February 26, 2021
An OICR-supported research team at the Princess Margaret Cancer Centre has shown that adding a targeted drug to chemotherapy results in longer survival and a stronger response to treatment in a difficult-to-treat form of ovarian cancer.
When a patient’s ovarian cancer becomes resistant to treatment, the patient has few alternative options and faces an estimated survival of less than 18 months. This is a reality for approximately one in four women with the disease.
Against this challenge, a team OICR-supported through OICR’s Ovarian Cancer Translational Research Initiative (TRI), headed by Dr. Stephanie Lheureux, Princess Margaret (PM) Clinician Investigator and Dr. Amit Oza, PM Senior Scientist and OICR TRI leader, led a Phase II clinical trial including nearly 100 women across 11 centres to evaluate the combination therapy of adavosterib and gemcitabine. Their discoveries, which were recently published in The Lancet, demonstrated that this combination increased survival by 4.3 months relative to chemotherapy and placebo alone. 23 per cent of patients’ cancers responded to the chemotherapy, in contrast to a 6 per cent response rate seen using chemotherapy alone.
“By combing two drugs, we were able to change the trajectory of cancer for a high-risk group of women with advanced disease who did not have many choices left,” says Oza, Medical Director of the Cancer Clinical Research Unit and Co-Director of the Bras Drug Development Program at Princess Margaret Cancer Centre. “That is significant.”
Lead author Dr. Stephanie Lheureux says that the study provides a signal of hope for women with ovarian cancer who develop drug-resistance to treatment. The study included some women who had received up to eight different previous treatments which had stopped working.
“As we learn more and more about the biology of tumours, we can target treatments more precisely to the molecular changes in a cancer to improve the type and response of our treatments. That will change outcomes for patients,” says Lheureux, who is also the Princess Margaret Site Lead for Gynecological Oncology. “I want our patients to know there is hope to find better treatment to control their cancer.”
By combing two drugs, we were able to change the trajectory of cancer for a high-risk group of women with advanced disease who did not have many choices leftDr. Amit Oza
The study participants had high-grade serous ovarian cancer – the most malignant form of ovarian cancer, accounting for up to 70 per cent of all ovarian cancer cases. They were randomly assigned to receive either adavosertib plus gemcitabine (chemotherapy) or placebo plus gemcitabine.
The patients’ tumours were biopsied before and during treatment to assess the effectiveness of the drug regimens. Analysis of genetic mutations and changes in DNA damage response pathways was performed by the Joint Genomics Program at OICR and the Princess Margaret Cancer Centre.
“This discovery underscores the importance of bringing scientists and clinicians together to tackle difficult questions from different perspectives to offer new insights into the biology of cancer,” says Dr. Laszlo Radvanyi, President and Scientific Director, Ontario Institute for Cancer Research. “It shows how we can push these damaged cancer cells right smack into mitotic catastrophe to their demise. This clinical trial has validated good science that has begun to uncover how a cancer cell’s own DNA repair mechanism can be used against it and capitalizes on this unique vulnerability by combining drugs in a smart way. The small-molecule DNA repair inhibitors used in this study targeting the G2-M checkpoint hold great promise as chemotherapy enhancers by further damaging and ultimately destroying tumour cells, thereby overcoming treatment-resistant ovarian cancer.”
In addition to improving overall survival by 4.3 months, the combination of adavosertib and gemcitabine improved progression-free survival by 1.6 months relative to chemotherapy alone.
“Taken together, these three outcomes give us a strong signal that we can potentially improve survival for these patients who face bleak prospects,” says Dr. Oza, adding that the study carefully co-ordinated patients with similar genomic backgrounds with a targeted drug that exploits a defect in cancer cells.
“This is precision medicine at its best,” he adds. “This is how we will develop better treatments for our patients.”
Through whole-exome sequencing, the study found that patients’ tumours acquire several changes – or mutations – that play an important role in regulating critical cell cycle checkpoints. These mutations could disable these “quality control” checks, allowing cancer cells with damaged DNA to continue dividing and growing unimpeded.
Further, they discovered that the drug adavosertib could effectively target tumour cells that harbour the key TP53 mutation.
“We exploited a fatal flaw in cell division, diverting and stopping the damaged cells from growing into a tumour,” explains Lheureux. “We showed the potential of targeting the cell cycle in a specific subgroup of patients with highly resistant ovarian cancer. This opens up new avenues of treatment possibilities.”
The research group now plans to evaluate the impact of this combination on patients’ quality of life and analyze patients’ blood samples to search for blood-based indicators of treatment resistance.
