Scientists work across disciplines to fight breast, ovarian cancers
The Women’s Cancers Program at City of Hope unites scientists from across disciplines who aim to prevent cancer, seek out better treatments and help survivors live whole, healthy lives. Led by Joanne Mortimer, M.D., the program strives to bring hope and healing to women fighting cancer. Here's a snapshot of the current research efforts:
Predicting risk for cancer
Susan L. Neuhausen, Ph.D., the Morris & Horowitz Families Professor in Cancer Etiology and Outcomes Research, has been studying women with breast and ovarian cancers since 1992 and was part of the team that discovered the BRCA1 and BRCA2 gene mutations. Now, Neuhausen and her team are collaborating with gynecologic surgeons and medical oncologists at City of Hope to investigate mutations in genes involved in the response to DNA damage.
They seek to understand how these mutations impact a woman’s risk for developing ovarian cancer and her response to treatment. Information gathered from this study will be used to develop preventive strategies and design more targeted treatments to reduce the risk of ovarian cancer recurrence.
Assessing cancer risk in underserved populations
In Hispanic women, breast cancer is the most commonly diagnosed cancer, and the leading cause of cancer death. Jeffrey N. Weitzel, M.D., director of the Division of Clinical Cancer Genetics, and a team of researchers seek to understand genetic predisposition in this population.
In his studies, he confirmed that there is a high prevalence of BRCA mutations in Hispanic women. One specific BRCA mutation that can be traced to Mexican ancestry, and which is not detectable on standard testing, emerged during this study. These results reaffirm the need for access to in-depth BRCA testing for Hispanic women.
Weitzel’s research, published in the Journal of Clinical Oncology, is the largest one of Hispanic breast/ovarian cancer families in the United States to date.
Overcoming resistance to treatment
Shiuan Chen, Ph.D., professor and chair of the Department of Cancer Biology, studies aromatase inhibitors, a class of drugs that block aromatase. The enzyme plays a key role in producing estrogen, a hormone that fuels many breast cancers.
Aromatase inhibitors are effective in helping women treat breast cancer, or reduce the risk of recurrence, but some develop resistance to the drugs. Chen and his colleagues are studying various treatment methods to overcome this resistance.
In preclinical studies in his laboratory, Chen compared two delivery methods of these drugs — continuous treatment versus intermittent treatment — and found that cancer cells built up resistance more quickly when treated continuously with the aromatase inhibitors. One possible explanation is that expression of certain estrogen-responsive cancer-promoting genes was higher in the cells treated continuously compared to the cells treated intermittently.
Based on these findings, he and his team have initiated a clinical trial to examine the effect of intermittent treatment of aromatase inhibitors in women with breast cancer.
Finding more effective ways to target cancer
Linda H. Malkas, Ph.D., deputy director of basic research for the Comprehensive Cancer Center and a professor in the Department of Molecular and Cellular Biology, wants to enhance the effectiveness of cancer treatments by making them more specifically directed to cancer cells.
She has found a target in cancer cells, called cancer-associated proliferating cell nuclear antigen (caPCNA), that plays a role in DNA repair and helps cancer survive and proliferate. She and her team have developed a synthetic peptide that blocks caPCNA from repairing DNA — causing cancer cells to die. And because the compound is specific to caPCNA, it will impact only cancer cells.
Malkas believes that these peptides could form the basis for new, more effective anti-cancer chemotherapeutics.
Determining the best treatment for each woman
Jeremy Stark, Ph.D., associate professor in the Department of Radiation Biology, is conducting research to predict how different types of ovarian cancers will respond to therapy. He's specifically studying the role of a process called homologous recombination.
Cells use this process to repair DNA, and in cells treated with chemotherapy, this process can block the effects of treatment — allowing cancer cells to thrive. As a result, women with certain types of ovarian cancer that have lost the ability to perform homologous recombination have better outcomes.
Stark is working on a pilot project to evaluate homologous recombination in clinical samples of ovarian cancer. He aims to translate this research into a clinical test for homologous recombination deficiency in ovarian cancer, and thereby improve the choice of therapy for women.
Such a test will also enhance the development and analysis of clinical trials with experimental therapeutics for women with ovarian cancers.
