Innovative Treatment Modalities and Innovative Models of Care

In developing its priorities for research funding, the Breast Cancer Research Council (BCRC) identified etiology as a critical topic. A major goal of the BCRP is to reduce the incidence and morbidity of breast cancer among women in California. Understanding the etiology (causes) and pathogenesis (development) of breast cancer was deemed an essential first step in developing methods to prevent breast cancer.

It is well known that breast cancer affects some groups in the population at higher rates than others. A better understanding of who gets breast cancer and who doesn't might lead to clues about risks and protective factors for breast cancer occurrence. Under the broad topic of etiology, the BCRC envisioned a variety of possible studies, ranging from laboratory research looking at potential cancer-causing agents and genetic abnormalities in breast cancer cells or tissue, to large scale population studies that might examine dietary, hormonal, and environmental factors associated with breast cancer. The BCRC thought that these would be important first steps in enhancing our ability to recommend interventions for larger scale clinical testing. The BCRC deemed this a high priority area because of its potential to shed light on the causes of breast cancer and the development of preventive intervention strategies in the future.

The funded studies focus on examining various potential causes of breast cancer, including: an agent found in cooked meat, industrial pollutants, a virus found in cows (potentially passed through ingestion of beef and milk) and hormones. The examination of these possible causes of breast cancer offer the potential for a variety of prevention measures.


Innovative Treatment and Models of Care Awards

top


Development of Diphtheria Toxin Breast Cancer Therapeutics

Senyon Choe, Ph. D.
The Salk Institute for Biological Studies

Normally, the growth of human breast cells is closely controlled by the levels of hormones (such as estrogen) and growth-promoting proteins (such as heregulin). Heregulins are a class of proteins known to promote the unwanted growth of breast cancer cells under certain conditions. The overabundance of heregulin on the surface of breast cancer cells often indicates that the cancer has progressed to the stage that the cells are no longer responsive to estrogen treatment using a drug like tamoxifen. The counter balancing activities of these two classes of molecules, steroid hormones and growth-promoting proteins, are important in determining the progression of breast cancer. The ultimate goal of this proposal is to disrupt this balance in order to stop growth of breast cancer cells. In practice, our specific aim is to design a toxin protein that will kill cells carrying the growth-promoting protein heregulin.

Diphtheria toxin is known to kill certain types of cells carrying a specific receptor protein on their surface. This toxin will serve as the starting material in our design of a new toxin for killing breast cancer cells. Our strategy is to create a toxin variant that is capable of recognizing and killing only those cancer cells carrying heregulin. We hypothesize that the targeted delivery of this toxin variant to these cells will effectively reduce the overall growth of breast cancer.

Our experimental approach is to custom design the toxin by using a three-dimensional picture as a guide. With the help of x-rays, we have recently obtained this three-dimensional picture. This picture shows in detail how atoms of the toxin fit together with atoms of the receptor, like pieces of a jigsaw puzzle. This detailed view will allow us to identify key atoms dictating the fit between toxin and receptor. In our designed toxin, these key atoms will be modified using molecular biology techniques with the aim of targeting the toxin to heregulin-bearing cancer cells. Since the molecular makeup of heregulin is similar to that of the natural toxin receptor, our design strategy appears to be feasible, needing only a small change on the toxin to change the target. The function of this designed toxin against breast cancer will first be tested in test tubes. Once successful, it will provide an alternate therapeutic means of controlling the progression of breast cancer.

back  top

Radiosurgery of Early Breast Cancer

Silvia Formenti, M.D.
University of Southern California

Early detection of breast cancer by mammography has mostly benefitted post-menopausal women by diagnosing tumors that measure less than 2 cm in diameter. The conventional management of these small tumors has been either mastectomy (removal of the entire affected breast) or segmental mastectomy (removal of the tumor with a rim of surrounding normal tissue) followed by six weeks of daily radiation therapy directed to the residual breast tissue of the affected breast. These six weeks of radiation therapy often represent a considerable inconvenience, especially among older women.

Four large clinical studies have shown that most recurrences of cancer occur at the site of intial tumor. These findings suggest that, for small tumors, it may be possible to limit the radiation treatment to the initial tumor area only, without treating the entire breast volume. This reduction in the volume of breast tissue that needs to be irradiated makes it possible to investigate ways to safely deliver the radiation dose in shorter time, with potential advantages, both in terms of the patient's quality of life and health care costs.

