Innovative Treatments: Search for the Cure

A critical goal of the CBCRP is to move basic science as quickly into the clinic as possible. The Innovative Treatments priority issue offers the opportunity for researchers, both clinical and basic science, to undertake innovative projects that could improve breast cancer therapy. These research projects often represent a critical ‘bridge’ from the bench to the bedside.

Research Conclusions

Gene therapy and other treatments: new frontiers

Robert Debs, M.D. at the California Pacific Medical Center completed a 2-year project to investigate Gene Therapy for Breast Cancer. The focus of this grant was to use microscopic fat globules, called liposomes, as a vehicle to deliver genes that block angiogenesis (the process of new blood vessel growth) to the sites of breast cancers. Using this approach, he was able to show a prolonged anti-tumor effect using both the angiostatin gene (the anti-angiogenesis protein that has received extensive press coverage) and the p53 gene (a commonly defective tumor suppressor gene in breast cancer). The results of this project were published in the Journal of Biological Chemistry (May 7, 1999; 274(19): 13338-44). Thus, the actively dividing endothelial cells that allow angiogenesis in tumors are an attractive new target for gene therapy. Using support from the CBCRP for this “high risk/high reward” project, Dr. Debs was able to validate his innovative approach, publish his findings, and compete successfully for an NIH grant to continue this project on a much larger scale.

Herve LeCalvez, Ph.D. from The Burnham Institute completed a 2-year Postdoctoral Fellowship to study The Role of Meltrin-alpha in Breast Cancer-Associated Bone Loss. Meltrin-alpha is a protein on the surface of bone cells that allows them to fuse together to form bone-destroying osteoclast cells. Osteoclast formation is a common side-effect in breast cancer and causes high blood calcium levels, which can be a fatal complication of the disease. Dr. LeCalvez used molecular biology techniques to understand the protein domain structure of meltrin-alpha. First, he found a region of meltrin-alpha that would support cell fusion. Second, he found another region that might inhibit cell binding, but this segment of meltrin-alpha did not appear to interact with cell lines chosen for this study. More work is needed to manipulate and express meltrin-alpha in model cell lines to confirm this preliminary structural information.

Boris Rubinsky, Ph.D. of the University of California, Berkeley completed a project entitled “Pre-Clinical Cryosurgery Testing in Breast Cancer Treatment.” He performed pre-clinical studies to determine the parameters required for complete destruction of breast tumor through cryosurgery, which is a minimally invasive technique. Dr. Rubinsky used a small probe to freeze breast tumors and found that mouse tumors that were frozen to -40oC at a rate of 5oC/min still had surviving cells after one freezing cycle, but that destruction of the tumors occurred after two rounds of freezing. He also found that cryosurgery in the presence of a class of proteins call “antifreeze proteins” can completely destroy tumor cells, even if the conditions are otherwise sub-optimal. This approach may provide a new, less invasive way to perform breast cancer surgery.

Marc Shuman, M.D., Randall Hawkins, M.D., Ph.D., and Laura Esserman, M.D. at the University of California, San Francisco completed a pilot grant on the Inhibition of Angiogenesis in Breast Cancer. The development of the blood supply for tumors, called angiogenesis, is critical for growth and spread in the body. This project involved, first, a new way to block angiogenesis by using an inhibitory monoclonal antibody to an angiogenesis protein, called VEGF. Secondly, they explored state-of-the-art imaging technologies (MRI and PET) to observe the clinical effects of treatment. They found that a new method of MRI imaging, called Triple Acquisition Rapid Gradient Echo Technique (TARGET), could reproducibly detect changes in breast cancers with 48 hours of treating mice with the anti-VEGF antibody. In other experiments, these investigators surveyed human breast cancer cell lines and found important differences for the specific angiogenesis factors critical to their growth. This indicates that human breast tumors may differ in response to anti-angiogenesis therapy, so the TARGET method could give a rapid ‘read out’ of efficacy.

