COMPLEXITY
of
CANCER
One of the major problems faced by biological research is that of complexity, a mathematical concept regarding the behaviour of systems with large numbers of elements within it. Understanding how the components in a system work in isolation is often little help when trying to predict how the whole system will behave, because of the complex interactions that are present between the components. Cancer is arguably the most complex biological system of all.
“The whole is greater than the sum of its parts.”
ARISTOTLE
Gastrointestinal cancer encompasses a complex and extensive group of diseases including esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer and many others. Each disease is different, each patient is different, demanding an adapted treatment plan for each individual patient.
Our motivated team spans a broad range of disciplines including gastroenterologists, oncologists, surgeons and biologists, all looking at gastrointestinal cancer from a different angle. This enables us to identify and understand cancer at different levels and helps us to grow and excell in our research field. Our mission is and will always be to ensure, in all integrity, the best care for each person.
RESPONSIBLE
EXPERIENCED
VERSATILE
PROGRESSIVE
Every patient with a cancerous condition should receive the treatment that best suits his or her own situation.
“Primum non nocere.”
HIPPOCRATES
VALUES
of
PERSONALIZED
MEDICINE
Beyond the specific tumor mutations, often the only element used for treatment personalization, we should also take into account the physical state and the patient's body composition, his or her immune status, the composition of the intestinal bacterial flora and the tumoral biological characteristics, including its level of heterogeneity, and sensitivity to treatments
Our research aims to enrich the possibilities of personalized patient care through a multidisciplinary integration of available data and a rapid identification of the treatment’s effect to avoid useless toxicities in case of partial or total ineffciency. First do no harm.
VALUES
of
PERSONALIZED
MEDICINE
SHARING
our
RESEARCH
GUTS Laboratory is founded on the notion of transparency, because we believe that the sharing of scientific knowledge advances public health and serves the betterment of mankind.
A
KIND
GESTURE
The main funding of our projects has currently been obtained
from external grants coming from public sources such as the
F.N.R.S or private sources, including the 'foundation against
cancer', and the King Baudouin Foundation as well as the
'friends of Bordet'.
A couple of our projects are also sponsored by the Industry.
This is however far from being sufficient to cover all are
expenses. Therefore, we would be real grateful if you are
willing to support our research projects.
Donations will go towards all laboratory expenses as well as
investigator's salaries.
A
KIND
GESTURE
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CONTACT
Jules Bordet Institute Gastro-oncology
3rd floor - room 2B
Boulevard de Waterloo 127
1000 Brussels -
Belgium
Artemis
The aim of the Artemis project is to describe in the most extensive way the immune cells present within the tumor, to better determine how these former can impact treatment response or prognosis. These findings will be correlated to viral and bacterial presence in the tumor, and with body mass composition parameters such as obesity or lean muscle mass.
Description
Artemis - Esophageal and gastro-esophagael junction cancer With a new diagnosis in more than 450,000 patients annually, esophageal cancer is the 8th most common cancer worldwide with a poor prognosis as more than 400,000 deaths are recorded per year.
Esophageal cancer consists of two primary types, squamous cell carcinoma, that originates in flat cells lining the upper part of the esophagus and adenocarcinoma, which begins in glandular cells present at the junction of the esophagus and the stomach. Although squamous cell carcinoma is globally predominant, esophageal adenocarcinoma has a higher incidence in Westernized countries.
It has become clear that the microenvironment and especially the immune system plays an important role in cancer development. Still little is known of how the immune system reacts within the tumor. We will use next-generation sequencing technology to deeply characterize the tumoral environment and and its interactions with the tumor cells. Next-generation sequencing technology has revolutionized modern biological science by allowing sequencing of DNA and RNA in a quick and relatively cheap manner.