This study aims to explore the effect of a novel form of radiotherapy, called radiosurgery, on small breast cancers. It is called radiosurgery because it has the potential to ablate (kill) tumors by radiation with the precision, specificity and efficacy of surgery. This technique has already proven itself painless, safe and effective in the treatment of benign (non-cancerous) malformations of brain vessels and brain tumors.

Radiosurgery is a radiation technique that delivers, in a single session (lasting approximately one hour) a radiation dose that may be biologically equivalent to what is received over six weeks of daily treatments. This is made possible by advanced technology that concentrates the received radiation on a small volume while sparing most of the surrounding normal tissue.

We are proposing to test the use of a single session radiosurgery as a substitute for surgery plus six weeks radiation in ten post-menopausal women with small tumors. The tumor will be irradiated, and then will be surgically removed so that it can be examined to determine the effectiveness of the treatment. This will provide preliminary data that, if promising, can be confirmed in a subsequent clinical study. If confirmed successful, a radiation session of one hour could substitute for six weeks of daily treatments after segmental mastectomy.

back  top

Outpatient Stem Cell Transplants for Breast Cancer

Kathryn Hollenbach, Ph. D.
University of California, San Diego

High-dose chemotherapy with bone marrow or stem cell transplant is a treatment that has been increasingly recommended to women with advanced (metastatic) or high-risk primary breast cancer. Studies have shown that this therapy, which uses very high doses of chemotherapy, may lead to better results in women with high-risk disease. The technique of stem cell transplant has been developed over the past decade to allow the use of extremely high doses of chemotherapy. Stem cells are collected, frozen and then used to rescue blood counts following high-dose chemotherapy.

However, a major barrier to more widespread use of this treatment is the very high associated costs, typically ranging from $100,000 to $150,000. Because of this high cost, there has been a great deal of resistance on the part of insurers to include this procedure as a covered benefit. Controversy surrounding this has manifested itself by law suits, arbitration hearings, testimony before Congress, and attempts at legislation in many states. It is clear that no matter how successful this therapy is, it will have little impact for the majority of women who might benefit from it unless it is more widely available. More widespread availability, in turn, depends on reduction of total costs.

One major source of the high cost has been the traditional need for prolonged inpatient hospitalization. However, in the last few years it has become possible to deliver this therapy in a less costly setting. At Scripps Clinic, early discharge programs have been developed which safely and effectively reduce the total duration of hospitalization as well as the total costs associated with this procedure. We have treated over 150 patients with high-dose chemotherapy and stem cell transplants in an outpatient clinic. Preliminary results demonstrate that this program is extremely safe (procedure-related death rate of less than 1.5 %) and highly acceptable to patients. Preliminary financial analysis suggests a 35% to 43 % reduction in total charges for patients treated in the outpatient setting. However, there is no information on the financial impact of this type of program on the patients and their families. Further, effects on patients emotional and psychological health have not been adequately examined.

We propose to conduct a detailed analysis of the financial impact of outpatient transplantation for breast cancer by comparing the total hospital and clinic costs associated with stem cell transplantation among patients receiving traditional inpatient care and those receiving the identical treatment in this innovative model of outpatient care. In addition, we will examine the financial impact on the patients and their families in the two settings to determine whether any shift in costs from insurers to patients and families is occurring. We will also compare the "quality of life" and psychological impact of treatment for the different treatment settings.

If outpatient transplants are shown to reduce total costs without unduly burdening patients or their families, substantial barriers to more widespread use of this potentially life-saving therapy should be reduced.

back  top

T-cell Immunotherapy of Breast Cancer

Malcolm S. Mitchell, M.D.
University of California, San Diego

We hope to be able to use the body's immune response to get rid of breast cancer cells remaining after high dose chemotherapy and stem cell transplantation. Among the white blood cells collected for the transplant are T cells, white blood cells capable of killing tumor cells specifically without injuring normal tissues. There are also other white blood cells capable of presenting foreign proteins (antigens) from the breast cancer cell to the T cells, so the T cells can react more strongly to the proteins. We propose to take the T cells and the other white blood cells after the stem cells needed for the transplant have been separated from them. We will then try to immunize two subtypes of T cells, T helper cells and T killer cells, with different fragments of the breast cancer protein, because each subtype responds best to a different sized fragment. It will be necessary to find out which fragments immunize best, and whether only one or two are needed to immunize the T cells of all patients.