Robert Stern, M.D. from the University of California, San Francisco was funded for a 3-year project to investigate The Breast Tumor Suppressor Function of Hyaluronidase. Hyaluronic acid (HA) is a component of the extracellular matrix, and it opens up tissue spaces to promote cell movement. The amount of hyaluronic acid on the surface of breast cancer cells correlates with tumor aggressiveness. Thus, the enzyme that degrades hyaluronic acid, hyaluronidase, has potential as a breast cancer therapeutic. Using support from the CBCRP, Dr. Stern published the purification, protein sequencing, and cloning of hyaluronidase in the journal FEBS Letters (Nov 17, 1997; 417(3): 307-10). And, in completely new and unexpected results, the relationship of hyaluronidase to an already sequenced tumor suppressor was published in the journal Genomics (Feb 15, 1998; 48(1): 63-70). Hyaluronidase is found in normal breast cells. Dr. Stern found that increasing the amount of hyaluronidase in aggressive breast cancer cells lines slows cancer cell growth. In addition, injecting hyaluronidase protein into animals with experimental tumors reduces the size of the tumors. Dr. Stern is continuing this work by performing “knock outs” of the hyaluronidase gene in mice and exploring the relationship of this cell surface tumor suppressor activity with other known tumor suppressors, such as p53. Even more than when this project was funded in 1995, it appears that hyaluronidase has a potential to treat breast cancer.

Mary Wieneke, Ph.D. of the California School of Professional Psychology looked at the long-term effects on brain functioning of conventional chemotherapy and Tamoxifen for early stage breast cancer, and tried to identify the contribution of psychological and emotional distress such as depression/anxiety, to mental functioning. Women in the study were newly diagnosed with early stage (I or II) breast cancer and received either adjuvant chemotherapy (with or without Tamoxifen), or only Tamoxifen. A third group, with no chemotherapy or drug treatment, served as the comparison group. Women were tested shortly after diagnosis (baseline), shortly after completion of treatment, and about one year after the second test, or about eighteen months post-diagnosis.

At baseline, psychological measures revealed a range of mild depression in the majority of the women (69%). Anxiety levels were significantly elevated at first testing, with results further suggesting that elevated anxiety levels may impair overall cognitive functioning at this time. This would have implications for decision-making and how newly diagnosed patients take in and process information at this critical time. At the third measurement, anxiety/depression levels had fallen close to or within normal range. Anxiety level was still elevated for the chemotherapy group, and the least comparative cognitive improvement over time was seen in the chemotherapy group. Thus, anxiety may indeed be a factor in cancer patients' cognitive functioning and ability to comprehensively process critical information at time of diagnosis and initial treatment planning. Some areas of cognitive functioning had not returned to “normal”18 months after diagnosis. A longer time may be needed to evaluate long-term treatment effects of adjuvant chemotherapy and tamoxifen upon cognitive functioning.

We currently have no way to predict which women with breast cancer will benefit from chemotherapy and which women will not benefit. Therefore, current practice is to give chemotherapy to almost all women diagnosed with breast cancer, thus subjecting many patients to painful and risky therapies to benefit only some of them. Recent evidence suggests that a woman's specific tumor marker profile may be an important predictor of response to adjuvant therapy. Drs. Shelley Enger, of Kaiser Permanente, Southern California and Michael Press of the University of Southern California conducted a pilot study to lay the groundwork for a full research study to definitively assess the value of breast tumor markers in predicting response to adjuvant therapy regimens. The investigators worked together to resolve problems encountered during the course of the study and they evaluated the resulting data to assess the feasibility of carrying out a large-scale study of breast tumor markers and therapeutic response. Their results confirmed the prognostic significance of the molecular markers; HER2/neu and p53 expression and BCL2 non-expression were clearly associated with poor outcome in the study population. They also confirmed that there is significant variation in treatment in this population, and this variability is not related to differences in molecular marker status. These results enabled them to be awarded a full grant the following year to examine whether molecular markers can predict the response to different therapies.