We will also study the bacterial and viral communities present within the tumor. Indeed, it is well known that bacteria and viruses are in constant interaction with the immune system, modulating its action. Some bacterial communities could potentially even enhance or diminish response to antitumor treatments. Our analysis will therefore shed light on a topic that is gaining more and more interest in the oncology field. "What I like about this project is also what makes it a difficult one : its multidisciplinarity. The project involves molecular biology, bioinformatics, microbiology, anatomo-pathology, medical imaging etc… it is clear that biomedical science has to extend its domains of investigation to look for new therapeutic means." '(Maelle Anciaux, PhD student)
Limonade-P
The Limonade-P study aims to identify biomarkers that allow a very close and personalized monitoring of the effect of a specific treatment in patients with pancreatic cancer. This would allow a more efficient treatment readjustment and avoid useless toxicities.
Description
Limonade-P study Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Few patients are eligible for curative intent surgery with even in these cases a 5-year survival not exceeding 20%.
Chemotherapy only adds little benefit in terms of survival, at the cost of significant toxicities. Hence, there is an urgent need to find predictive biomarkers able to closely monitor the treatments’ effects and consequently adapt therapy in a timely manner to avoid unnecessary toxicities.
It has been shown that KRAS mutations can be detected and followed over time in plasmatic circulating tumor DNA (ctDNA). KRAS is the most commonly mutated gene in PDA, suggesting a potential role in non-invasive cancer diagnosis, monitoring and consequently in the clinical decision-making process. Our study will focus on quantitative changes over time and under treatment of KRAS mutation copy numbers to assess the positive and negative predictive value of ctDNA as an early biomarker of tumor resistance to treatment.
Two different technologies will be used: the IdyllaTM test, a new, fully automated, real-time PCR based molecular diagnostics system with a short runtime, suitable for easy clinical application and the digital droplet PCR guided by next-generation sequencing.
NEOPAC (NCT00359219)
Pancreatic ductal adenocarcinoma (PDAC) remains a highly resistant cancer with poor therapeuticoptions; treating unselected patients population failed to add any significant benefit despite some progress with combined chemotherapy. New therapeutic options are emerging but could be active onlyin subgroups of patients, that should be defined by molecular profiling of the tumor. Genuine understanding of the subtype determinants and responsiveness to therapy is still lacking.
Description
NEOPAC/NEOPAX platform allows treating operable patients according to a window of opportunity master protocol where patients are treated by a/ chemotherapy (folfirinox or gemcitabine-abraxane) 6-8 cycles, b/ short course of immunogenic stereotactic radiation therapy (SBRT) and/or c/immunotherapy (in the future), before surgical resection.
The platform is used as a master protocol that allows to incorporate and evaluate new therapeutic interventions as well as evaluating tumor dynamic changes during the treatments by different techniques (PET, MRI). From these patients, fine needle biopsy of tumor tissues are taken at the time of diagnosis and post resection samples are collected as well.
These tissues are further analyzed by several state-of-the-art molecular biology techniques and novel bioinformatics and “omics” integrative approach, with the aim to identify several PDAC subtypes based on their molecular profile. At the same time it is possible to explore molecular and pathological changes according to different therapeutic interventions. In parallel, the patient's circulating blood DNA is collected at the time of diagnosis and at different time points during follow up of treatment. The blood samples are analysed in order to evaluate and compare the mutations identified in the tumor with those of the circulating DNA.
This approach, called liquid biopsy, is very promising because it allows to quickly obtain information on the profile of the tumor from a blood test. The main goal of the project is to show the feasibility of obtaining this information quickly (2-4 weeks delay), in order to be able to treat patients in a better way. Thanks to this approach, the management of pancreatic cancer should be improved enabling to allocate treatment to patients based on the tumor molecular fingerprint, so each patient would receive a specific treatment with the best chance for response.
Liver metastasis
The main goal of this project is to identify metastatic colorectal cancer patients that will or will not benefit from liver surgery. We will explore the tumor as well as the tumor environment for genetic and immune markers.
Description
Liver metastasis In patients with metastatic colorectal cancer, surgery represents the only potentially curative option.
After curative-intent resection, 5-year overall survival ranges from 35 to 50%, while cure, defined as disease-free survival superior to 10 years may reach 20 to 25%. In contrast, in non-operated patients treated with chemotherapy only, survivals exceeding 3 years remain exceptional.
