Personalized Medicine for the Most Lethal Endometrial Cancer

The Inaugural Wendy U. and Thomas C. Naratil Pioneer Awardee:

Alfred L.M. Bothwell, Ph.D.,Professor of Immunobiology 

Endometrial cancer is the most common gynecological cancer in the United States, with approximately 50,000 new cases and more than 8,000 deaths annually. Uterine serous cancer, a particularly aggressive form, accounts for 10 percent of endometrial cancer cases, but is responsible for nearly 40 percent of endometrial cancer deaths. New, more effective treatment strategies are desperately needed. Dr. Bothwell has begun to tackle this challenge by developing a radically innovative mouse model of uterine serous cancer that more closely simulates a patient’s experience than existing models, integrating the patient’s immune system and tumor pathology. This model seeks to usher in a more personalized medicine, allowing treatments to be tailored and optimized for individual patients. Specifically, Dr. Bothwell is testing, for the first time, how drugs or drug combinations interact simultaneously with immune response, tumor response and genetic factors. Because uterine serous cancer spreads quickly, the evaluation of therapies must be completed as rapidly as possible to benefit patients. If successful, this experimental model will allow evaluation much faster than would be possible in human clinical trials, thus providing tremendous clinical benefit.

Using Inflammation as a Target for Breast Cancer Therapies

Carlo Bifulco, M.D.

Carlo Bifulco, M.D.,   Assistant Professor of Pathology

Inflammation in tissues and cells is the body’s response to attack by disease-producing processes. However, certain aspects of the inflammatory process may contribute to the development and progression of abnormal cell growth and cancerous tumors. Dr. Bilfulco’s research was designed to validate inflammation as a target of therapy for cancers most likely found in women (such as breast cancer), and to identify groups of patients most sensitive to anti-inflammatory chemoprevention efforts.

Highlighted Study Findings

Dr. Bifulco’s funded study explored the role of macrophage migration-inhibitory factor, or MIF, in breast and gynecological cancers. MIF is a regulator of the body’s innate immune system and inflammatory response, and affects multiple processes related to cancer. Thus it is believed to be a good candidate as a target for potential drugs to limit its effect on cancer development. Dr. Bifulco’s laboratory analyses focused on the potential association between an inherited predisposition to MIF hyper-secretion and four different types of malignancies: breast and ovarian carcinomas, as well as melanoma and Hodgkins Lymphona. This study’s results provided support for an association between MIF hyper-secretion and the risk of development and severity of human malignancies, particularly with respect to melanoma and prostate cancer. Further work was under way to evaluate the potential of inhibiting MIF’s effects on tumor generation and growth, as a means of combating cancers such as melanoma.

Pilot Project Study was funded in 2006, Dr. Bifulco is now in Portland, OR

Improving Chemotherapy for Ovarian Cancer

Priscilla S. Dannies, Ph.D.

Priscilla S. Dannies, Ph.D.,   Professor of Pharmacology

Most patients with ovarian cancer respond fully to the initial standard therapies including surgery and chemotherapy. However, the cancer very often recurs and becomes resistant to treatment, and women with ovarian cancer suffer the highest mortality rate among patients with gynecological cancers. Dr. Dannies investigated a new approach to treatment of ovarian cancer that involves interfering with the functioning of tumor cells to make them more susceptible to destruction by chemotherapy, thus providing a new way to improve the survival rate of women with ovarian cancer.

Highlighted Study Findings

In a project employing innovative molecular techniques, Dr. Dannies studied potential ways to interfere with the normal functioning of cells in order to “stress” the cells and, thus, make them more vulnerable to toxic agents such as those used to treat cancer. One routine event in every cell is the folding of newly made, or synthesized, proteins into a special compartment in the cell called the secretory pathway. All cells need to make such proteins, and all cells have a secretory pathway through which the proteins are transported to where they belong. Cells have mechanisms to help proteins fold, and feedback systems to increase these “help mechanisms” if needed. When cells are forced continually to make proteins in the secretory pathway that cannot fold, the cells become “stressed.” Dr. Dannies was able to find a protein that cannot be folded properly or disposed of easily by the secretory pathway of ovarian cells. Subsequent research has incorporated this methodology in using techniques developed for gene therapy.

