August 25, 2020

New advances towards targeted therapies for triple negative breast cancer

OICR-supported researchers demonstrate new drug may eliminate triple negative breast cancer cells in certain patients, discover a new method to identify which patients will benefit

Dr. Mathieu Lupien
Dr. Mathieu Lupien (Images by Delmar)

Adapted from UHN’s Media Release.

Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that often spreads to other organs and accounts for one in four breast cancer deaths. OICR-supported researchers at the University Health Network’s Princess Margaret Cancer Centre are zeroing in on the molecular mechanisms that fuel this deadly cancer’s runaway growth to develop more effective treatments for this disease.

In their study, recently published in Nature Communications, they found a promising approach that could potentially identify the patients who could benefit from a more precise, targeted therapy for TNBC.

“This disease has no precision medicine, so patients are treated with chemotherapy because we don’t have a defined therapeutic target,” says co-lead of the study Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre and OICR Investigator. “Initially, it works for some patients, but close to a quarter of patients recur within five years from diagnosis, and many develop chemotherapy-resistant tumours.”

“These savage statistics mean that we must improve our understanding of the molecular basis for this cancer’s development to discover effective, precise targets for drugs, and a companion test to identify which patients are most likely to benefit the most from such a therapy.”

The study investigated how TNBC cells are dependent on a specific protein called GLUT1 and its associated molecular pathways. Prior studies suggested that TNBC cells were dependent on GLUT1, but this study is the first to demonstrate that blocking GLUT1 function may be an effective therapeutic strategy for certain patients with TNBC.

Using a collection of cell lines, the researchers found that blocking this pathway with a drug-like chemical compound “starved” the cancer cells, but only in a subset of TNBC patient samples. The group investigated further and found a common trait between the cell lines that were sensitive to the drug – they had high levels of a protein called RB1. This indicates that patients with TNBC and high levels of RB1 may, one day, benefit from this drug.

“Having access to diverse cell models of triple-negative breast cancer allows us to distinguish where the potential drug will work, and where it won’t,” says Lupien. “Without this broad spectrum of samples, we might have missed the subset of triple-negative breast cancers that respond to our compound.”

Dr. Cheryl Arrowsmith
Dr. Cheryl Arrowsmith (Photo credit: The Princess Margaret Cancer Foundation)

Collectively, this study suggests that clinical evaluation of targeting GLUT1 in certain patients with TNBC is warranted.

“The more we understand about the molecular complexity of cancer cells, the more we can target with precision,” says co-lead of the study Dr. Cheryl Arrowsmith, Chief Scientist for the Structural Genomics Consortium Toronto laboratories and Professor of Medical Biophysics at the University of Toronto. “And the more we can build up a pharmacy of cancer drugs matched to specific changes in the cancer cell, the greater the chance of a cure.”

Read UHN’s Media Release.

July 17, 2019

New research unfolds the DNA “origami” behind brain cancers

Collaborative research group maps the three-dimensional genomic structure of glioblastoma and discovers a new therapeutic strategy to eliminate cells at the roots of these brain tumours

Current treatment for glioblastoma – the most common type of malignant brain cancer in adults – is often palliative, but new research approaches have pointed to new promising therapeutic strategies.

A collaborative study, recently published in Genome Research, has mapped the three-dimensional configuration of the genome in glioblastoma and discovered a new way to target glioblastoma stem cells – the self-renewing cells that are thought to be the root cause of tumour recurrence.

The research group integrated three-dimensional genome maps of glioblastoma with other chromatin and transcriptional datasets to describe the mechanisms regulating gene expression and detail the mechanisms that are specific to glioblastoma stem cells. They are one of the first groups in the world to perform three-dimensional genomic analyses in patient-derived tumour samples.

Dr. Mathieu Lupien

“The 3D configuration of the genome has garnered much attention over the last decade as a complex, dynamic and crucial feature of gene regulation,” says Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre, OICR Investigator and co-author of the study. “Looking at how the genome is folded and sets contacts between regions tens to thousands of kilobases apart allowed us to find a new way to potentially tackle glioblastoma.”

Through their study, the group discovered that CD276 – a gene which is normally involved with repressing immune responses – has a very important role in maintaining stem-cell-like properties in glioblastoma stem cells. Further, they showed that targeting CD276 may be an effective new strategy to kill cancer stem cells in these tumours.

Lupien adds that advancements in three-dimensional genomics can only be made through collaborative efforts, like this initiative, which was enabled by OICR through Stand Up 2 Cancer Canada Cancer Stem Cell Dream Team, OICR’s Brain Cancer Translational Research Initiative and other funding initiatives.

“This research was fueled by an impressive community of scientists in the area who are committed to finding new solutions for patients with brain cancer,” Lupien says. “Our findings have emphasized the significance of three-dimensional architectures in genomic studies and the need to further develop related methodologies to make sense of this intricacies.”

Senior author of the study, Dr. Marco Gallo will continue to investigate CD276 as a potential therapeutic target for glioblastoma. He plans to further delineate the architecture of these cancer stem cells to identify more new strategies to tackle brain tumours.

Dr. Marco Gallo

“A key problem with current glioblastoma treatments is that they mostly kill proliferating cells, whereas we know that glioblastoma stem cells are slow-cycling, or dormant. Markers like CD276 can potentially be targeted with immunotherapy approaches, which could be an effective way of killing cancer stem cells, irrespective of how slowly they proliferate,” says Gallo, who is an Assistant Professor at the University of Calgary. “Being able to kill cancer stem cells in glioblastoma could have strong implications for our ability to prevent relapses.”

Read more about OICR’s Brain Cancer Translational Research Initiative on oicr.on.ca or read about the Initiative’s current findings on OICR News.

August 9, 2017

Mutation in prostate tumours shown to change epigenetic identity, the make-up of DNA

Prostate cancer researchers have mapped the impact of an acquired mutation that alters epigenetic identity, the make-up of DNA, in about 50 per cent of patient tumour samples. The discovery also identifies a new opportunity for targeted therapy.

Continue reading – Mutation in prostate tumours shown to change epigenetic identity, the make-up of DNA