Jan. 12, 2016

According to the National Cancer Institute, an estimated 12,900 new cases of cervical cancer occurred in the United States in 2015.  The disease also caused an estimated 4,100 deaths. But the dawn of 2016 ushers in exciting opportunities for a new year of progress in cancer research, prevention, and treatment. January is National Cervical Cancer Awareness Month, and member institutions of the Big Ten Cancer Research Consortium are leading the fight against this highly preventable, highly treatable cancer.

Discovering disparity: Study addresses disparity in cervical cancer deaths

While studying cervical cancer statistics compiled by the U.S. Centers for Disease Control and Prevention, Sabrina Ford noticed a discrepancy that she initially thought must be a mistake: While African-American women undergo screenings for cervical cancer at a higher rate than white women, they die from the disease at nearly twice the rate.

“I couldn’t believe it,” said Ford, PhD, a psychologist and assistant professor in the Michigan State University College of Human Medicine.

She showed the figures to her colleague, Karen Patricia Williams, PhD, a professor in the college’s

Michigan State University, College of Human Medicine’s Richard Leach, MD, chair Dept. of Obstetrics, Gynecology and Reproductive Biology, Karen Patricia Williams, PhD, professor, Dept. of Obstetrics, Gynecology and Reproductive Biology, and Sabrina Ford, PhD, psychologist and assistant professor, Dept. of psychology.

Department of Obstetrics, Gynecology and Reproductive Biology, who agreed the disparity didn’t make sense.

Her research confirmed what Ford calls “the black women paradox.” While African-American women undergo Pap tests more often than white women, their mortality rate from cervical cancer is nearly twice as high.

Now she wants to know why.

Ford hopes to have what she has found so far published in a medical journal, and she plans to conduct further research to uncover the reasons for the higher death rate among African-American women. At the heart of the disparity, she believes, are barriers that prevent many women who receive positive tests for cervical cancer from getting the follow-up care that can cure it.

Ford’s findings are important, because cervical cancer was previously one the most common causes of cancer deaths for American women.  Though the death rate has been cut in half following the development of the Pap test over the past 30 years about 12,900 new cases of invasive cervical cancer are diagnosed in the U.S. each year, and about 4,100 women die of it.

About four of every 100,000 African-American women died of cervical cancer in 2012 compared with about two per 100,000 white women, CDC figures show.

“The ability to home in on this finding is very important,” said Richard Leach, MD, chair of the Department of Obstetrics, Gynecology and Reproductive Biology. “This can save lives dramatically.”

The study also underlines the significance of the sociological research conducted by Ford, Williams, and their colleagues, in addition to the biomedical studies of others in the college to find better treatments and cures for gynecologic cancers and other diseases.

Targeting multiple pathways

The exact molecular mechanisms underlying HPV-driven cervical cancer initiation and progression are largely unknown. At the Fred & Pamela Buffett Cancer Center (University of Nebraska Medical Center), recent studies by the OB/GYN Research team found that the Hippo/YAP signaling pathway interacts with the EGFR pathway to form a positive feedback signaling loop to drive the proliferation and migration of cervical cancer cells.

“The research results in this project unveil a novel molecular mechanism of cervical cancer development and progression and suggest that combined targeting of the Hippo and the ERBB signaling pathways may provide a new therapeutic strategy for prevention and treatment of cervical cancer,” says Cheng Wang, PhD, Assistant Professor at UNMC. “The clinical relevance of our findings is further supported by results from multidimensional analysis The Cancer Genome Atlas (TCGA) database – an NCI/NHGRI initiative to identify genomic changes in more than 30 types of cancer.”

As part of ongoing efforts to impact cancer within specific populations, students within the College of Public Health at UNMC had the opportunity to conduct research through the Cancer Epidemiology Education in Special Populations (CEESP). CEESP provides funding for students to travel and conduct summer research in minority sites or international settings. This program is funded by a research training grant from the National Cancer Institute. In 2014, cervical cancer projects included:

• Reproductive and clinical demographics of patients undergoing visual inspection of the cervix in rural Tanzania
• Cervical cancer screening among HIV-positive women in rural Tanzania
• Epidemiologic profiles of cervical cancer screening and treatment patients in Burkina Faso
• Cost-benefit of screening versus treatment for cervical cancer in Tanzania

Increasing vaccination rates

The “Minnesota HPV” (MNhpv) initiative brings together University of Minnesota students and faculty from medicine, nursing, dentistry, and pharmacy to meet one objective: increase HPV vaccination rates across Minnesota.

