A groundbreaking discovery by a group of TFRI-funded scientists in Toronto is paving the way for the creation of combination therapies that could make radio-chemotherapy much more effective – and less toxic – for patients with cervical cancer.
In a paper published in the British Journal of Cancer (June 2019), the team co-led by Dr. Michael Milosevic (Princess Margaret Cancer Centre) outlined how targeting a little-known pathway called CXCL12/CXCR4 could help bring new hope to these cancer patients.
“What we show in this paper is that current treatments with radio-chemotherapy upregulate the CXCL12/CXCR4 pathway, and that when this occurs myeloid cells from the immune system flood the tumour, protecting it from the effects of radiation,” explains Dr. Milosevic, director of research for radiation medicine. “When we block that pathway, in this case with a drug called plerixafor, we don't get the same degree of upregulation, we don't get the same influx of these myeloid cell populations, and we see improved radiation treatment response.”
The finding, which was made using mice models of patient-derived cervical cancers, are extremely promising: not only did blocking CXCL12/CXCR4 make tumours much more sensitive to radiation but it also reduced the side effects of radiation.
“What we found in our preclinical testing was a very strong suggestion that there was not only no increase in toxicity when adding this drug, but that the drug seemed to protect normal tissue from the effects of radiation, decreasing overall toxicity,” says Dr. Milosevic. “This was a completely unexpected result and is a real a win-win situation for our patients going forward.”
Given these promising results, the team hopes these discoveries will move into clinical trials over the next two years. For this, they have spoken with several clinical trial groups in Canada and the US and are looking to gain access to an alternative CXCL12/CXCR4 inhibiting drug that is easier to administer than plerixafor, which requires patients to wear a pump for several weeks.
The team is also accelerating its research into the use of this combination therapy in other cancer types, such as prostate, pancreas and head and neck cancers, in which radiation is also administered.
“Our gut feeling is that the upregulation of CXCL12/CXCR4 is not tumour-type specific, but rather that it's specific to treatment with radiation,” says Dr. Milosevic. “If that is the case, this opens us up to a landscape of possibilities that could be really, really exciting and could have a fantastic impact on patients with curable cancers who need to undergo radio-chemotherapy.”
Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy
Magali Lecavalier-Barsoum, Naz Chaudary, Kathy Han, Melania Pintilie, Richard P. Hill and Michael Milosevic
This study was partially find by The Terry Fox New Frontiers Program Project Grant in Triggers and Targets In the Tumour Microenvironment Hypoxia and Beyond