Rectal Cancer (NeoRect) study at Clarunis
Interview with Dr. Salvatore Piscuoglio, Head of the research group of the Visceral Surgery and Precision Medicine at Clarunis, University Center for Gastrointestinal and Liver Diseases. By Dr. Sebastian Staubli.
Dr. Piscuoglio, can you tell us a little bit about yourself and your background?
Saltvatore Piscuoglio: «My name is Salvatore Piscuoglio, I am the Head of the research group of the Visceral Surgery and Precision Medicine at Clarunis (Department of Biomedicine, University of Basel). I am originally from Naples, Italy, where I obtained my B.Sc and M.Sc. in Medical Biotechnology.
In 2009 I moved to Basel and obtained my PhD in Genetics in 2012 from the Department of Biomedicine. From 2013 to 2016 I did my postdoctoral experience in New York at the Memorial Sloan Kettering Cancer Center where I specialized in applying next generation sequencing technologies for the identification of new driver genes in human cancer.
Finally, in 2016 I was back in Basel first as a Principal Investigator and co-Director of the research activities at the Institute of Medical Genetics and Pathology, then in 2019 as Head of the research group of the Visceral Surgery and Precision Medicine at Clarunis. In 2021 I was awarded the Clöetta Medical position for the identification of new biomarkers in rectal cancer (NeoRect).»
Can you explain the idea of the NeoRect study?
S. P.: «The idea about the NeoRect study took off in a meeting with Prof. Markus von Flüe. He pointed out that patients with locally advanced, non-metastatic rectal cancers are typically treated with neoadjuvant chemoradiotherapy followed by surgical excision to remove any residual disease.
Post-surgery histologic analysis reveals that ~25% of the patients achieve complete response to chemoradiotherapy, meaning that they would not have needed surgical intervention. For the remaining patients that do not achieve complete response to chemoradiotherapy, alternative therapeutic options would be desirable. For these reasons we decided to design a study where the major aim was the identification of robust biomarkers that may predict which patients would likely achieve good response to chemoradiotherapy, thus sparing them the unnecessary surgery. On the other hand, to derive model systems that reflect the biological behavior of the tumors in individual patients to test alternative therapeutic options in an ex vivo/ in vivo manner.»
Can you walk us through the processing steps of the samples we send you from the hospital? What are the important details to look out for?
S. P.: «Once a patient consents for the NeoRect study and the sample collection procedure is scheduled, the person responsible from the laboratory (Dr. Mairene Coto) will collect the specimen directly from the operation theater and place them in a solution that retain the viability of the cells. This is a very important step because having live cells is vital for the generation of the patient derived organoids as ex-vivo models. The samples collected prior to neoadjuvant chemoradiotherapy will be used for the following tasks:
- Diagnostics, immunophenotyping (e.g. IHC)
- Whole-exome and (sc)RNA-sequencing, methylation and microbiome analyses
- Quantitative proteomics and phosphoproteomics analyses
- Organoid generation for ex-vivo drug profiling
- In-vivo models from patient-derived organoids
After surgery, a gross examination of the surgical specimens will be performed and the suspected residual disease will be dissected into several pieces. Similar to the pre-treatment biopsies, one portion will be used for diagnostics, and, when sufficient tumor cells are present, the remainder will be subjected to multi-omics profiling and ex vivo model generation.»
What are you specifically looking for in the samples we send you? Are there any markers you take a particular interest in? If so, why?
S. P.: «So far clinically applicable biomarkers have not been identified to stratify patients to optimise treatment plans. One of the main reasons is that these cancers have diverse etiologies and molecular profiles, and it is highly likely that there exist multiple distinct mechanisms of resistance/sensitivity to chemoradiotherapy among patients, which severely hampers our ability to derive meaningful predictive biomarkers. Given the molecular heterogeneity of rectal cancer, it is unsurprising that single-molecule biomarkers or biomarkers based on a single type of molecular information have failed to translate into the clinic.
In this study we hypothesize that biomarker identification using an unbiased, data-driven, multi-omics approach in conjunction with in-vivo/ ex-vivo drug testing will help clinicians stratify patients based on their need for surgical intervention after neoadjuvant chemoradiotherapy and will lay the foundation for future studies on the discovery of biomarkers and treatment options for these patients.
So to answer your question, at the moment we will look at the data that will be generated in an unbiased, data-driven manner to identify putative biomarkers or molecular signatures that will be then validated in a different cohort of patients and if successful we may start a clinical trial to test these markers.»
Do you see differences in the speed and extent of growth of tumor organoids between different patients? If so, what could this mean?
S. P.: «It has been demonstrated that organoids growth may be linked to the tumor stage and other factors. In our experience on rectal cancer so far, we have a success rate of ~90% and this is in line with other studies on rectal cancer organoids. Given that the study has just been started, it is too early to correlate molecular/ clinical features with the organoid growth rate.»