Hormone and chemotherapy targets: improving today's arsenal

Joel Gottesfeld, Ph.D. at The Scripps Research Institute completed a 2-year project to study Inhibitors of the Breast Cancer Her-2/neu Gene. With his colleague, Dr. Peter Dervan, at the California Institute of Technology, he developed novel DNA-binding molecules, called pyrrole-imidazole polyamines, to block a critical gene needed for breast cancer growth. Their target was the regulatory region (TATA-box) of the Her-2/neu gene. Their laboratory experiments demonstrated that a normal TATA-box regulatory protein was blocked by the polyamines. Then, the ability of polyamines to inhibit Her-2/neu synthesis and decrease motility in breast cancer cell lines was demonstrated. Thus, this project showed promising results using a novel means of inhibiting critical genes, and the treatment did not show toxicity and unwanted side-effects in cell models. More work will be needed to (i) validate these findings using animal models of breast cancer, and (ii) optimize the structure of the polyamines and specify the DNA sequence to be targeted.

Richard Pietras, M.D., Ph.D. of the University of California at Los Angeles completed a project entitled “New Endocrine Strategy to Prevent Breast Cancer Progression”. Dr. Pietras investigated the role that HER-2 has in regulating how breast tumors respond to estrogen and to drugs that block estrogen (anti-estrogens). He found that breast cancer cells with high levels of HER-2 are much less sensitive to estrogen and to tamoxifen than similar cells with low levels of HER-2 gene. He also found that stimulating the HER-2 receptor leads to activation of the estrogen receptor even in the absence of estrogen. This process circumvents the regulation of tumor growth by estrogen and could provide a biological basis for tamoxifen resistance in breast tumors with large amounts of HER-2. Resistance of these cancer cells to tamoxifen can be reversed by treatment with an antibody, such as Herceptin, that counteracts the ill effects of the HER-2 protein.

Paul Webb, Ph.D. of the University of California, San Francisco completed a New Investigator Award entitled “Understanding Tamoxifen - A Drug for Breast Cancer.” This project investigated the mechanism of tamoxifen action by examining its interaction with AP-1 (a set of proteins responsible for cell growth and implicated in cancer). Dr. Webb has found that the estrogen receptor binds to AP-1 in the presence of tamoxifen by way of a “molecular sandwich” in which the estrogen receptor binds the coactivator p160, which binds the coactivator CBP, which binds AP-1. Tamoxifen and estrogen activate this complex differently; however, tamoxifen causes the estrogen receptor to stimulate the activity of p160 component of the sandwich. This cascade partially explains the estrogen-like effect of tamoxifen on cell growth. The second form of the estrogen receptor that was discovered during the span of this grant, ER-beta, stimulated the antiestrogen component of the complex, indicating that it may be one of the mechanisms for resistance to treatment with anti-estrogens. This investigation has led to at least three scientific publications: Science 1997, 5; 277(5331): 1508-10; Mol Endocrinol 1998 Oct; 12(10): 1605-18; and Endocrinology 1997 Jul; 138(7): 2900-8.

Immune therapy: Mobilizing the body's defenses

Thomas Kipps, M.D., Ph.D. of the University of California, San Diego completed a project entitled “Peptide Vaccines for Immunoprevention of Breast Cancer.” The object of this grant was to develop a breast cancer vaccine by devising new ways to make the immune system sensitive to a protein found on some tumors called erbB2. Dr. Kipps used short chains of amino acids (peptides) as well as DNA as the means for stimulating the immune system. He found a sequence of amino acids that caused the production of antibodies, but did not protect mice from developing breast cancer. He was more successful with DNA vaccines that coded most or all of the erbB2 protein. Dr. Kipps found that tumors containing the erbB2 protein did not grow well in mice vaccinated with the DNA-based vaccines.