Special methods of putting the protein fragments into the antigen-presenting white blood cells, and of growing the T cells outside the body will be developed, with new molecules that conduct the fragments to the part of the antigen-presenting cell where they will be presented best, and with new T cell-growth stimulating substances. Methods of doing these procedures in a clinically relevant way will be developed too, which will enable them to be used together with, or immediately after, the stem cell transplantation itself. We will immunize the patients later, to keep their level of immunity high. As an essential part of this study, we will adapt assays we already use in our laboratory to measure how many anti-breast cancer T cells are circulating in the patient at various times after the T cells are put back and after the patient is immunized. These experiments will not only help us in treating breast cancer patients with helper and killer T cells, they will also tell us what parts of the breast cancer protein patients most strongly react to, enabling the further scientific development of specific breast cancer vaccines.

back  top

Structure of Est-1: A Potential Drug Target for Breast Cancer

Hillary Nelson, Ph. D.
University of California, Berkeley

Breast cancer is a growth disorder of cells: breast cancer cells can divide uncontrollably, whereas normal breast cells only divide under carefully controlled conditions. Cell division requires duplication of the DNA, the genetic material. In humans, DNA is organized into 46 units, known as chromosomes. At their ends, chromosomes have special structures called telomeres. The telomere is thought to be an important factor in controlling duplication of the DNA, and hence cell division. Telomeres shorten with age in normal breast cells, but the shortening process is reversed in breast cancer cells. If we can understand how telomeres are different in breast cancer cells, we might be able to design new therapeutic approaches to inhibit the growth of tumors in breast cancer while not affecting the normal breast cells.

The long range goal of our research is to understand how telomeres are assembled. There is a protein complex, called telomerase, which is thought to be responsible for fully duplicating the DNA ends, thus preventing shortening of the DNA. One postulated component of telomerase, called Est-1 (Ever Shorter Telomeres), is thought to be involved in regulation of telomerase activity, and hence, maintenance of telomere length over time. The role of Est-1 at the telomere has been extensively studied; that fact combined with its regulatory action in cell growth and proliferation, make Est-1 both important and feasible to understand.

The specific aim of this research project is to understand how Est-1 physically associates with the telomere. We will use several different approaches, including molecular biology, biochemistry, and X-ray crystallography, to help us study the structure of Est-1 and how it binds telomeric DNA. These studies may lead to the design of specific drugs to disrupt the interaction of Est-1 and telomeres, which would lead to shorter telomeres and eventually the death of breast tumor cells.

back  top

Improved Delivery of Pharmaceuticals to Breast Cancer

Demetrios Papahadjopoulos, Ph.D.
University of California, San Francisco

Patients with breast cancer receive drug therapy to suppress tumor growth and spread of metastasis. Major drawbacks of current anticancer drug therapies are the general toxicity of anticancer drugs and the often insufficient effect on tumors. One of the ways to improve this situation is to ensure that the injected anticancer agent is delivered mostly into the tumor tissue. In this project, we propose a novel strategy to achieve such enhanced delivery of anticancer agents to the breast cancer tumors.

Our strategy brings together two modalities. The first one is known as liposome-mediated drug delivery. The antitumor agent, prior to injection, is packed into liposomes (submicroscopic vesicles surrounded by a lipid membrane resembling that of a living cell). To make the drug-loaded liposomes invisible to the scavenger cells in the liver and spleen, which routinely remove foreign material from the blood, the surface is coated with a protective compound, polyethylene glycol. The second modality is heat treatment of the tumor. Heat treatment would substantially increase the tumor accumulation of such "sterically stabilized" liposomes, or SSL, and therefore of the SSL-carried antitumor agent. In our preliminary study, one hour exposure of the human breast tumor grown in mice to heat increased the accumulation of SSL fourfold compared to a tumor without heat treatment. In the proposed project, we will optimize and test the proposed two-modality strategy on an established animal model, human breast cancer tumors implanted subcutaneously in mice. First, using radioisotope-labeled SSL, we will optimize the protocol of heat treatment (temperature, duration), SSL administration, and SSL composition to achieve maximum accumulation of SSL in the heat-treated tumor. Then we will study the dynamics of SSL accumulation in heat-treated tumor and non-treated tumor. Using light microscopy and SSL labeled with colloidal gold, we will study the penetration of SSL in the tissue of heat-treated and non-treated experimental tumors. We will further use SSL bearing antibodies that recognize certain types of breast cancer cells in order to determine whether their attachment on the surface of SSL is beneficial for enhanced localization of SSL in experimental tumors. Finally, with the developed optimized protocol, we will test the efficacy of the proposed strategy for the suppression of tumor growth in the same animal model using SSL loaded with doxorubicin, a drug regularly used for breast cancer chemotherapy.