Targeting the Mechanisms for Treating Lung Cancer

Michael P. DiGiovanna, M.D., Ph.D.

Michael P. DiGiovanna, M.D., Ph.D.,   Associate Professor of Medicine (Oncology) and Pharmacology

Dr. Michael DiGiovanna’s study focused on lung cancer, the leading cause of cancer death in women in the United States. His work examined the use of anti-estrogen treatments, used to reduce relapse in breast cancer, to lower the chance of developing lung cancer. Initial work deciphering the intricacies in the cell biology of breast cancer and estrogen receptors led to unexpected findings of estrogen receptors in certain forms of lung cancer. Because the growth of these lung tumor cells is fueled by estrogen, treatments for this type of tumor will likely rely on inhibiting estrogen or blocking estrogen receptors.

Highlighted Study Findings


Dr. DiGiovanna’s funded study showed that certain combination chemotherapies that target estrogen receptors were more effective against certain lung cancers in women than in men. His work has helped prompt further research on development of treatments that rely on selecting the appropriate “targeted” receptor-inhibitor combinations to treat tumors in various parts of the body. Laboratory research not infrequently leads scientists to unexpected results, and following such leads down new paths is one way important discoveries can be made. Dr. DiGiovanna’s is an example of this.

Enhancing Treatment of BRCA-Deficient Breast and Ovarian Cancers

Peter Glazer, MD, PhD

Peter M. Glazer, M.D., Ph.D., Professor and Chair of Therapeutic Radiology

Dr. Glazer’s study is moving a powerful new antibody (a protein made by immune cells to attack disease agents such as cancer cells) toward clinical application for improving breast and ovarian cancer treatments. 

He discovered that this antibody, 3E10, can increase the vulnerability of various types of cancer cells to radiation and chemotherapy. Early evidence shows this effect is greater in breast and ovarian cancer cells related to mutations of two particular genes, BRCA1 and BRCA2. Inherited mutations involving these genes increase risk for breast and ovarian cancers, and many non-familial breast and ovarian cancers are associated with cell-repair defects involving mutations of these two genes. 

The ultimate goal is to provide new, more effective treatments for women with breast and ovarian cancers.

This study is funded in conjunction with the Yale Comprehensive Cancer Center.

Finding Out if BRCA1 and BRCA2 Genes are Risk Factors for Locally Recurrent Breast Cancer

Bruce G. Haffty, M.D.

Bruce G. Haffty, M.D.,  Professor of Therapeutic Radiology

One in every approximately eight women in the United States will develop breast cancer in their lifetime, and breast cancer is the second leading cause of cancer mortality. Although it was known that women with BRCA1 and BRCA2 gene mutations are at greater risk for developing breast cancer, it was not known whether these women were at higher risk for recurrence of breast cancer. Dr. Haffty focused his study on determining the risk of recurrence for women with these gene mutations.

Highlighted Study Findings

Using a unique data set allowing a 15 year follow-up of women with breast cancer, Dr. Haffty found that women with mutations of BRCA1 or BRCA2 genes were significantly more likely to develop additional tumors in either breast following treatment for an initial occurrence, than are women without this genetic risk factor. These findings have become crucially important to women weighing treatment options at time of initial diagnosis and developing plans for follow-up. The results now routinely inform treatment decisions. These findings also provided the impetus for expanding this work to African-American and Korean populations of women who had never previously been studied.

