Large-scale biobanking in research

In 2014, Exactis Innovations was created thanks to a $15 million grant awarded to Dr. G. Batist from SSHRC-CIHR-NSERC and with another $15 million from private and public organizations worldwide. This large-scale biobanking effort aims to be active across Canada and already includes multiple Quebec centers such as the CHUM, CHUS, and CHUQ. By creating a much larger database and platform accessible to many, Exactis hopes to create a shift in how we classify patients and identify appropriate groups for clinical trials. In turn, this could lead to an increased rate of cancer targets being discovered and which would accelerate the development and implementation of new treatments in Canada.

Discovering new drugs to target lethal forms of prostate cancer

Current treatment options for advanced prostate cancer include blocking the androgen receptor (AR). However, if cells can reactivate the AR, it leads to castration-resistant prostate cancer, a lethal form of the disease. This reactivation can happen in a number of ways, including mutations to the receptor or by cross-talk with other pathways like NF-κB. Dr. J. Hui Wu’s research team had previously found ionone-based compounds that could block normal and mutated ARs so they went on to use these compounds to test their effectiveness in castration-resistant prostate cancer. Using derivatives of their compounds, they were able to show that one of the derivatives was effective against mutated AR and NF-κB, even at very low-dose levels. Their new compound may be a promising new treatment in cases of castration-resistant prostate cancer.

Using bacteria to deliver drugs

Tumours can be dense pockets of tissue that at their core contain very little oxygen. The dense nature of tumours makes it difficult for drugs to be effectively delivered to the central cells. The head of the Experiment Therapeutics axis, Dr. G. Batist, collaborated with Dr. S. Martel to create a multidisciplinary project bridging engineering, biomedical research, clinics, physicians and treatments. The team focused on a type of bacteria that is drawn to low-oxygen levels. They were able to show that this specific type of bacteria could be loaded with anti-tumour drugs and then deliver the drugs into the low-oxygen core of tumours much more effectively than current practices. This team went on to win the Canada First Research Excellence Award.

Open access results lead to advances in acute lymphoblastic leukemia

The BCLQ collects samples coming from many types of cancers, including acute lymphoblastic leukemia (ALL). Select ALL samples were analyzed via RNA sequencing by the Leucegene group who went on to published their findings and ensured that their data was accessible to all researchers. Groups could then access samples that had been fully analyzed and sequenced, which lead to multiple publications and discoveries in the field, including a potential new therapy for ALL. Some of these researchers went on to use the open access data in order to obtain grants to support their ongoing projects.

Bridging fundamental and clinical science using biobanked samples

Translational science refers to research performed in a lab, or fundamental research, which is then applied to patients in a clinical setting. It is unquestionably important to moving forward in the fight against cancer. This type of research requires collaborations between researchers in different fields and settings as exemplified by many of our researchers. In one such example, Dr Borden, a fundamental researcher at IRIC, collaborated with Dr. Assouline, a clinician from the JGH to produce results that spanned their fields. Dr. Borden published her findings on a protein, eIF4E, that controls cellular transcription and how it’s dysregulation impacts cancers such as acute myeloid lymphoma. They found that the protein in question could be a treatment target and used BCLQ samples to test inhibitors of this protein such as ribavarin which lead to a Phase I trial. BCLQ samples were again used to test ribavirin resistance which had been found in the initial trial. This led to a Phase II trial that brought together multiple hospitals using ribavirin and another drug, vismodegib. This collaboration not only brought results from the bench to the clinic, it also resulted in clinical trials and multiple successful publications in prestigious journals.

Banking tumour samples for research

In the effort to fully understand tumour biology, it is important to study tumour samples from patients. These are frequently biopsies taken during surgeries and stored in a biobank, destined for research. In order to make sure data stemming from tumour samples is reproducible and standardized, there must be guidelines and procedures for tumour collection, treatment, and storage. To this end, researchers including Drs. G. Batist and M. Basik from the RRCancer wrote a review published in Nature Reviews Clinical Oncology describing the best practices for biobanking guidelines in order to preserve tumour biopsies for research purposes.