Understanding resistance to treatment
Women with late-stage breast cancers often receive neoadjuvant chemotherapy, which is administered before surgery to reduce the size and spread of cancer. However, only a small number of women benefit from this therapy.
Emily Wang, Ph.D., assistant professor in the Department of Cancer Biology, conducted research on microRNAs (miRNAs), which regulate gene expression. Her goal was to find a molecular “signature” that indicates a response to neoadjuvant chemotherapy.
She identified two miRNAs that regulate two genes that are related to chemotherapy resistance. These results have been published in Oncogene and Molecular Cancer Research. With this research, Wang has gained important insight into miRNAs as potential biomarkers and therapeutic targets for breast cancer treatment.
Reactivating the immune response to cancer
Hua Yu, Ph.D., associate chair of the Department of Cancer Immunotherapeutics and Tumor Immunology, was the first to validate STAT3, which regulates tumor survival, as a molecular target for cancer therapy in animal models. She recently conducted a study in which she genetically modified STAT3 in cancer cells and found this reduced tumor growth and reactivated several tumor-supressor genes that stimulate the immune system to fight cancer.
Yu also found a serendipitous occurrence in triple-negative breast cancer cells. Genetically altering STAT3 activates the estrogen receptor gene, sensitizing the tumor cells to anti-estrogens. This popular class of anti-cancer drugs are proven effective for women who have cancer that is fueled by estrogen. This study was published in the Proceedings of the National Academy of Sciences.
Helping the immune system recognize and remember cancer
Stephen J. Forman, M.D., the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, is working on a new immunologic approach to the treatment of cancer. This approach is known as adoptive central memory T cell therapy.
Forman is currently expanding the approach to treat women with ovarian cancer. The strategy involves removal and genetic engineering of a woman’s central memory T cells to specifically recognize proteins displayed by ovarian cancer cells. Once reintroduced to women, these T cells hunt down and attack the cancer.
This class of T cells has the capacity to persist long-term and “remember” the cancer, so that if cancer recurs, the T cells can swiftly destroy it, giving women potential lifelong immunity against their disease. Clinical trials of one kind of modified T cells are set to begin this year, and another trial will begin after preclinical studies of a second kind of T cell are completed this year.
Stoking the immune system to attack cancer
Peter P. Lee, M.D., who joined City of Hope in 2011, is focused on finding novel ways to harness a patient’s own immune system to attack and kill cancer. Lee, a professor in the Department of Hematology & Hematopoietic Cell Transplantation, is pursuing a model of therapy that he calls integrated immunotherapy — using immune-boosting drugs and treatments in a sequence such that the immune system’s response is effective against cancer.
This response is launched in three distinct phases: immune cells recognize cancer, expand and surround cancer, and then kill cancerous cells. Lee believes the types of drugs and how they’re administered can help the immune system to coordinate all three stages against cancer.
Lee was awarded a $3.1 million grant from the Department of Defense Era of Hope Scholar Expansion program to pursue these studies. He was one of only two researchers to receive this highly prestigious award.
Finding cures in nature
John Hosei Yim, M.D., associate professor and surgeon in the Division of Surgical Oncology, is investigating the tumor-fighting capabilities of a compound called baicalein, which is found in a Chinese herb called Baikal skullcap root.
Yim has found that baicalein helps to suppress the growth of tumors by encouraging cancer cells to kill themselves and making them more vulnerable to the immune system. In lab tests, baicalein inhibited cancer cell growth and showed no toxicity, making it a promising compound for therapy. And in animal trials, baicalein was found to work against ovarian cancer cells that have become resistant to chemotherapy.
This research was presented at the International Gynecological Cancer Society meeting in October 2012.
Using City of Hope’s new Chemical GMP Synthesis Facility, Yim will soon begin manufacturing a baicalein pill for human consumption. A phase I clinical trial will help researchers to determine the proper and safe dosage of baicalein for women with advanced ovarian and breast cancers.
Creating a clear image of cancer
John C. Williams, Ph.D., associate professor in the Department of Molecular Medicine, is developing a new way of imaging breast cancer to find and treat it sooner. He is using meditope technology he discovered here at City of Hope.