Sherie Morrison, Ph.D. of the University of California, Los Angeles completed a project entitled “Antibody Fusion Proteins for the Therapy of Breast Cancer.” Dr. Morrison used genetic engineering techniques to fuse antibodies that recognize a protein (Her-2/neu) found in many breast tumors with molecules that stimulate the immune system (B7.1, IL-2, IL-12 and GM-CSF). All of the combinations were able to stimulate immune cells in culture at similar levels to the immune stimulatory proteins alone. She found that the fusion proteins of anti-HER-2/neu and IL2 or B57.1 were able to retard tumor growth in mice, and the anti-HER-2/ neu-IL12 fusion protein could stop the growth or cause the regression of new tumors. These are promising results for the possibility of using fusion antibodies to treat breast tumors that have high amounts of HER-2/neu. This investigation has led to the publication of at least five journal articles: Journal of Immunology, 1999, 163:250-258; Lab Animal Science, 1999, 49:179-188; Journal of Immunology, 1998, 161:3729-3736; Journal of Interferon Cytokine Research 1998, 18:597-607; and Journal of Immunology, 1998, 160:3419-26.

Michael Roth, M.D. from the University of California, Los Angeles completed a 2-year project to investigate A New Approach to Immune Therapy for Breast Cancer. Breast cancer patients appear to inactivate a key cell type in the immune response, the dendritic cell. Dr. Roth removed dendritic cells from the blood of breast cancer patients and re-energized them with a cytokine (immune cell regulatory protein), called IL-7. He also worked to stimulate the response of dendritic cells to a major breast cancer oncogene, Her-2. In this project the potential for the technique was validated. However, future work is needed using gene therapy approaches to develop a more permanent dendritic cell response by enabling them to produce their own cytokines, and for them to more strongly respond to breast tumor antigens.

Jeffrey Smith, Ph.D. of the Burnham Institute completed a project entitled “Targeting T Cells to Breast Cancer”, in which he investigated the viability of certain immune cells (T Cells) engineered to specifically attack breast cancer cells. During this project, Dr. Smith was able to advance the technology for generating breast cancer-specific proteins. However they were not able to graft these proteins onto T Cells and make the T Cells breast cancer specific. These studies were able to rule out the use of the loop grafting technique as a general method for re-engineering T Cell receptors. Dr. Smith was able to create fusion proteins between the T Cell receptor and breast cancer antigens, which may ultimately be useful for targeting T Cells to breast cancers.

New Drug Design

Joseph Couto, Ph.D. and Jerry Peterson, Ph.D. of The Cancer Research Fund of Contra Costa completed a project entitled “Molecular Design for Prevention of Breast Cancer Progression.” The goal of the research was to develop novel IFab2 fragments (pieces of antibodies) that could be connected to radioisotopes and targeted to breast cancer metastases. They found that in mice the fragment localized to the tumor better than whole antibodies and were cleared from the body just as well. They published these results in two scientific journals Hybridoma (16/243-248, 1997) and Molecular Immunology (33:1095-1102, 1996). These researchers are finding that the whole antibody is yielding a measurable response in Phase I trials in humans (funded by a different grant). Dr. Peterson has designed humanized versions of the IFab2 fragments and, based on the results from the mouse studies, these fragments should improve upon the success of the whole antibody in humans, both in terms of specific targeting to the tumor and reduced toxicity.

Dr. Qing Zhou, Ph.D. at the University of Southern California completed a 2-year Postdoctoral Fellowship to study Breast Cancer Gene Therapy Using a Metastasis Inhibitor. This challenging project succeeded in cloning the gene for contortrostatin (CN), a possible anti-tumor protein derived from snake venom. Dr. Zhou was able to deduce protein sequence and structure of contortrostatin, and to express the protein. However, issues of protein folding and activity need to be addressed in more refined protein expression systems prior to beginning gene therapy experiments.

