Medical researchers at UNSW Sydney have identified the gene known as ROR1 as a future target for the therapeutic treatment of aggressive endometrial cancer.
ROR1, which plays a role in cell specialization in the developing embryo before it is turned off in adult cells, is used not only in endometrial cancer, but also in other cancers common in both women and men, including leukemia and pancreatic cancer, turned back on abnormally.
The researchers say drugs that target this gene are already being tested on other cancers, arguing that their research calls for a clinical trial against this gene in women with endometrial cancer that contain these changes. The same research team previously identified a role for ROR1 in ovarian cancer.
One of the study’s researchers, Associate Professor Caroline Ford of UNSW Medicine’s School of Women’s and Children’s Health, says endometrial cancer has received very little attention and funding for research, let alone the most common gynecological cancer including one of the fastest growing cancers in women worldwide.
However, she is optimistic that drugs for ROR1 could soon be tested in Australia to test their effectiveness in “silencing” the ROR1 genes in these aggressive endometrial cancers.
“Together with the Australia New Zealand Gynecological Oncology Group (ANZGOG), my clinical colleagues and I are very excited about the opportunity to effectively treat these tumors and have started discussions with Pharma with a proposal for a clinical trial,” she says.
The study, just published as part of Nature Research in the journal Scientific Reports, was a retrospective examination of tumor samples from 499 women with endometrial cancer from the late 1990s to the early 2000s. It was found that women whose samples showed higher levels of ROR1 gene activity had worse health prognoses than women with lower levels.
“Patients with the highest ROR1 scores survived the shortest time or relapsed in the shortest time,” says A / Prof Ford.
“Our study also shows that the cancer cells no longer grow and no longer penetrate and no longer move if we artificially switch off ROR1 in aggressive tumors such as in the laboratory. Ultimately, this shows that we can inhibit their ability to metastasize – which means that they are less able to spread to other parts of the body.
“So we’ve shown that ROR1 is indeed a viable target for the treatment of endometrial cancer and is associated with better chances of survival.”
One of the reasons that may have caused endometrial cancer to receive less attention than other cancers is the fact that women with the less aggressive version of the cancer (endometrioid subtype) tend to have good survival rates, especially if it is detected early. But as A / Prof Ford says, all-cause mortality hides the real effects of the aggressive version of the cancer – including those known as “serous endometrial cancer”.
“Mortality is pretty low because it’s completely skewed by this large percentage of women who have early-stage disease who are essentially cancer-free after surgery,” she says.
“The overall 5-year survival rate for endometrial cancer is 83%. But if you break them down into different subtypes, the story is different. The more common endometrioid subtype has a survival rate of over 90%, while serous tumors have a 5-year survival rate of only about 50%.
“This is similar to the 5-year ovarian cancer survival rate of 46%.”
When a clinical study shows that targeted treatment of the ROR1 gene with selective drugs is effective, women and doctors have more options to choose the best course of treatment.
“The more things we have in our arsenal that we can actually treat, the better patients can personalize treatment and give them options that are appropriate for their stage of life and circumstances,” says A / Prof Ford.
Interestingly, women with the less aggressive version can also benefit from this targeted approach.
“We found that when looking at a large cohort of endometrial cancers, including those with better prognoses, there was this aberrant overexpression of ROR1. We believe they might benefit from this therapy as well, which is one of the reasons we are so eager to get our study up and running. “
The spokeswoman for ANZGOG, Dr. Yoland Antill, Chair of the Uterine Cancer Working Group, said she was very confident that a lawsuit would be initiated in Australia.
“Through ANZGOG, we were able to develop a collaboration of preclinical and clinical researchers to develop an innovative Phase II study to evaluate the effectiveness of these drugs in women with advanced endometrial cancer whose tumors have ROR1 gene expression,” she said says.
“Women in this subgroup often have very aggressive tumors with limited treatment options, so this innovative and targeted study will be of great interest both locally and globally.”
The team is now seeking funding and support to enable a clinical trial of ROR1 against drugs in Australian women with endometrial and ovarian cancer.
The UNSW study received philanthropic support from the Ross Trust.
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