As a major result, we expect to establish the strategy of heat-enhanced delivery of SSL-carried pharmaceuticals into breast cancer tumors. This strategy will especially benefit patients with locally advanced and recurrent disease by allowing better tumor suppression with lower doses of anticancer agents, leading to fewer complications and better response to treatment. Since SSL-carried anticancer pharmaceuticals and heat treatment techniques (hyperthermia) for breast tumors are presently used in the clinic, the results of this study are likely to be quickly translated into medical practice. In the future, we plan to expand this strategy for the delivery of various agents to tumors, including other cytostatic drugs, therapeutic oligonucleotides and genes. We will also undertake necessary studies to bring the developed strategy to Phase I clinical trials.

back  top

Targeted Gene Therapy Using Anti-p185HER2 Immunoliposomes

John Park, M.D.
University of California, San Francisco

This application proposes to develop anti-p185HER2 immunoliposomes containing genes as a novel strategy to treat advanced breast cancer. There are 3 key components to this new strategy.

The first component are liposomes, small particles of fat that are hollow and can be used to carry potent anti-cancer drugs such as chemotherapy. The second component are genes, which are made up of DNA and carry instructions to cells. The idea that genes can be given to patients as a form of treatment is called gene therapy or gene medicine. Since many cancers, such as breast cancer, involve defective or abnormal genes that have sprung up in cancer cells, it is possible to imagine correcting cancer or causing cancer cells to die by putting new genes into the cells. However, although genes can be put into cells in the test tube, scientists have not yet developed a practical and effective way to put genes back into breast cells in patients. Liposomes can be used to carry genes. However, the liposomes will not necessarily be able to find the tumor cells in the body so as to deliver the genes.

Antibodies, the third component of this strategy, are proteins produced by the immune system to fight invaders such as bacteria, viruses, and cancer cells. Antibodies can recognize different parts of these invaders with precision. A single antibody type that recognizes a single target, such as a part of a cancer cell, is called a monoclonal antibody, and can be produced in the laboratory.

When antibodies are linked to liposomes, the resulting particles are called immunoliposomes (ILs). ILs can use their antibody part to recognize cancer cells. ILs can be made that recognize a target called p185HER2, a cancer protein produced by the HER2 oncogene. This protein molecule plays a carefully regulated role in the growth and development of certain normal cells. However, in many patients with breast cancer, the breast cancer cells contain many times more copies of the p185HER2 protein than normal, which helps the cancer to form in the first place and to grow rapidly.

We have developed different versions of anti-p185HER2 ILs (liposomes containing an antibody that recognizes and targets breast cancer cells with high levels of p185HER2). We can use anti-p185HER2 to target breast cancer cells and deliver to them high concentrations of effective chemotherapy drugs. This should result in enhanced killing of cancer cells as well as diminished side effects due to exposure of normal cells and tissues to chemotherapy. For this reason, these ILs have been likened to "smart bombs" in their ability to selectively find and hit cancer cells, while avoiding normal cells.