Francis Markland, Jr., Ph.D. from the University of Southern California completed a 3-year project looking at this same potential anti-tumor agent in Breast Cancer Progression and the Extracellular Matrix. The goal was to explore the potential of the snake venom protein, contortrostatin, for prevention of metastasis and growth of breast cancer in mice. Contortrostatin blocks the adhesion of cells by interfering with a group of receptors, the integrins. An interesting discovery in this project was the finding that contortrostatin served to both (i) arrest breast cancer cell growth, and (ii) block the development of the tumor blood supply by the process of angiogenesis. Dr. Markland was funded by the CBCRP in 1998 to explore pre-clinical development of contortrostatin using both a liposome delivery strategy and modifying it as a synthetic peptide.

Renata Pasqualini, Ph.D. from The Burnham Institute completed a 2-year project to develop Superfibronectin: a Novel Anti-Breast Cancer Agent. Fibronectin is a protein found in the material that surrounds cells (the extracellular matrix) of breast cells and circulating in the blood. Dr. Pasqualini studied the effect of a polymerized form of fibronectin, called superfibronectin, for inhibition of breast cancer spread in animal tumor models. She found that superfibronectin could be absorbed into the circulation from the peritoneal cavity, did not stimulate an immune response in the host animal, and showed in preliminary experiments that both tumor growth and metastasis were inhibited. Thus, it is clear that breast cancer cells use attachment to fibronectin for growth and spread, and blocking this process represents a potential therapy for treating the disease.

Research In Progress

Gene therapy and other treatments: new frontiers

Two of the grants currently in progress may offer ways for to make the initial surgery in breast cancer more effective. Shanaz Dairkee, Ph.D. of the California Pacific Medical Center is investigating whether she can identify areas around the margins of a breast tumor that look physiologically normal, but are genetically predisposed to forming tumors. This will allow pathologists to determine if not only all cancer cells, but also other cells that may appear normal but actually be cancerous or pre-cancerous, have been removed in surgery. She has optimized the procedure for analyzing DNA taken from tumors and their adjacent sections of tissue and identified the particular cases that will give the most informative data for this study. Hillary Klonoff-Cohen, Ph.D. of the University of California, San Diego, and Helena Chang, M.D., Ph.D. and Hungyi Shau, Ph.D. of the University of California, Los Angeles have teamed up to undertake a 3-year Translational Research Collaboration project. The goal of their project is to determine whether the timing of breast surgery during the phase of a patient's menstrual cycle will affect the likelihood of successful treatment. They have pilot tested their forms: coordinated their surgeons, centers, and data collections and begun to enroll participants. The outcome of this study may provide surgeons with a guideline for optimizing the timing for performing breast cancer surgery.

Hormone and chemotherapy targets: improving today's arsenal

Silvia Formenti, M.D., Peter Danenberg, Ph.D. and Franco Muggia, M.D. at the University of Southern California are undertaking studies that will help physicians identify the patients that will benefit from chemotherapy or chemotherapy and radiation treatments together. They are identifying the tumor characteristics that indicate a predisposition to respond to the chemotherapeutic agent, paclitaxel. The investigators have accrued most of the patients for the study and have begun to look at the biological correlates. They have also begun to look at whether the biological correlates will predict tumor response to paclitaxel and radiation.

Immune therapy: Mobilizing the body's defenses

Some CBCRP-funded investigators are actively exploring the potential power of the immune system in treating breast cancer. Yoko Fujita-Yamaguchi, Ph.D. of the Beckman Research Institute — City of Hope is exploring an approach to target the receptor for insulin-like growth factor, IGFR. The hypothesis is that tumor cells require insulin-like growth factor for growth, so blocking this receptor and shutting off the insulin-like growth factor signals should stop cancer cell growth. Dr. Fujita-Yamaguchi has successfully constructed alpha-IGFRs that block the insulin-like growth factor receptor and is testing their effectiveness in blocking tumor growth in mice. Joseph Lustgarten, Ph.D. at the Sidney Kimmel Cancer Center is continuing a new investigator award to train T cells to specifically recognize tumors by making a fusion protein of Her-2/neu (a protein found in many breast cancers) and IL-2 (a factor that attracts white blood cells). They have found that in the presence of these fusion proteins, T cells are capable of killing all Her-2/neu, Her-3 positive tumor cells tested in cell culture and delayed the growth of tumors in mice.