Meditope technology works like a key in a key hole. In this case, the antibodies (engineered with a key hole) gather around the tumor site by seeking out tumor cells overexpressing Her2, a protein that indicates an aggressive form of cancer. Then, the meditope, acting as the key, and carrying an imaging agent, attaches to the antibody and lights up the tumor area.
Williams is working with Jinha Park, M.D., Ph.D., assistant professor in the Department of Diagnostic Radiology, who discovered two novel Her2 antibodies that bind to Her2, but in a different manner than Herceptin.
The ability to use multiple antibodies, each bearing a meditope site, should permit Williams and Park to enhance the image sensitivity. With this technology, physicians can determine where cancer is and how much it has spread, allowing them to choose the ideal treatment for each woman with aggressive breast cancer.
Understanding treatment in older women
Arti Hurria, M.D., director of the Cancer and Aging Research Program, is an international expert in cancer care for patients age 65 years and older. Recognizing that there has been relatively little research conducted about older people with cancer, Hurria believes there is an urgent and growing need to understand and address the unique challenges faced by older cancer patients.
Recently, Hurria conducted research to understand the connection between cancer treatment and memory loss in older women treated for breast cancer. She seeks to understand if specific cancer treatments impact memory, as well as identify those patients at risk for memory loss.
Hurria and colleagues evaluated the memory of women treated with aromatase inhibitors, which are used to treat women with estrogen receptor positive breast cancer. In this study, researchers explored objective/subjective memory in postmenopausal women who were being treated with aromatase inhibitors, and found that, compared to a control group, aromatase inhibitors contributed to no additional memory loss.
Researchers are now working to identify predictors of memory loss using PET scans of the brain and skin, and blood and urine samples. Because most common type of breast cancer is estrogen positive, this investigation benefits all women who are postmenopausal.
Easing the impact of surgery
During surgery, lymph nodes are often removed, which can cause lymphedema. This painful swelling of the arm requires women to wear a special compression sleeve and, in the worst cases, it inhibits everyday functioning. Chen is conducting a randomized trial to understand whether a technique called axillary reverse mapping can help reduce lymphedema after breast cancer surgery that requires removing most of the lymph nodes under the arm.
In reverse mapping, surgeons inject the arm with the blue dye, lighting up lymph channels associated with the arm that can often be spared. Opened at City of Hope in July 2012, this trial is the first in the United States to test this technique in a randomized fashion.
More than 30 patients have been accrued to date, and the goal is to accrue 72 women at City of Hope, University of California, Davis, and University of North Carolina.
Ensuring equal access to quality cancer care
Laura Kruper, M.D., director of the Rita Cooper Finkel and J. William Finkel Women’s Health Center at City of Hope and head of breast surgery service, is studying inequalities in health care for women with breast cancer.
She has led several studies evaluating reconstruction rates after mastectomy. In collaboration with Leslie Bernstein, Ph.D., professor and director in the Division of Cancer Etiology, Kruper has investigated disparities in care using California hospital inpatient databases, and found that insurance, ethnicity and where a woman receives care are all important factors that affect her decision to receive breast reconstruction. These findings have been presented at several national meetings, published in peer-reviewed journals and generated significant media attention.
Most recently, Kruper and Bernstein investigated disparities regarding reconstruction among the California Teachers Study cohort, and presented their findings at the San Antonio Breast Cancer Symposium in December 2012. Kruper’s overarching aim is to recommend changes in health care policy to provide equal care to all breast cancer patients.
Helping women during and after treatment
Carolyn Behrendt, Ph.D., associate professor of biostatistics, is collaborating with several physician-scientists in the Women’s Cancers Program to understand how women fare during and after breast cancer treatment.
Along with Joanne Mortimer, M.D., she recently surveyed 50 survivors of breast cancer who were at least a year beyond diagnosis and treatment. Behrendt and Mortimer learned that far more women than previously recognized continue to experience severe menopausal symptoms well after treatment, and that these symptoms don’t diminish with time.
Now they're conducting a longer-term study, surveying women at six-month intervals from the time that they begin treatment for breast cancer through several years of survivorship.
Edited from the Women’s Cancers Program Impact Report, March 2013