Pilot Project Study was funded in 1998, Dr. Haffty is now at Robert Wood Johnson Medical School in New Jersey

Distinguishing Between Harmful and Harmless BRCA Mutations to Guide Treatment

Ryan Jensen, Ph.D.,Assistant Professor of Therapeutic Radiology 

Genetic tests for BRCA or breast cancer susceptibility gene mutations are becoming widely available. While certain mutations have been specifically linked to cancer risks, these genetic tests are increasingly showing thousands of mutations and variations that have not been characterized. The standard of care for women with harmful BRCA mutations, known to dramatically increase cancer risk, can involve preventive double mastectomy. However, when genetic tests show mutations not yet known to be definitively linked to cancer risks, these ambiguous findings leave patients and health care providers with no clear options. Capitalizing on the latest biochemical, analytical tools, Dr. Jensen will characterize a multitude of BRCA variations and mutations. His ultimate goal is to develop a high-speed test, a biochemical assay, to distinguish between harmful mutations and innocuous, routinely occurring genetic variations. This test will be invaluable in guiding decisions for patients who undergo genetic tests, and potentially for designing new treatments to specifically target tumor cells related to BRCA mutations.

Developing an In Vitro Assay for Ovarian Cancer Drug Sensitivity

Barry M. Kacinski, M.D., Ph.D., Professor of Therapeutic Radiology

Ovarian cancer remains the most lethal gynecological cancer, and optimal treatments remain elusive. Dr. Kacinski and his colleagues worked to develop a measure of the sensitivity of ovarian cancer cells to therapeutic drugs—practical tests that predict the likelihood of individual tumor responses to particular drugs. Such laboratory tests have increased the effectiveness of chemotherapy choices and reduced exposure to treatments that are unlikely to be useful while inducing unnecessary side effects.

Highlighted Study Findings

In this study, Drs.Kacinski and Maryann Flick worked to develop a measure of the sensitivity of ovarian cancer cells to therapeutic drugs. The researchers compared the response of specific tumor cells to various chemotherapeutic agents in the laboratory - to the response of the patient with ovarian cancer in a clinical setting, utilizing two of the most widely used types of chemotherapy for ovarian cancer. Their results showed that the laboratory test correctly predicted the patient’s response to chemotherapy more than 75% of the time. These results represented the first steps toward practical tests to predict the likelihood of individual tumor responses to particular drugs. Such tests will permit the choice of anti-cancer agents to which the patient’s tumors are most sensitive, and avoid treatment with drugs to which a tumor is already resistant, thus avoiding unnecessary drug side-effects while maximizing available treatments.

Pilot Project Study was funded in 2000, Dr. Kacinski †

Targeting a Breast Cancer Invasion Control Switch

Anthony Koleske, Ph.D.

PI: Anthony J. Koleske, Ph.D., Professor of Molecular Biophysics and Biochemistry and Neurobiology

Titus Boggon, Ph.D.
Titus J. Boggon, Ph.D., Associate Professor of Pharmacology

Metastasis, or the spread of a primary tumor, is the greatest cause of mortality from breast cancer. Dr. Koleske’s research has shown that three particular proteins come together to form a control “switch” in breast cancer cells which when turned on enables the cells to invade surrounding tissues, where they can develop secondary tumors.

He and co-investigator Dr. Boggon are investigating this switch to develop ways to keep it from forming. Their plan is to identify the small molecule compounds that disrupt the interaction of the three proteins, to prevent the switch from turning on. They are taking the first important steps toward developing a new class of drugs to target this switch and thus limit the spread of breast cancer cells. Currently, there are no drugs that selectively target breast cancer metastasis.

Finding Out Whether Alternative Therapies Affect Breast Cancer Treatments

Sara Rockwell, Ph.D.,   Professor of Therapeutic Radiology and Pharmacology

Approximately one in eight women in the United States will develop breast cancer. Due to the prohibition of hormone therapy and the use of estrogen-blocking drugs for women with breast cancer, women often report severe menopausal symptoms, particularly hot flashes. Dr. Rockwell was among the first in the country to study the effects of black cohosh, a commonly used herbal treatment for hot flashes, showing its affect on breast cancer therapies. 