This application proposes to develop anti-p185HER2 ILs capable of carrying genes to breast cancer cells. First, a test gene will be used to determine the best procedure or recipe for making the ILs. Tests in test tubes and in mice will be done to determine the ability of different versions of Ils to recognize cancer cells and deliver the gene to them. Next, using what appear to be the best recipes, ILs containing a gene called HSVtk will be prepared. This gene can activate an ordinarily harmless drug called ganciclovir (GCV), turning it into a lethal drug. Thus, cancer cells targeted by ILs will get the HSVtk and become susceptible to killing by GCV. ILs will be tested for their ability to deliver the HSVtk gene in test tubes and in mice, and to cause their death when exposed to GCV. If this strategy is successful, it may mean that anti-p185HER2 ILs can be used to deliver other cancer-fighting genes to breast cancer cells as well.

back  top

Novel Retinoids that Induce Apoptosis in Breast Cancer Cells

Magnus Pfahl, Ph.D.
Sidney Kimmel Cancer Center

In North America, breast cancer is the most common cancer among women. In 1992 alone, approximately 180,000 new cases were found in the U.S. and more that 45,000 died in that year from breast cancer. In the last twenty years, significant progress in the detection of this cancer has been made, but the number of deaths due to this cancer has not changed significantly. New treatments are therefore urgently needed.

Retinoids belong to a class of substances that are synthetic (man made) copies and derivatives of retinoic acid, which is one active form of vitamin A. We have discovered several new retinoids that effectively inhibit the growth of breast cancer cells when these cells are grown in culture dishes. Some of these retinoids not only inhibit the growth of the breast cancer cells, but directly kill them. They start a so-called suicide program (called "apoptosis") in these cells.

The general mechanisms by which retinoids function are quite well understood today. Their action is much more specific than that of chemotherapeutic agents used often in treatment of cancer. We want to analyze how our new retinoids induce cell death of breast cancer cells and whether their action can be increased when they are used together with other agents that are already used in the treatment of breast cancer. We expect that our proposed research will give us important data that can form a basis for the development of new breast cancer treatments.

back  top

Pre-Clinical Testing of Cryosurgery for Breast Cancer Treatment

Boris Rubinsky, Ph.D.
University of California, Berkeley

This study propose to establish the use of imaging monitored cryosurgery for treatment of breast cancer. This is an innovative, minimally invasive surgical technique, that may have advantages over other surgical techniques by producing excellent medical results, with less distress and disfiguration, at a lower cost.

Cryosurgery is a surgical procedure that uses freezing to destroy undesirable tissue. Cryosurgery itself is not new. It began in England over one hundred and fifty years ago, where it was used to treat skin cancer. While the first use of cryosurgery employed brine to freeze tissue, modern procedures are performed with long and thin cylindrical probes cooled internally with liquid nitrogen, insulated except at the tip. In a typical procedure, several probes are inserted, needle-like, through the skin, with the tip in the tumor, and freezing begins from the probe outward, until the tumor is completely frozen. Afterward, the probes are removed and the treated tissue is left in the body to be removed by the immune system. The procedure is simple to perform and, by using several probes, can treat varying sizes, shapes and numbers of individual tumors, while sparing the surrounding healthy tissue. The advantages of cryosurgery are that it is minimally invasive, results in minimal disfiguration, is not dose limited, and is relatively inexpensive.

During the last twelve years, a collaborative study between the University of California at Berkeley and at San Francisco has produced a breakthrough in cryosurgery. The breakthrough involves using imaging techniques, such as intraoperative ultrasound and magnetic resonance imaging, to monitor the process of freezing deep in the tissue with excellent accuracy. This has extended the use of cryosurgery to the treatment of tumors deep in the body, particularly in the liver and prostate, with excellent results. We began applying imaging-monitored cryosurgery to the clinical treatment of cancer eight years ago. During the last three years, over 160 medical centers have begun using imaging monitored cryosurgery and over six thousand patients, primarily with non-operable liver and prostate cancer, have been treated. If the success of using cryosurgery on other tissues is any indication, imaging monitored cryosurgery could potentially become an effective technique for treatment of breast cancer.

In order to apply cryosurgery to breast cancer, it is necessary to establish the process of freezing because freezing itself does not necessarily destroy tissue, as evidenced by the common practice of preserving various cells such as red blood cells and sperm in a frozen state. To ensure destruction, the tissue must be frozen with certain thermal parameters which are different for different types of cells and are not yet known for breast cancer cells. The main goal of this study is to establish the thermal parameters needed for the destruction of human breast cancer by freezing. To this end, the study will pursue three different specific aims. First, we will study various human breast cell lines and determine which thermal parameters are needed to destroy these cells. Then we will study human breast tissue from resection surgery, to determine if the same thermal parameters apply in the tissue itself. Lastly, we will study imaging monitored cryosurgery of tumors in mice. This should help us determine how our studies with cells and resected tissue can be extrapolated to life organisms. The completion of this study will allow us to design a reliable clinical procedure that will be proposed at the end of the two years of this study.