Studies of the physiology of tumors can lead to clues to eradicate them. One type or breast cancer (medullary breast cancer) is characterized by having large numbers of white blood cells (B cells) infiltrating them. Medullary breast cancer is typically less aggressive than other breast cancer. Henrik Ditzel, M.D., Ph.D. of The Scripps Research Institute is investigating whether these B cells contribute to the control of medullary tumor growth. He has found that these B cells are producing specific types of antibodies and is in the process of characterizing the antibodies to determine whether they can ultimately be used as a basis for designing a vaccine.

New Drug Design

Several projects have made progress in exploring new sources for drugs to treat breast cancer. Kent Erickson, Ph.D. of the University of California, Davis is exploring the potential of a specific type of dietary fat (conjugated linoleic acid, or CLA) to reduce and prevent the spread of breast cancer to other parts of the body. He has looked at how very low dietary concentrations of conjugated linoleic acid may reduce or prevent breast cancer metastasis by adding small amounts of conjugated linoleic acid to a high fat polyunsaturated diet. Tumor growth in mice is significantly reduced by addition of conjugated linoleic acid to their diets. (Previous work has shown that experimental animals' diets containing high levels of polyunsaturated vegetable oils increased the incidence, growth and spread of breast tumors.) Tumor spread is significantly decreased when even a very small amount of conjugated linoleic acid is added to the diet. Moreover, the total amount of tumor in the body was decreased in animals fed the conjugated linoleic acid. While the means by which conjugated linoleic acid reduces cancer spread are unknown, Dr. Erickson has assessed whether certain proteins important for invasion during tumor growth and spread are altered by conjugated linoleic acid.

Nurulain Zaveri, Ph.D., at SRI International is continuing a project to develop small molecule inhibitors of a breast cancer enzyme involved in tumor cell invasion. Interestingly, this enzyme, stromelysin-3, does not directly degrade the extracellular matrix; instead it destroys a protein that blocks other matrix-destroying enzymes. It also allows breast cancer cells to respond to other growth factors. Dr. Zaveri is using ‘rational drug design’ both to target the active site of stromelysin-3 with high affinity and to avoid inhibiting other, related enzymes. The test compounds are ready for animal experiments. Daryl Drummond, Ph.D., from the California Pacific Medical Center is using a novel combination of technologies to deliver chemotherapeutics to breast cancer cells. He ‘packages’ the drug inside of liposome particles, and he targets breast cancer cells by placing a Her-2 antibody on the outside of the liposome. An especially novel element is the use of acid-sensitive lipids, which are expected to release the chemotherapeutic only when the liposome is absorbed into breast cancer cells. Thus, the drug concentration in side the cancer cells will be very high, but elsewhere in the body the concentration will be low, avoiding the toxic effects of chemotherapy on the body.

Newly Initiated Awards

The CBCRP funded 11 new grants for innovative treatments of breast cancer in Cycle V. These projects cover a wide range of topics from uses of Chinese herbs to the emerging technology of ‘gene chips’ for the diagnosis of breast cancer. With the explosion of new genetic information, many of these projects work at the gene level. This is a tremendous improvement over the previous simple endpoints of growth, metastasis, and cell death for therapeutic evaluation. Thus, as more genetic information on breast cancer becomes available these findings will fill in the genetic puzzle of the disease. It is clear that there will not be one, single effective therapeutic or preventative strategy for all breast cancer(s). Treatments of the 21st century will recognize the diversity of the disease and approach it from many opportunistic angles. Both patients and physicians will be offered many choices that combine the need to eliminate the cancer and to maintain the quality of life.