MNhpv released this draft consensus state at the end of 2015, which captures the reason for launching the program earlier last year:

“The Human Papilloma Virus (HPV) infects about 79 million each year in the United States and over 27,000 women and men are affected by a cancer caused by HPV – that’s a new case every 20 minutes. Yet, the most life threatening HPVs are preventable with the availability of the safe and effective vaccine. HPV vaccination prevents several deadly cancers and is life saving. HPV vaccination is a game changer for several cancers including cervical, anal, and oral cancers.” 

One of the many initiatives of MNhpv is the upcoming statewide HPV vaccine summit coming up on April 25, 2016. The Gynecologic Oncology Translational Working Group (Gyn Onc TWG) through Masonic Cancer Center brings together cancer experts and healthcare leaders with one goal in mind: maximizing the success of research for the prevention and treatment of gynecologic cancers.

Exploiting previous successes: Decades-Old Research is Basis for New Cervical Cancer Clinical Trial

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.

Precision Medicine in Gynecologic Cancers

While January is cervical cancer awareness month, there are four other types of cancer that can affect a woman’s reproductive organs, including ovarian, uterine, vaginal, and vulvar. As a group, they are referred to as gynecologic cancers.  One of the Big Ten Cancer Research Consortium’s clinical trial working groups focuses on gynecologic cancers. One of the co-chairs in the group is Lorna Rodríguez, MD, PhD from Rutgers Cancer Institute of New Jersey.

Lorna Rodriguez, MD, PhD, is the former chief of gynecologic oncology at Rutgers Cancer Institute, who specializes in ovarian and other female reproductive cancers. She is also the director of the precision medicine program at Rutgers Cancer Institute. The blending of such expertise is exactly what 28-years-old, Rachael McCleery needed while battling a second bout of ovarian cancer. “When I first saw Rachael in January of 2014, I wanted to have her tumor genetically profiled. At that time our clinical trial examining that approach was not open, and after many discussions with both Rachael and her family we decided to perform surgery,” recalls Dr. Rodriguez, who is also a professor of obstetrics, gynecology and reproductive sciences at Rutgers Robert Wood Johnson Medical School.

“Dr. Rodriguez had many options prepared. She gave us hope and a new outlook on the whole thing. She was optimistic and helped restore my fighting spirit,” says McCleery, who observed that “Dr. Rodriguez has her own uplifting spirit.”  “As soon as we met Dr. Rodriguez, we knew we were in the right place,” adds McCleery’s mom. “With Rachael, we need to think out of the box.”  “Out of the box” is exactly what Rodriguez had in mind. Because McCleery’s cancer was slow growing, the surgery was scheduled at Robert Wood Johnson University Hospital (RWJ) – the flagship hospital of Rutgers Cancer Institute – where Rodriguez removed her uterus and obtained a biopsy sample.

It was after that time that a unique clinical trial at Rutgers Cancer Institute had re-opened to accept additional patients. The trial examines tissue samples of those with rare forms of cancer and those whose cancer has stopped responding to traditional treatment.

Advances in precision medicine at Rutgers Cancer Institute of New Jersey are giving Rachael McCleery and her supporters renewed hope.

Read full story: Read Rachael McCleery’s full story in Cancer Connection, published by Rutgers Cancer Institute of New Jersey.

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This story was compiled by Alecia Burkhardt, communications associate for the Big Ten Cancer Research Consortium, with contributions from the Michigan State University Breslin Cancer Center, the Fred & Pamela Buffett Cancer Center, University of Minnesota Masonic Cancer Center, the UW Carbone Cancer Center, and Rutgers Cancer Institute of New Jersey.

About the Big Ten Cancer Research Consortium: The Big Ten Cancer Research Consortium was created in 2013 to transform the conduct of cancer research through collaborative, hypothesis-driven, highly translational oncology trials that leverage the scientific and clinical expertise of Big Ten universities. The goal of the Big Ten Cancer Research Consortium is to create a unique team-research culture to drive science rapidly from ideas to new approaches to cancer treatment. Within this innovative environment, today’s research leaders collaborate with and mentor the research leaders of tomorrow with the unified goal of improving the lives of all patients with cancer.

About the Big Ten Conference: The Big Ten Conference is an association of world-class universities whose member institutions share a common mission of research, graduate, professional and undergraduate teaching and public service. Founded in 1896, the Big Ten has sustained a comprehensive set of shared practices and policies that enforce the priority of academics in the lives of students competing in intercollegiate athletics and emphasize the values of integrity, fairness and competitiveness. The broad-based programs of the 14 Big Ten institutions will provide over $200 million in direct financial support to almost 9,500 students for more than 11,000 participation opportunities on 350 teams in 42 different sports. The Big Ten sponsors 28 official conference sports, 14 for men and 14 for women, including the addition of men’s ice hockey and men’s and women’s lacrosse since 2013. For more information, visit www.bigten.org.