New cell model may reveal treatment vulnerabilities in rare cervical cancer
Findings highlight how tumor genetics could help shape treatment strategies
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Scientists have developed a new human cell model to study rare cases of cervical cancer that aren’t associated with human papillomavirus (HPV) infection.
Few laboratory models have been available to study HPV-negative cervical cancer, a type of gynecological cancer. Testing of the cells, which came from a tumor surgically removed from a patient, revealed several genetic abnormalities. Based on the affected genes, the researchers tested chemotherapies and targeted cancer drugs or compounds that they predicted would exploit the cells’ genetic vulnerabilities. The cells proved sensitive to several of the treatments.
“This study highlights the potential of in-depth genetic analysis to identify genetic susceptibilities to guide personalized medicine approaches,” the team wrote.
The study, “Genomic profiling identifies actionable DNA-repair defects in a new cervical cancer model,” was published in Scientific Reports.
HPV-negative cervical cancer lacks reliable laboratory models
More than 90% of cervical cancers are associated with HPV, a common infectious virus. While the immune system can often clear HPV, the virus can sometimes alter cells in the cervix, making them cancerous. Much less is known about the development of cervical cancer that isn’t related to HPV. These cases have a poorer prognosis, and more research is needed to understand how best to treat them.
An important step in developing new cancer treatments is testing them in a laboratory setting using human tumor cells. These models allow researchers to evaluate how cancer cells respond to potential treatments. However, few models are available for HPV-negative cervical cancer.
“Therefore, novel model systems are crucial to enhance understanding and enable targeted therapeutic advancements for HPV-negative cervical cancers,” the researchers wrote.
They developed a new cell line, a population of tumor cells that could be maintained and grown long term in the lab. The cells came from a woman with HPV-negative cervical cancer whose tumor was surgically removed. After testing multiple strategies, the team developed a method to maintain and grow these cells, which they named CeCa-5.
To better understand CeCa-5 cells, they performed a variety of genetic analyses. These revealed several mutations, including in genes involved in DNA repair, cell-cycle control, and growth signaling. Together, these abnormalities may have contributed to the original cervical cells becoming cancerous.
“The combination of these genetic aberrations that target distinct hallmarks of cancer presumably contributed to the transformation of CeCa-5 cells,” the researchers suggested.
Next, they identified potential treatment strategies that might exploit these genetic vulnerabilities. These included chemotherapies and targeted treatments.
They tested two platinum-based chemotherapy drugs that damage DNA — cisplatin and carboplatin. Because CeCa-5 cells had genetic abnormalities affecting DNA-repair pathways, the researchers expected the cells to be vulnerable to the DNA damage caused by these drugs. The cells were sensitive to both, although they were more sensitive to cisplatin.
DNA-repair defects point to potential treatment vulnerabilities
Additionally, they tested Lynparza (olaparib), a targeted medication that inhibits the PARP protein. Cancer cells with certain DNA-repair defects can become more reliant on PARP to repair damaged DNA. Blocking PARP can interfere with that repair and ultimately lead to cell death. CeCa-5 cells were sensitive to Lynparza, and the drug was less effective against the HPV-positive cervical cancer cells used for comparison.
Combining cisplatin and Lynparza — a medication that causes DNA damage and one that blocks a DNA-repair pathway — led to a deeper response than either medication alone. This suggests the combination may be worth further study as a potential treatment strategy for HPV-negative cervical cancer.
The team also evaluated paclitaxel, another chemotherapy drug, and a PI3K-alpha inhibitor, which blocks a signaling pathway involved in cell growth. CeCa-5 cells were also sensitive to both treatments.
“Extensive genetic profiling … provided insights into the molecular evolution and characteristics of this carcinoma and make CeCa-5 cells a promising new resource to study the features and vulnerabilities of HPV-negative cervical cancers,” the researchers concluded.
The researchers said the new model could support future drug testing and help reveal potential treatment vulnerabilities. More broadly, they wrote that in-depth genetic analysis could identify genetic susceptibilities that may help guide personalized medicine.
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