The discovery of new drug compounds, refining their key structural elements and mode of action, and exploring the appropriate clinical uses continue to be major areas of investigation. Traditional medicines are recognized as potentially safe and effective treatment methods. Unfortunately, Western medicine has not yet been able tap this reservoir of new drug options. Perhaps as many as 50% of breast cancer patients and survivors use herbs, green tea, and other plant compounds to self-medicate as an adjunct therapy. Debasish Tripathy, M.D. of the University of California, San Francisco is funded to study traditional Chinese medicine by investigating botanicals used in Chinese medicine for anti-tumor activity. The aim is to gain more information on which agents are most effective as a first-step for additional clinical studies. Michelle Tabb, Ph.D. of the University of California, Irvine is investigating a novel intracellular protein that could provide a key common link between the action of phytoestrogens (i.e., plant estrogens), the drug tamoxifen, and Vitamin A in regulating breast cancer cell growth. This project could clear up confusion about why seemingly unrelated compounds act to control cancer. Two newly-funded projects investigate compounds derived from cruciferous vegetables (e.g., brussel sprouts) for their effect on breast cancer. Gary Firestone, Ph.D. of the University of California, Berkeley is continuing a project initially supported by the CBCRP in 1997 to investigate indole-3-carbinol (I3C). This compound will inhibit breast cancer cell growth and it appears to work effectively in estrogen-independent tumors. He plans to develop derivatives of I3C to overcome hurdles of potency and bioavailability in tumor models representative of the human disease. Working with Dr. Firestone is Liqun Zhang, Ph.D., who is funded to examine how I3C works at the molecular level in breast cancer cells. It appears that I3C inhibits the passage of cells through checkpoints necessary for cell division and growth. Finally, Mai Nguyen, M.D. of the University of California, Los Angeles is funded to purify and study novel compounds derived from a Chinese palm tree for their activity in inhibiting the process of blood vessel growth, which is necessary for metastasis and tumor growth.

Two newly-funded projects focus on detecting and evaluating biomarkers for breast cancer that are associated with clinical diagnosis and treatment, rather than earlier detection. First, Stefanie Jeffrey, M.D. of Stanford University will use gene chips to survey breast cancer samples for gene expression patterns. These gene chips have thousands of human gene sequences, and they can simultaneously detect increases and decreases in gene expression in a rapid, automated fashion. Dr. Jeffrey's interest is whether this technology can be applied to smaller biopsy samples from patients at a point where therapy and treatment decisions are critical to a successful outcome. Secondly, Shelley Enger, Ph.D. of Kaiser Permanente Southern California and Michael Press, M.D., Ph.D. of the University of Southern California (co-PIs) are funded to study the relationship of existing biomarkers, such as Her-2 and p53, in predicting the success of different adjuvant therapies from large numbers of women diagnosed and treated for breast cancer in the Kaiser Permanente and University of Southern California systems. It is critical to know how women respond to chemo-, radio-, and hormonal treatments following their diagnosis. Women who have breast cancer with the Her-2 growth receptor oncogene have new therapies (i.e., the Herceptin monoclonal antibody) available. But, research continues on Her-2 to better target and treat breast cancer. Michael Campbell, Ph.D. at the University of California, San Francisco is exploring a molecular approach to combine parts of the Her-2 protein with a virus in an attempt to create a novel immunovaccine. Richard Pietras, M.D., Ph.D. of the University of Southern California will study how radiation therapy can be combined with Herceptin treatment, and how this combined treatment works on the intracellular signaling pathways inside of breast cancer cells.

The CBCRP funded two research projects that explore the use of radiotherapy to target and treat breast cancer. First, Xiaofei Wang, Ph.D. of The Scripps Research Institute is examining how radiation-induced DNA damage leads to DNA repair. If these intracellular signaling proteins could be rendered inactive, then breast cancers could be made much more radiosensitive prior to therapy. Finally, Michelle Winthrop, Ph.D. of the University of California, Davis is funded to target radionuclides (i.e., radioactive molecules, rather than externally applied iodizing radiation) to breast cancer. Her approach is to make bispecific antibodies that both will transport the radionuclide and will selectively bind to cancer when injected into the circulation.