Testing the effectiveness of panobinostat in diffuse large B-cell lymphoma

In cells, DNA is wrapped around organizing proteins called histones. Different enzymes interact with the histones to make DNA more or less available to the cell. The histone modifying enzymes are known to be mutated in many diffuse large B-cell lymphoma (DLBCL) tumours, and so inhibitors of one such type of enzyme, histone deacetylases, were suggested to be effective as a treatment. One of these inhibitors, panobinostat, was tested in a Phase II trial with and without another known treatment for DLBCL, rituximab. The study, led by Drs. Assouline, Mann, Greenwood and Johnson, from the experimental therapies axis, found that almost 30% of patients responded to the new treatment, regardless of whether the known treatment was also used. The response to the treatment was durable in most responding patients and the researchers found that responsiveness could be predicted by a mutation in a specific gene (MEF2B) or by a drop in the amount of tumour DNA found in the blood after roughly 2 weeks. Effectively, this study helped identify a new treatment for some types of DLBCL as well as identifying tumour DNA in the blood as a marker or responsiveness.

Predicting patient responsiveness to PARP inhibitors

Patients suffering from ovarian cancer, whose cancers are known to have mutated BRCA genes, can be treated with drugs known as PARP inhibitors. Unfortunately, not every patient responds to this treatment. RRCancer Researchers Drs. A-M Mes-Masson, D. Provencher, and P. Tonin compared different ovarian cancer cells to study the variances in cells that did and did not respond to treatment. BRCA and PARP are already known to be associated with the cell’s mechanisms to repair damage to DNA. Repairing DNA in a cell is a complicated process that involves many different components and pathways. After studying the cell lines, researchers found that the cell lines with defects in more than one DNA repair pathway were most susceptible to PARP inhibitors. In the future, cancer patients can have a genetic screening that may be able to indicate how well they will respond to this type of treatment.

Immunotherapy targets in ovarian cancer

CD73 is an enzyme found on cell surfaces that can dampen the immune system responses. Already known to be involved in tumour progression and metastasis, a collaboration of RRCancer researchers (including the team of Dr. J. Stagg and 3 other network members) found that its levels can be used as an indicator of prognosis in high-grade serous ovarian cancer. High levels of CD73 were found to indicate poor prognoses in patients, because it allows tumour cells to bypass the immune system and spread. However, CD73 is also a promising target for immunotherapy. Patients with elevated CD73 may one day be able to be treated to lower their CD73 levels and improve their prognoses.

Identifying a new cancer susceptibility gene in the French Canadian population

Scientific research has already unearthed various predictors of ovarian cancer, included the BRCA1 and BRCA2 genes, however not all cases of ovarian cancers can be linked to these known genes. To this end, our researchers (including Drs P. Tonin, M. Tischkowitch, W.Foulkes, A-M Mes-Masson and D.Provencher) have sought to find new genes that might predict susceptibility. The PALB2 c.2323C>T [p.Q775X] mutation is a founder mutation found in the French Canadian community that was already known to increase risk of breast cancer. In this case, researchers hoped to see if this founder mutation might be linked to ovarian cancer as well. Researchers screened families of French Canadian descent, some of whom had cases of non-BRCA1/2 breast cancer, for this mutation, as well as women of French Canadian descent who had ovarian cancer or potential tumours. Their data found that the PALB2 c.2323C>T [p.Q775X] founder mutation should in fact be added to the list of cancer susceptibility genes.

A new technology to identify biomarkers

The Ziplex® system from Xceed Molecular was tested to evaluate the reproducibility of of gene expression signatures. Dr. Patricia Tonin applied this new technology to study the pattern of mRNA expression in ovarian tumours. Her results confirm that this new technology may prove to be an interesting research platform for identifying tumour biomarkers.

To learn more: Quinn, M.C., Wilson, D.J., Young, F., Dempsey, A.A., Arcand, S.L., Birch, A.H., Wojnarowicz, P.M., Provencher, D., Mes-Masson, A.-M., Englert, D.and Tonin, P.N. The chemiluminescence based Ziplex automated workstation focus array reproduces ovarian cancer Affymetrix GeneChip expression profiles. J Transl Med.7:55

Fibroblasts associated with breast cancer rarely contain chromosomal abnormalities

It is becoming increasingly clear that cells in the tumour microenvironemt play an important role in tumour growth and the formation of metastases. A RRCancer inter-axis collaboration demonstrated that carcinoma-associated fibroblasts should be considered as stable genomic compounds that exist within the complex microenvironment of the tumour. Their study suggests that the effects of these fibroblasts are unlikely to be due to genomic abnormalities in the fibroblasts themselves.

To learn more: Hosein AN, Wu M, Arcand SL, Lavallée S, Hébert J, Tonin P and Basik M. 2010 Breast carcinoma associated fibroblasts rarely contain TP53 mutations and chromosomal aberrations. Cancer research 70(14):5770-7