Navigating a new approach to one of the deadliest cancers

Pancreatic cancer remains a challenging problem for researchers to solve. Progress in diagnosing and treating the disease has been limited and pancreatic cancer remains extremely difficult to treat. Two years ago OICR established a multidisciplinary initiative called PanCuRx, which is using cutting-edge technology to bring new and improved treatments for pancreatic cancer to patients. The group’s findings are already redefining our understanding of pancreatic cancer and opening vital new avenues for treatment, and a new clinical trial called COMPASS is helping better match patients with therapies.

In Canada the five-year survival rate for pancreatic cancer is only eight per cent, a number that has not improved significantly in decades. A few main factors are responsible for the poor outcomes most patients with the disease experience. Pancreatic cancer is notoriously difficult to detect at an early, curable stage and instead is often caught when the disease is far advanced. In addition, only about 15 per cent of cases are operable, thus eliminating a possible avenue of treatment for many patients. There are few approved treatments that exist and they are only effective in a small number of patients. There are also very few second-line therapies available, meaning patients who relapse following their initial treatment have few treatment options.

The thinking behind our approach is that the answers will not come from one field or one research team, but that a truly collaborative approach is needed - Dr. Steven Gallinger

Since April 2015, PanCuRx has been working to make better treatments for pancreatic cancer a reality. Led by Dr. Steven Gallinger, the program’s researchers work with OICR’s Diagnostic Development, Genomics, and Informatics programs, as well as collaborators at University Health Network, Sunnybrook Research Institute and Mount Sinai Hospital, to approach pancreatic cancer in an interdisciplinary manner.

“The limited progress that has been made in treating pancreatic cancer over the last few decades shows just how tough it is from a research perspective,” says Gallinger. “The thinking behind our approach is that the answers will not come from one field or one research team, but that a truly collaborative approach is needed.”

Steven Gallinder and Faiyaz Notta

Dr. Steven Gallinger and Dr. Faiyaz Notta

Better understanding pancreatic cancer biology

Because the basic biology of pancreatic cancer is still not fully understood, PanCuRx researchers have been looking to better define the underlying characteristics of the disease. This work has paid off over the last year, with PanCuRx scientists sharing major new findings that improved the understanding of how pancreatic cancer develops and how it can be treated.

This year, PanCuRx researchers reported seminal findings about the development of pancreatic cancer that challenge traditional views of how the disease develops. Gallinger and Dr. Faiyaz Notta conducted whole genome sequencing on 100 pancreatic tumours and found that rather than slowly accumulating mutations over time, the genomic alterations behind the disease occur all at once – something that the researchers likened to the “Big Bang”. These findings offer insight into why pancreatic cancer is so aggressive and often not diagnosed until its advanced stages, and provide an opportunity to find better strategies for treatment.

The team also published the discovery of four genomic signatures in pancreatic cancer and explored the potential of using immunotherapies to treat the disease. One of the signatures, known as mismatch repair (MMR) was of particular clinical interest. Although the MMR signature only occurs in about one to two percent of pancreatic cancer cases, immunotherapy has shown to be an effective treatment for other types of cancer harbouring this signature. Given the lack of effective treatments for pancreatic cancer, this is encouraging news.

“Better understanding of how the cancer forms and identifying genomic signatures associated with the disease will help our group and others advance new diagnostic tools and therapies,” said Gallinger.

Moving knowledge into the clinic

The PanCuRx initiative aims to see laboratory advances result in tangible improvements for patients. To this end PanCuRx launched a clinical trial called COMPASS that is performing whole-genome and RNA sequencing on patient samples during the time they are receiving standard first-line chemotherapy. These results are shared with the patient’s oncologist in a timely manner to help inform the selection of second-line therapies, including experimental agents being evaluated in other clinical trials, where appropriate.

“Through this trial we are showing that precision medicine is possible in the context of pancreatic cancer. Bringing technologies such as whole genome sequencing into clinical use to treat this disease will result in improved outcomes,” says Gallinger. “It is great that we are able to help some patients access second-line treatments and advance our understanding of the disease at the same time.”

So far 51 eligible patients have consented to join the COMPASS trial. Nine patients who were healthy enough to undergo further treatment have been matched with therapies based on the information provided to their physician through the COMPASS study, with three of them receiving investigational agents. PanCuRx is planning to expand the trial to more sites across Ontario.

Overcoming challenges and developing resources

Access to pancreatic tumour samples for research is essential to PanCuRx’s success. The team is developing a tissue sample repository that will combine clinical, pathological and molecular information to help researchers continue to define the biological pathways that drive the disease. This information will contribute to the identification of biological markers that can be used to predict the formation of pancreatic cancer and help provide a prognosis. The tissue resource will also allow scientists to investigate new target molecules for therapy and identify sub-classes of pancreatic cancer.

Being able to tap into the cutting-edge technologies and expertise available in Ontario has been invaluable - Dr. Steven Gallinger

A major problem with pancreatic cancer tissues samples available for study is that they are often of low cellularity – meaning it is difficult to obtain the cancer cells critical to study. To overcome this issue PanCuRx worked with scientists from OICR’s Diagnostic Development Program and The Princess Margaret Cancer Centre, who used a technology called laser capture microdissection to separate the tissue needed for research from other cells that can interfere with results.

“Being able to tap into the cutting-edge technologies and expertise available in Ontario has been invaluable,” says Gallinger. “We are very confident that our collaborative effort will continue to produce results and ultimately help those with pancreatic cancer.”

PanCuRx was the first of OICR’s five current Translational Research Initiatives. Four more were launched in May 2017. The early success of PanCuRx has shown its collaborative, cross-disciplinary approach can be an effective way to approach some of the biggest challenges in cancer. OICR’s new Translational Research Initiatives are building on PanCuRx’s success but target other difficult to treat cancers, ensuring Ontario’s top researchers are working together to solve some of the most challenging problems in cancer today.

Lead image courtesy of Vanya Peltekova