Highlighted Study Findings

Women with breast cancer are increasingly turning to alternative medicines, either to supplement their traditional cancer treatment or to treat conditions for which traditional medicines are not recommended (such as estrogen to treat menopausal symptoms). One herb often used to treat menopausal symptoms by women who have stopped taking hormone replacement therapy is black cohosh.  This herb is purchased over-the-counter and has been advertised as safe and effective for the treatment of menopausal symptoms.  Yet, such over-the-counter agents do not require the approval of the Food and Drug Administration and previously had not been the target of scientific inquiry. Dr. Sara Rockwell’s research was designed to investigate the effect of black cohosh on breast cells using a mouse model. Dr. Rockwell’s study indicated that when black cohosh is used concurrently with traditional types of chemotherapy, it can either increase or decrease the effectiveness of the treatment depending on the specific type of chemotherapy used. Furthermore, her study showed that it was also possible for black cohosh to increase the levels of toxicity associated with traditional chemotherapy drugs. With the use of complementary and alternative medicines on the rise, it is critically important to determine whether these agents are safe.  Armed with the facts, patients can make informed decisions about their treatment.

Developing the Use of Nanoparticles as a Novel Mechanism for Advancing Chemotherapy of Ovarian Cancer

Alessandro D. Santin, M.D.

Alessandro D. Santin, M.D.Professor of Obstetrics, Gynecology and Reproductive Sciences 

Co-Funded by the Yale Cancer Center and Women's Health Research at Yale

Because ovarian cancer almost always is followed by a recurrence which is resistant to current interventions, women with ovarian cancer suffer the highest mortality rate among patients with gynecological cancers. With this reality in mind, Dr. Santin (who has studied the molecular underpinnings of ovarian tumors) and his collaborator, Dr. Mark Saltzman, Professor of Bioengineering (who is creating new uses for nanoparticles in the delivery of health care treatments) are seeking to develop a new, effective strategy to treat ovarian cancer and improve survival rates.

Highlighted Study Findings

Dr. Santin is collaborating with Dr. Saltzman to develop specially-formulated nanoparticles, ultra-tiny particles, which can be fabricated as “homing devices” to preferentially target and bind to ovarian cancer cells, and deliver a potent chemotherapy agent as cargo inside the nanoparticle. Thus far, the team has been able to accomplish their first two aims. First, they have synthesized novel biodegradable polymers to create nanoparticles for this purpose. Second, by adding fluorescence as a marker to observe binding, they have shown that these nanoparticles can find and selectively bind with the target cells in cell lines donated by volunteer patients.  The next step of the research, now under way, is to demonstrate that these nanoparticles can target ovarian cancer cells and deliver chemotherapy in animal models. The ultimate goal is to develop a nanotechnology-based treatment to be tested in clinical trials.

Using Human Immune Responses to Create a New Model for Breast Cancer Therapies

Joann Sweasy, Ph.D., Professor of Therapeutic Radiology

Co-funded by the Yale Cancer Center and the Maximilian E. & Marion O. Hoffman Foundation Inc.

Existing model (animal) systems for studying human breast cancer utilize therapeutic agents and human tumors, yet they do not consistently predict patient outcomes. Dr. Sweasy has hypothesized that this reduced translation from model systems (e.g. using the mouse) to human biology is likely because female animals are often not used and because models do not replicate the human immune system, which affects tumor growth and responses to cancer therapies.

Highlighted Study Findings

In this ongoing funded study, Dr. Sweasy (in collaboration with Dr. Richard Flavell who developed the “humanized” mouse model) is developing a model system of breast cancer that simulates the human immune system’s responses to therapies more closely than existing models. Preliminary findings show that immune compromised mice reconstitute very well with a human immune system, and ionizing radiation in combination with a human immune system acts synergistically in the control of human breast tumors. These preliminary data represent steps toward providing a new way of enabling creation of “personalized” breast cancer treatments to improve outcomes for women treated for breast cancer.