In addition to OICR’s support, the study was also funded by the Princess Margaret Cancer Foundation, the U.S. National Cancer Institute Cancer Therapy Evaluation Program, the U.S. Department of Defense Ovarian Cancer Research Program, and AstraZeneca.
December 13, 2018
What can we gain from looking at the outliers?: An investigation into long and short-term ovarian cancer survivors
Researchers investigate the clinical, molecular and microenvironment factors that contribute to extreme therapy response and resistance in ovarian cancer patients
Some patients with high-grade serous ovarian cancer (HGSOC) respond exceptionally well to therapy, while others experience rapid disease relapse. The mechanisms behind these disparate outcomes are poorly understood, but a group of researchers based at the Princess Margaret Cancer Centre (PM) supported by OICR’s Ovarian Cancer Translational Research Initiative (TRI) are working to change that.Continue reading – What can we gain from looking at the outliers?: An investigation into long and short-term ovarian cancer survivors
July 12, 2017
Given the advancements in treating many other types of cancer, it may come as a surprise that outcomes for patients with the most deadly form of ovarian cancer have not improved in 50 years. This form, known as High Grade Serous Ovarian Cancer (HGSOC), accounts for 80 per cent of ovarian cancer deaths in Canada. Surgery and chemotherapy can be effective, but ultimately three-quarters of women with HGSOC will see their disease return. To deliver better outcomes for patients, OICR has launched a new ‘all star team’ of ovarian cancer researchers.
May 25, 2017
OICR launches five all-star teams of Ontario scientists to tackle some of the deadliest forms of cancer
Great strides have been made in cancer research, but much work remains to develop better treatments for the most lethal cancers and to advance new anti-cancer technologies. OICR is taking on a new approach, building on the success of the Institute’s first ten years and Ontario’s strength in particular cancer research areas. Reza Moridi, Ontario’s Minister of Research, Innovation and Science announced that the Institute is funding five collaborative, cross-disciplinary and inter-institutional Translational Research Initiatives (TRIs) with a total of $24 million over the next two years.
The TRIs will bring together some of the top cancer researchers in Ontario and be led by internationally renowned Ontario scientists. Each team will focus on a certain type of cancer or therapeutic technology. To maximize the positive impact of research on patients, the TRIs all incorporate clinical trials into their design. The TRIs, which were selected by an International Scientific Review Panel, are:
- Acute Leukemia TRI (led by Drs. John Dick and Aaron Schimmer at the University Health Network (UHN))
- Brain Cancer TRI (led by Drs. Peter Dirks and Michael Taylor at SickKids)
- Immuno-oncology TRI (ACTION) (led by Drs. John Bell and Marcus Butler at The Ottawa Hospital and UHN)
- Ovarian Cancer TRI (led by Drs. Amit Oza and Rob Rottapel at UHN)
- Pancreatic Cancer TRI (PanCuRx) (led by Dr. Steven Gallinger at UHN)
The funding will also support Early Prostate Cancer Developmental Projects led by Drs. Paul Boutros and George Rodriguez.
“In just over 10 years, the Ontario Institute for Cancer Research has become a global centre of excellence that is moving the province to the forefront of discovery and innovation in cancer research. It is home to outstanding Ontario scientists, who are working together to ease the burden of cancer in our province and around the world,” said Moridi.
“Collaboration and translational research are key to seeing that the innovative technologies being developed in Ontario reach the clinic and help patients,” said Mr. Peter Goodhand, President of OICR. “These TRIs represent a unique and significant opportunity to impact clinical cancer care in the province.”
— SickKids_TheHospital (@SickKidsNews) May 25, 2017
— UHN (@UHN_News) May 25, 2017
— The Ottawa Hospital (@OttawaHospital) May 25, 2017
May 25, 2017
OICR launches five large-scale Ontario research initiatives to combat some of the most deadly cancers
Toronto (May 25, 2017) – Reza Moridi, Ontario’s Minister of Research, Innovation and Science, today announced the Ontario Institute for Cancer Research is launching five unique, cross-disciplinary, multi-institutional Translational Research Initiatives (TRIs), each focused on a single type of or treatment approach to cancer. With $24 million in funding over two years, the TRIs will bring together world-leading scientists to tackle some of the most difficult to treat cancers and test innovative solutions to some of the most serious challenges in cancer today.
The TRIs build on Ontario’s proven strengths in areas such as stem cells, immuno-oncology, pediatric cancers, genomics, clinical trials and informatics. Working together, the province’s top scientists and clinicians will accelerate the development of much needed solutions for patients around the globe, with a focus on acute leukemia and brain, ovarian and pancreatic cancers. Each TRI includes clinical trials to maximize patient impact.