back  top

A New Approach to Immune Therapy for Breast Cancer

Michael Roth, Ph.D.
University of California, Los Angeles

Breast cancer now affects one out of every nine women in the United States and is a leading cause of cancer death. While surgery, radiation and chemotherapy are very effective at curing woman when their cancers are caught at an early stage, these therapies are rarely effective when used in patients with more advanced disease. New approaches are needed. One such approach is to use the body's own immune system to fight the cancer, so called "cancer immunotherapy". Our research focuses on how to stimulate the immune system so that it will recognize breast cancer cells as abnormal and destroy them. There are several steps to this process. First, we must find something that is unique about breast cancer cells that will act like a flag to identify them. We believe that a specific protein, the HER-2/neu protein, fulfills this need. HER-2/neu is a protein that is found on very few types of cells and usually in very small amounts. However, about one-third of the cases of breast cancer produce excessive amounts of HER-2/neu - as much as 50 to100 times the normal amount. By directing the immune system to recognize HER-2/neu as abnormal, we hope that it will preferentially destroy breast cancer cells and not normal cells. The next step in our work is to figure out how to program the immune system so that it will indeed recognize this HER-2/neu protein. This is done by feeding pieces of HER-2/neu protein to a special type of white blood cell called a dendritic cell. A dendritic cell is capable of taking up these pieces of HER-2/neu and programming the immune system to respond to it. We have recently developed ways to grow these dendritic cells from patient's blood and we will determine the best way to load them with pieces of the HER-2/neu protein. This is a difficult process because just the right "piece" must be found and it differs from one person to another. We can simplify this task by using genetic engineering. We will take the gene that tells the body how to make the HER-2/neu protein and insert it into dendritic cells. In this manner, each person's dendritic cells will be able to make just the right piece of HER-2/neu necessary to stimulate the immune system. By the end of our study, we will be able to put all of these steps together and test whether or not the immune system can be programmed to recognize and destroy breast cancer cells. Preliminary results are very encouraging. If we are successful, we will have developed a new way to treat breast cancer that is painless and long-lasting.

back  top

Tibetan Medicine for Advanced Breast Cancer

Debasish Tripathy, M.D.
University of California, San Francisco

Standard treatment for metastatic breast cancer does not follow any rigid guidelines and is individualized depending on the patient's tumor characteristics and clinical situation. Chemotherapy regimens and hormonal therapies can be effective for a variable period of time and in some cases the benefits of treatment in terms of improving symptoms and quality of life can outweigh the side effects. However, it has been difficult to show that standard or experimental treatments can prolong life significantly. Alternative and traditional approaches to medicine such as herbal and homeopathic medicine are widely used in the United States and throughout the world, although they have not been evaluated in formal clinical trials, especially in randomized trials. Therefore, it is difficult for patients and physicians to be able to logically choose what form of treatment might be most effective in controlling the cancer and maintaining an optimal quality of life.

We propose a method to start early testing of Tibetan Medicine as an example of a treatment that has been used for centuries, but has not been evaluated using clinical response criteria and quality of life analyses. The initial study will be an open study for all women with metastatic breast cancer that have no or minimal symptoms. Traditional diagnosis and herbal treatment by a world-recognized Tibetan physician will be conducted under the care of a California-licensed acupuncturist and herbalist. In parallel, patients will be seen and evaluated by a California-licensed and Board Certified medical oncologist experienced in clinical trials whose practice is devoted to breast cancer. A measurement of side effects, antitumor response or freedom from progression of tumor will be conducted. Quality of life and patient cost measures would be gathered and analyzed and a patient survey of standard and alternative medicine will also be conducted. If this study demonstrates effectiveness in terms of tumor shrinkage or freedom of tumor growth that is nearly comparable to Western treatments such as chemotherapy or hormonal therapy, a randomized trial would then be designed as part of this project, though the actual study would be activated as a separate project. The direction set forth by this project would therefore be the development of a scientifically sound clinical trials method to properly evaluate alternative medical approaches for breast cancer.

back  top