The emergent properties of the
immense complexity of interactions among macromolecules are poorly predicted by initial condition
measurements alone. Therefore, Dr. Letai’s group has focused on making targeted perturbations of
living, functioning cancer cells. To do this the patient’s cancer cells are put in direct contact with the
therapeutics of interest. Following this perturbation, it is essential to measure a component that rapidly
captures key information about the ability of the therapeutic that kill the cancer cells. To achieve
this, they have focused on profiling BH3-only proteins. BH3 profiling, as shown by IACR member
Dr. Triona Ni Chonghaile (Royal College of Surgeons in Ireland, Dublin, Ireland) [34], can identify
how close a cell is to the threshold of apoptosis. When this approach is preceded by a brief ex vivo
drug treatment, dynamic BH3 profiling can measure the potential of a drug to push a cell closer to the
threshold of apoptosis. Data from Dr. Letai’s group have shown that taking this approach could be an
excellent predictor of the efficacy of a specific drug in vivo. Since an exposure of no more than 24 h is
required, long -term ex vivo culture of cancer cells is not required, rendering this strategy feasible for
almost any primary cancer tissue. Currently Dr. Letai and his group are pursuing this strategy in a
wide variety of both solid and liquid tumours.
Cancers 2018, 10, 208 6 of 9

7. Extracellular Vesicles as a Therapeutic Strategy

Prof. Clotilde Thery (The Institut Curie, Paris, France) delivered the annual Irish Cancer Society
keynote lecture on the molecular and functional diversity of exosomes and other extracellular vesicles
in tumour-immune system cross-talk. Cells secrete different types of extracellular vesicles (EVs) into
their environment with distinct properties depending on their intracellular site of origin. Exosomes
are a subtype of EVs with a mean diameter lower than 150 nm that are formed inside multivesicular
compartments of the endocytic pathway. Exosomes secreted by dendritic cells (DCs) have been shown
to bear functional major histocompatibility complex (MHC) class I and class II molecules able to
activate cognate T lymphocytes and induce anti-tumour immune responses. These findings motivated
the use of DC-derived exosomes in cancer clinical trials although with limited clinical effects. Other
EVs also bear functional immune molecules and may thus represent alternative immunotherapy
tools, but side-by-side comparison of exosomes and other EVs in terms of biochemical and functional
properties must be performed to determine their respective therapeutic values.
Prof. Thery described her recent work optimising the isolation of different subtypes of EVs
simultaneously released by live human primary DCs to characterise their protein composition and
their abilities to activate T lymphocytes. Specific markers to allow isolation and analysis of EVs were an
unmet need. Extensive proteomic analysis identified markers used for exosome identification (MHC,
flotillin, HSP70) as general markers of EVs [35]. Within small EVs, Prof. Thery’s group identified
exosomal and non-exosomal subpopulations that can be differentiated using CD9, CD63 and CD81.
An additional layer of complexity was demonstrated through the findings that the functionality of EV
subtypes produced by immature DCs differs from those derived from mature DCs [36]. When produced
by IFN-gamma matured DCs, both large and mixed exosomal/non-exosomal small EV populations
induce secretion of TH1-cytokines. However, large EVs produced by immature DCs induce secretion
of TH2-associated cytokines with the small EVs maintaining the Th1 cytokine profile. Now that
the isolation methodologies and functional characterisation are advancing, Prof. Thery emphasised
the need to determine the respective roles of exosomes and other EVs in cancer:immune system
cross-talk to fully exploit these potentially powerful and versatile biological tools [37]. EV-TRACK
(http://evtrack.org) is a valuable resource for EV scientists to ensure the standards of EV isolation and
characterisation, while developments in the area can be followed through meetings of the International
Society for Extracellular Vesicles (www.isev.org).

8. Discussion and Concluding Remarks

It is clear that innovative technologies are being utilized to inform and alter our understanding
and treatment of cancer. While all of the technologies discussed at the IACR face challenges and are
still developing, many are already impacting patients. Approved clinical stage nanomedicines are
exemplified by liposomal irinotecan for metastatic pancreatic cancer and nab-paclitaxel for breast
lung and pancreatic cancer [4]. Radiomics approaches have been shown to enable differentiation
of cancerous from noncancerous prostate tissue [38]. Multiple radiosensitisers are currently being
assessed in the clinic across a breadth of disease types including prostate and cervical cancer as well as
glioblastoma [8]. High-throughput transcriptomics such as next-generation RNAseq has become a
cornerstone of translational protocols with gene expression profiles generated from RNA transcripts
forming the basis of tests like Oncotype DX, used routinely to predict treatment benefit in breast
cancer [39]. BH3 and the metabolomic profiling of oesophageal cancers are currently undergoing
clinical investigation [NCT03223662]. Dendritic cell exosomes have been the subject of clinical studies
in lung, colorectal, and breast cancers [40].
Each plenary session at the 2018 IACR annual meeting featured advanced technology employed
directly and indirectly in the research reported. Technology is now essential in the progression of
modern cancer treatment, pushing the boundaries of personalized and targeted medicine to improve
patient outcomes. Exciting new possibilities will continue to emerge as knowledge, technical expertise,
and accessibility converge within multi-disciplinary academic research groups.
Cancers 2018, 10, 208 7 of 9

Author Contributions: Writing—Original Draft Preparation, M.P., S.C., M.K. and D.M.C.; Writing—Review and
Editing, M.P., S.C., M.K. and D.M.C.; Project Administration, M.P., S.C., M.K., D.M.C., G.P.P.
Funding: This work received no external funding.
Acknowledgments: We would like to thank all speakers at the IACR meeting with apologies to those speakers
whose work could not be included. Thank you to the speakers whose work is included and who contributed to
the writing of this report, we are most grateful (Table A1). The IACR annual meeting is organized and run by the
IACR council. We would like to extend thanks to all council members for their efforts in planning such a valuable
and successful international conference. Our thanks to the conference sponsors, whose support allows us to host
international speakers that are global leaders in their fields.
Conflicts of Interest: The authors declare no conflict of interest.

Appendix A
Table A1. Contributing speakers.

Speaker Affiliation
Prof. Valentina Cauda Politecnico di Torino, Italy
Center for Computational Imaging and Personalized Diagnostics, Case
Prof. Anant Madabhushi
Western Reserve University, USA
Trinity Translational Medicine Institute, Trinity College Dublin, St. James’s
Prof. Jacintha O’Sullivan
Hospital, Ireland
Dr. Eric Chevet French Institute of Health and Medical Research, University of Rennes, France
Dr. Anthony Letai Dana-Farber Cancer Institute, Harvard Medical School, USA
French Institute of Health and Medical Research, Institut Curie, PSL Research
Prof. Clotilde Thery
University, France

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