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.
July 27, 2020
Evolving treatment to evolving tumours: How OICR-supported researchers are getting ahead of ovarian cancer
OICR-supported Phase II trial uncovers how ovarian cancers become resistant to treatment, identifies new opportunities to personalize treatment for future patients
Clinician investigator Dr. Stephanie Lheureux has seen many women fight ovarian cancer – some who overcome the disease and unfortunately many who die. These women inspire Lheureux to find new effective treatments and to continue improving how we treat the disease.
One remarkable patient inspired the EVOLVE trial. After years of keeping her ovarian cancer in check, her cancer began to grow again, indicating that it had become resistant to the maintenance treatment she was on. Lheureux presented the option of palliative chemotherapy, as the latest guidelines suggest, but her patient declined – she wanted a different treatment that would allow her to have a healthy life outside of the hospital.
“This type of chemotherapy requires several visits to the hospital and it’s associated with side effects on patients’ hair, skin and nails,” says Lheureux, Clinician Investigator at the University Health Network’s Princess Margaret Cancer Centre. “This patient didn’t want to go on standard chemotherapy. She had participated in several clinical trials before, and she urged me to find her another option.”Continue reading – Evolving treatment to evolving tumours: How OICR-supported researchers are getting ahead of ovarian cancer
June 11, 2020
OICR-funded researchers identify promising targets to shut down the spread of ovarian cancer
Despite new targeted therapies, ovarian cancers often spread to other organs in the body and become resistant to drugs, leading to nearly 2,000 deaths in Canada each year according to the Canadian Cancer Society. Dr. Trevor Shepherd is committed to finding new solutions for women with this disease.
In an initiative supported by local ovarian cancer survivors and philanthropic donors, Shepherd and collaborators have discovered a new way to shut down the spread of ovarian cancer. In their recent study published in Cancers, they found a molecular pathway that ovarian tumours require to spread to other organs. The study pinpoints two key proteins along this pathway – LKB1 and NUAK1 – as potential drug targets.Continue reading – Community-driven initiative finds new potential avenue of ovarian cancer treatment
March 24, 2020
Ovarian and pancreatic cancer researchers join forces to debunk which treatments work for which patients
Ovarian and pancreatic cancer are some of the most challenging cancers to treat but their common characteristics have pointed to new treatments for certain subsets of patients. Drs. Stephanie Lheureux and Grainne O’Kane have teamed up to find out which patients can benefit from these new therapies.
Over the next year, with the support of an OICR Translational Research Initiative (TRI) Collaboration Award, Lheureux and O’Kane will be taking a deeper look into patient tumour samples that have a specific DNA damage repair deficiency, called homologous recombination deficiency (HRD). These tumours are thought to be sensitive – meaning, they can be eliminated – with a certain class of drugs called PARP inhibitors, but it is difficult to predict in the clinic whether a patients tumour has HRD or not. Further, it is difficult to determine whether a patient will benefit from using PARP inhibitors.
Lheureux, who is a medical oncologist specializing in ovarian cancers, and O’Kane, who is a medical oncologist specializing in pancreatic cancers, have set out to perform whole-genome analyses on patients with HRD to find a better way to identify which patients may respond to PARP inhibitors. Both researchers are excited to tap into each other’s expertise.
“Dr. Lheureux cares for many patients facing these challenges,” says O’Kane. “She has deep clinical expertise in this area.”
“Dr. O’Kane and her closest collaborators have excellent expertise in whole genome sequencing and bioinformatics,” says Lheureux. “We’re eager to work together.”
Their analyses may help them understand the biological mechanisms driving HRD and how HRD tumours become resistant to treatment. Their findings may also extend beyond ovarian and pancreatic cancers.
“We want to define the biological response to PARP inhibitors and the mechanism of resistance so that we can help these patients make the best treatment decisions for their specific disease,” says O’Kane.
“We’re motivated to redefine HRD and understand it on a deeper level to help us overcome resistance to treatment and extend the lives of those with these cancers,” says Lheureux.
Lheureux and O’Kane’s collaboration is supported by OICR’s TRI Collaboration Award, a pilot funding stream to support the training of young investigators and encourage collaboration amongst OICR’s TRI teams.
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
November 6, 2018
Researchers studying ovarian cancer identify adapter protein 3BP2 as a key component of immune system function and a powerful tool that could be used to activate the immune system against hidden tumour cells.