Decades-Old Research is Basis for New Cervical Cancer Clinical Trial
From Bench to Bedside
Madison, Wisconsin - Due to high rates of early detection and surgical success, cervical cancer is often a curable disease in the U.S. But in parts of the developing world, such as Bangladesh, cervical cancer is commonly among the top three causes of cancer-related deaths in women.
Research that began at the UW Carbone Cancer Center and McArdle Laboratory for Cancer Research decades ago has led to a promising clinical trial for these women, and could lead to more treatment options all over the world.
"In Bangladesh, there is only one site in the entire country, in Dhaka, that has treatment facilities for patients with advanced cervical cancer," said Lisa Barroilhet, MD, assistant professor of gynecologic oncology at the Carbone Cancer Center. "For most women, simply getting there for treatment is not practical for so many financial and cultural reasons."
Barroilhet, who worked in a maternal medicine clinic in Bangladesh as a medical student, recently teamed up with Richard Love, MD, professor emeritus of medicine at the Cancer Center, who is currently working with a breast cancer clinic in the rural region of Khulna.
"He kept seeing more and more women with advanced cervical cancer, and it became clear to him that this was a huge problem, very different from what we see in the US where there is more early screening," Barroilhet said. "He thought, 'What research is being done that could help these women have access to therapy?'"
As it happens, the research was already done.
Over 90 percent of all cervical cancer cases are caused by certain strains of human papillomavirus, or HPV.
Beginning nearly two decades ago at the UW Carbone Cancer Center, Paul Lambert, PhD, professor of oncology and director of McArdle Lab, and his research team developed mice that overexpressed the key cancer-causing genes from HPV in their cervices, and many of those mice developed cervical cancer late in their life. Another research group found that if these mice were treated with excess estrogen, above their natural levels, they would develop cervical cancer within six months.
Estrogen, a small molecular hormone that stimulates growth of cells that express its receptor, ER-alpha, clearly played a role in the progression of HPV-induced cervical cancer. Lambert's group first showed that mice which express the HPV cancer genes but lack the gene for ER-alpha do not develop cervical cancer, the first hint that cervical cancers are dependent on estrogen.
"That research opened up the opportunity to ask, 'Are drugs that are known to inhibit ER-alpha useful in controlling cervical cancer in our mouse model?'" Lambert said. ER-alpha is also expressed in 70 percent of breast cancers and is the target of commonly prescribed endocrine therapies used to reduce disease recurrence, based on a long-term study of breast cancer patients pioneered by Love at the Cancer Center in the 1980s.
"We did the obvious next step of taking HPV transgenic mice, treating them with estrogen so that they develop cervical cancer, and then giving them one of two anti-estrogens, raloxifene or fulvestrant, and the tumors are gone," Lambert said. "And that's where [Barroilhet and Love] come into the picture." He and Barroilhet both credit Carbone Cancer Center director Howard Bailey, MD, with recognizing how they and Love could work together.
Barroilhet, Lambert and Love are co-investigators on a clinical trial in Bangladesh using those anti-estrogens already prescribed to breast cancer patients to target a stage of the disease known as 'locally advanced.' Barroilhet said that women with this intermediate stage of disease are curable, and often are cured in developed countries, but that the five-to-eight weeks of daily radiation treatment is neither affordable nor tenable for women in rural regions of Bangladesh.
"The fact that an anti-estrogen medication can be made available to these patients that is taken orally, so they can take it in their communities, and is known to be really darn safe from decades of use in breast cancer patients, makes it a very logical next step for patients who have limited to no treatment options," Barroilhet said.
The trial is under review and they expect it to be open by the end of the year.
If successful, both Barroilhet and Lambert envision anti-estrogens as a potential treatment to reduce the recurrence of cervical cancer, much like it is used with breast cancers, or to hinder tumor growth in advanced cases, which could reduce disease burden.
Date Published: 01/06/2016