Accordingly, surgery is proposed as the first choice in all patients with technically resectable colorectal cancer with liver metastases. Among patients operated with curative-intent, the analysis of survival outcomes reveals 2 different profiles. First, a substantial proportion of patients in whom the tumor will rapidly reappear after surgery, leading to cancer-related death in the first postoperative years. Second, a population in whom long-term survival is obtained, eventually after multiple liver resections.
This study involves the early identification of these 2 categories of patients. We aim to improve the selection process and reduce the risk of futile surgery in patients with aggressive tumor behavior in whom surgery will not significantly improve the prognosis and to recognize patients with oligometastatic disease who will benefit from surgery. Therefore, a multidisciplinary platform is organized to explore different potential markers of tumor biology, including immunology and genetic tumor sequencing.
PePiTA (NCT00994864)
Despite being the standard of care in stage III colon cancer, FOLFOX chemotherapy is associated with high toxicities. The importance of the PePiTA study is to individualize the treatment and avoid toxicities in patients that do not respond to FOLFOX by searching for genomic and imaging biomarkers of non-response.
Description
PePiTA Colorectal cancer (CRC) is a major public health problem accounting for over one million new cases and about half a million deaths worldwide per year.
In Belgium, there are about 7700 new patients per year. Even with limited disease, the risk of recurrence is high despite intended curative surgery. The most important prognostic indicator of survival in early colon cancer is tumour stage, determined by the depth of penetration through the bowel wall and involvement of regional lymph nodes.
Adjuvant chemotherapy such as FOLFOX is the current standard of care in stage III colon cancer, associated with a statistically significant improvement in overall survival compared to surgery alone. Yet, the majority of patients are exposed to a toxic and expensive therapy for the theoretical benefit of a small minority. In order to reduce unnecessary toxicity and the administration of ineffective therapies to colon cancer patients, one needs to detect specific and sensitive biomarkers that predict tumor burden and therapy response.
The main goal of this research project is to assess the genomic factors that correlate with response to FOLFOX treatment in patients with stage III colon cancer by the use of Next generation sequencing (NGS) technology. The response to treatment will be guided by metabolic imaging using FDG PET/CT in patients included in the clinical trial PePITA.
RegARd-c (NCT01929616)
The goal of the Regard-c study is to identify markers of non-response to regorafenib therapy in patients with chemorefractory colorectal cancer. This would avoid needless toxicities and allow a more efficient redirection of the treatment plan.
Description
RegARd-C – Colorectal cancer Colorectal cancer affects about 150.000 people per year in Western Europe. About half of the patients with colorectal cancer are or will become metastatic, with only 20 % of them showing resectable metastatic disease.
The RegARd-C study includes patients with advanced colorectal cancer that do not respond to standard chemotherapy treatments. In order to increase their life expectancy, targeted therapy drugs have been developed, such as regorafenib (Stivarga) that affect specific parts of cancer cells.
However, this drug is not efficient in all patients and comes along with significant side effects. Therefore the aim of RegARd-C is to identify rapidly patients whose regorafenib treatment is inefficient in order to avoid them unnecessary related toxicities. To achieve this, we will monitor patients with ‘liquid biopsies’ or blood samples containing DNA fragments originating from cancer cells that are released in the blood (circulating tumor DNA). More specifically, we will collect patient’s blood samples before treatment initiation in order to investigate the genetic composition of the tumor.
By collecting blood samples as early as 14 days of treatment initiation and also in follow-up, we can investigate if a patient responds or not to the treatment or if he is developing resistance to regorafenib in a later stage. “Working in the field of cancer research was obvious to me as it affected my family as many others. My work involves the examination of circulating tumor DNA. It can become a way to assess early treatment effectiveness and offer clinicians the opportunity to monitor disease in order to readjust patient’s treatment for a more personalized medicine.” (Pashalina Kehagias, PhD student)
CORIOLAN (NCT01591590)
The CORIOLAN study aims to evaluate the spontaneous evolution of the tumor in patients with advanced colorectal cancer without any treatment. We will use imaging as well as genomic analyses to distinguish patients with a slow tumor growth from patients with more aggressive tumors.