Are you aware of any similar studies?
S. P.: «I am sure that around the world there are similar studies ongoing. So far, many molecular biomarkers have been proposed but none has reached the clinic. For instance, alterations in the TP53 and KRAS genes have been associated with unfavourable and favourable response, respectively, to neoadjuvant chemoradiotherapy. Gene expression profiling has also been used to derive predictive gene signatures, variably involving genes related to the immune system, DNA replication and repair, proliferation, apoptosis, gene transcription, cell cycle and drug metabolism. A large number of protein markers have also been associated with response to neoadjuvant chemoradiotherapy including the serum carcinoembryonic antigen. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), COX-2, thymidylate synthase, the p53 tumor suppressor and key mediators of cell cycle arrest (p21, p27) and apoptosis (Bcl-2) are also among the protein markers currently of interest as potential predictors of pathological response, prognosis and recurrence-free survival in rectal cancer patients following neoadjuvant therapy. Features of the tumor immune microenvironment including densities of tumor-infiltrating lymphocytes and programmed cell death ligand 1 (PD-L1) expression have also been investigated as predictive biomarkers but the results have thus far been inconsistent.
Furthermore, some studies have recently been published suggesting the utility of rectal cancer organoids to understand response to therapy and to generate in vivo models for the testing of novel drugs in rectal cancer patients.
Finally, I believe that if other scientific studies are running in parallel with ours, this will help to increase the number of subjects where the results of a single study can be cross validated to obtain much strong results.»
How can this study potentially affect treatment of rectal cancer in the future?
S. P.: «The innovation of this project is threefold. Firstly, this clinical study represents a one-of-a-kind study integrating many layers of molecular profiling in the identification of predictive biomarker/s of response to neoadjuvant chemoradiotherapy. The power to detect robust and meaningful biomarkers is increased substantially by identifying the candidate biomarkers that are consistent across the many layers of molecular information.
Secondly, one of the most important contributions of this study to precision medicine in rectal cancer is the establishment of large biorepositories of patient-derived organoids and patient-derived xenografts. These models represent renewable sources of clinical tissue materials that recapitulate the genetic/genomic diversity of the disease. They can be used in understanding the molecular mechanisms of carcinogenesis and drug resistance in rectal cancer, delineating tumor heterogeneity and evolution, ex/in-vivo drug testing to predict response to a given agent, and developing new drugs in the preclinical setting.
Thirdly, we will be using state-of-the-art drug screening tools to identify putative predictive biomarkers to drugs that are not currently used in routine care. The identification of such biomarkers is an important step towards the successful implementation of precision medicine in rectal cancer patients.»
How do you expect patients to be able to benefit from this research, directly and indirectly?
S. P.: «Being able to accurately predict response to neoadjuvant chemoradiotherapy and other drug/s would enable tailoring treatment plans to individual patients. If successful, the results from this project may enhance precision medicine for rectal cancer patients and may pave the way for the discovery of new treatments for this deadly disease. Additionally, the integration of clinicopathological, molecular and functional data will provide mechanistic insights into tumor biology of rectal cancer.
Having a set of markers or molecular signatures that are able to predict response/ resistance to neoadjuvant chemoradiotherapy with good sensitivity and specificity will allow us to design specific prospective clinical trials. This will help us to stratify patients stratify patients based on their need for surgical intervention after neoadjuvant chemoradiotherapy and thus spare unnecessary invasive procedure.»
How would you describe working with the team at Clarunis?
S. P.: «The team at Clarunis has been incredible. The design of this complex study has been the result of huge teamwork. Every aspect of the NeoRect study, from the number of biopsies to be taken and the collection procedures to which drugs to be used for ex vivo testing, has been discussed and agreed with surgeons, gastroenterologists, oncologists and pathologists. The support of all the people involved has been exceptional and the level of organization reached so far between the clinics and the research laboratory has been critical to make this project happen.»
As a researcher, how do you foresee the future of cancer treatment in general and rectal cancer in specific?
S. P.: «I have high hopes for precision oncology, where clinical decisions are made on an individual level based on their clinical histories and molecular profiles. We are already starting to see results in other cancer types such as lung cancers. I believe that rectal cancer will move in a similar direction, where such personalized treatments will lead to better patient outcomes with fewer adverse effects. I think we have made huge steps forward, but we have not yet realized the full potential of precision medicine.»
Do you have a favorite thing about Basel?
S. P.: «I have lived in Basel for more than 10 years, this makes Basel my home. Here is the place where my daughter is born and where I am creating my family and my professional career. During this time, I was able to appreciate the city and Switzerland in general. In particular, of Basel I love the scientific environment and the tight connection between the university and the pharmaceutical companies. I love walking along the Rhein and having BBQ in the many green spaces Basel has to offer.»