Description
CORIOLAN Colorectal cancer affects about 150.000 people per year in Western Europe. Although surgery is a curative treatment, about half of the patients will experience a metastatic spread of their disease, which will in the vast majority of cases lead to the patient’s death.
Current management recommendations guide clinicians on the basis of anatomical or clinico-biologic considerations (ECOG general status, number of metastatic sites, alkaline phosphatases levels, transaminases levels) describing the patients’ clinical status more than the tumor biology.
The clinical aspects provide however only a partial picture of the situation. The natural history of tumors is a poorly studied subject, although often discussed by clinicians. The clinical evidence of some tumors aggressiveness as opposed to some other’s indolent behavior has never been formally assessed in daily practice or in clinical studies and remains largely unpredictable. The patient’s populations are in fact a mix between different tumoral phenotypes that while carrying the same apparent disease evolve with different outcomes.
The CORIOLAN study aims to assess the spontaneous evolution of the tumor measured by serial FDG PET-CT imaging without any intercurrent antitumor therapy and to investigate its impact on prognosis in patients with advanced colorectal cancer. We are also looking at several genetic determinants of tumoral progression available in the plasma via ‘liquid biopsies’.
Chronos & kairos
The Chronos & Kairos study aims to create a database of integrated clinical data AND biological information coming from tumoral samples, stool samples and serial blood samples. This database will try to describe for each patient included in parallel both its clinical history and the evolution of its tumoral genome, of his immune system as well as the composition of his microbiome. This will provide invaluable resources for understanding the mechanisms of evolution of the disease, its resistance to treatments and will allow future research in various tumor types.
Description
Chronos & Kairos
“The ancient Greeks had two words for time, chronos and kairos. While the former refers to chronological or sequential time, the latter signifies a time lapse, a moment of indeterminate time in which everything happens. While chronos is quantitative, kairos has a qualitative nature.”
The Chronos & Kairos study aims to create a prospective database of integrated clinical data AND biological information coming from tumoral samples, stool samples and serial blood samples. This database will try to describe for each patient included in parallel both its clinical history and the evolution of its tumoral genome,
the monitoring of his immune system as well as the composition of his microbiome. This will provide invaluable resources for understanding the mechanisms of evolution of the disease, its resistance to treatments and will allow future research in various tumor types.
Body composition
The body mass composition assessment project aims to globally assess the quantity and quality of muscle and adipose tissues in several digestive cancers. Although neglected in clinical routine, these markers could add major prognostic information, independently of cancer stage.
Description
Body Composition While clinicians in general accept tumoral characteristics (grade, stage, nodal involvement and distant metastasis) as prognostic factors for cancer, they often disregard that the body composition of a patient could also add major prognostic information, independently of stage factors.
Abnormal body composition including obesity, cachexia and sarcopenia are risk factors to contract cancer but may also affect the response to treatment. Obesity is defined by the body mass index (BMI) value and is in rapid rise worldwide. It is now recognized as an important risk factor of many cancers, including colorectal cancer.
Cachexia is defined as “a multifactorial syndrome characterized by a loss of skeletal muscle mass (with or without fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment”. Cachexia diagnostic criteria include either >5% weight loss over the past 6 months or >2% weight loss associated with either BMI<20 or sarcopenia. Sarcopenia is used to describe age-related decreasing skeletal muscle mass. Sarcopenia affects 5-13% of 60-70 year-olds and 11-50% of those ≥80 years.
The body composition studies in our laboratory involve the delineation of muscle, subcutaneous fat and visceral fat on diagnostic and follow-up CT scans and investigate their impact on prognosis in all gastro-intestinal cancer patients. When we started this research topic a couple of years ago in patients with advanced colorectal cancer, I was really surprised by the obtained results. We saw that not only the quantity of the muscle and the fat had a major impact on survival, but also the quality or density of the fat was equally important. These obtained results motivate me to investigate the impact of body composition in other disease settings. (Caroline Vandeputte, PhD, project manager)