Innovative Treatments: Search for a Cure
To stimulate the development of more effective treatments, we fund a variety of research approaches. These include alternative medicines, novel clinical approaches, testing promising leads in animal models of breast cancer, and rational drug design, which is a methodical approach based on understanding the molecule-level interactions between a potential drug and the disease process. For many of our investigators, research under this priority subject area is an extension of their research previously funded under our priority subject area of Pathogenesis.
We have divided the innovative treatment priority issue into four broad areas of research:
- Immune Therapy: Mobilizing the Body's Defenses
- New Drug Design: Creative Science
- Hormone and Chemotherapy Targets: Improving Today's Arsenal
- Gene Therapy and Other Treatments: New Frontiers
Research Conclusions Research in Progress Research Initiated in 2000 |
Research Conclusions
Immune Therapy: Mobilizing the Body's Defenses
Receptor Antibody-Enhanced Chemotherapy for Breast Cancer
In order to grow, tumor cells require a substance produced in the body, insulin-like growth factor. Insulin-like growth factor-I receptor (IGFIR) is a substance on tumor cells that allows them to take up insulin-like growth factor. Yoko Fujita-Yamaguchi, Ph.D., of the Beckman Research Institute - City of Hope, Duarte designed a therapeutic approach that blocked tumors' IGFIR as a means of stopping tumor growth. She successfully constructed an anti-IGFIR antibody that blocked the receptor and inhibited the growth of human tumors that were transplanted into mice. She tested whether the inhibitory effects of the antibody could enhance the effects of the chemotherapy drugs doxorubicin and tamoxifen. Anti-IGFIR did not enhance doxorubicin, but therapy with anti-IGFIR and tamoxifen was more effective than either component alone. Results from this project were published in Cancer Immunology and Immunotherapy 49: 243-252 (2000).
Peptide-Pulsed Dendritic Cell Therapy for Breast Cancer
Dendritic cells are white blood cells that enable the immune system to identify foreign proteins more effectively. CEA (carcino-embryonic antigen) is a protein that is present on the surface of some tumor cells but is not generally found on normal cells. Jeffrey Weber, M.D., Ph.D., of the University of California, Los Angeles completed an early clinical trial to determine (1) whether patients who had tumors with CEA could be treated with their own dendritic cells that had been taught to recognize CEA, and (2) whether this treatment caused side effects. He found that, since the patients had been heavily pre-treated with chemotherapy, the function of the dendritic cells was impaired and the treatment did not stimulate the immune system or cause tumors to shrink. However, dendritic cell therapy has succeeded in melanoma patients whose cancer has spread to other parts of the body, but who have not had chemotherapy. So Dr. Weber believes breast cancer patients with minimal disease who have not had chemotherapy would be ideal for future dendritic cell therapy trials.
New Drug Design: Creative Science
A New System for Breast Cancer Drug Delivery
Daryl Drummond, Ph.D., from the California Pacific Medical Center, San Francisco finished a project to modify liposomes (microscopic fat particles) that contain a chemotherapy drug, to target them more specifically and effectively toward breast tumors. This should reduce the toxicity of the drug to the rest of the body. The critical need was to administer these liposomes in the blood, then have them 'home in' on breast tumors. Using human breast tumors grown in mice, they targeted the liposomes to the breast cells by placing an antibody (anti-Her2) on the liposome surface. Overcoming a major technical hurdle, they formulated liposomes that did not release the chemotherapy drug they contained, doxorubicin, until after the breast cancer cells took up the liposomes. The initial success in cells and animal models indicted that this approach could greatly reduce systemic toxicity associated with chemotherapy. Dr. Drummond published his results in Pharmacological Reviews 51: 691 (1999) and Biochem. Biophys. Acta 1463: 383 (2000).
Novel Drugs to Inhibit Breast Cancer Metastasis
Joseph Konopelski, Ph.D., from the University of California, Santa Cruz targeted for drug development (1) a protein (laminin), which is needed by both normal and tumor cells and found in their immediate micro-environment and (2) its molecular interaction with a surface receptor on breast cancer cells (Laminin Binding Protein-LBP). The drug design involved only a small region of laminin, called peptide 11, which is responsible for this process. Dr. Konopelski's collaborators at Montana State University determined the amino acid side-chain and backbone molecular structure of peptide 11. Then, his team developed a chemical synthesis for a potential inhibitor of the laminin peptide 11-LBP interaction. They were unable to complete the complex synthesis in the time frame of BCRP's funding. However, the National Institutes of Health and the Congressionally Directed Research Program at the Department of Defense are funding the continuation of this work.
Mechanism of Novel Anti-Angiogenic Therapy for Breast Cancer
Continuing research BCRP funded from 1995-98, Francis Markland, Ph.D., from the University of Southern California, Los Angeles completed a project to develop the therapeutic potential of a protein from snake venom, called contortrostatin (CN). The net effect of CN is to block both blood vessel formation and the spread of breast cancer cells. Integrin adhesion receptors are found on all types of cells; they attach individual proteins found in the cells' micro-environment to the cells. Dr. Markland's team succeeded in identifying the specific breast cancer and blood vessel integrin adhesion receptors that CN blocks, and they moved towards defining how CN does this. In addition, Dr. Markland's group made important strides in developing a method for delivering CN to the body, and they studied small peptide compounds derived from CN. Several publications resulted from this support, including articles in Biochemistry & Biophysics Research Communications 267: 350 (2000), and Breast Cancer Research & Treatment 61: 249 (2000). BCRP is continuing to fund this project.
Novel Enzyme Inhibitors for Estrogen-Dependent Breast Cancer
Masato Tanabe, Ph.D., of SRI International, Menlo Park designed orally-administered drugs that inhibit estrone sulfatase, an enzyme responsible for producing estrogen. The drugs cut off the estrogen supply for estrogen-dependent breast tumors. He was able to develop three new estrone sulfatase inhibitors (ESIs) that have strong activity against human breast tumors grown in mice. An advantage of these ESIs over most estrogen inhibitors is that the ESIs do not themselves have estrogenic activity, and therefore cause fewer side effects. At least one of the new ESIs is effective enough to undergo further pre-clinical and clinical testing and may ultimately provide a viable, less toxic alternative to anti-estrogens currently in use.
Blocking Stromelysin-3 to Inhibit Breast Cancer Metastasis
Nurulain Zaveri, Ph.D., also at SRI International, Menlo Park investigated Stromelysin-3 (ST-3), one of a class of enzymes called proteases that tumor cells release to digest their immediate micro-environment and allow tumor cell movement. However, ST-3 does not actually act as a protease. Rather, it counteracts inhibitors of this process and permits other, more potent proteases to function. Dr. Zaveri synthesized inhibitors of ST-3. She first designed protein-like inhibitors, and then worked on synthetic, non-protein inhibitors. These were tested though a collaboration with Dr. Stephen Weiss at the University of Michigan. This research validated ST-3 as an attractive target for therapy to prevent the spread of breast cancer to other parts of the body. Dr. Zaveri's efforts advanced two approaches against ST-3 that are part of rational drug design: (1) using solid support, a quicker type of chemical synthesis useful with low yields; and (2) combinatorial chemistry, where the researcher produces and tests all types of a specific molecule.
Hormone and Chemotherapy Targets: Improving Today's Arsenal
Enhancing Breast Cancer Sensitivity to Chemotherapy
Daniel Mercola, M.D., Ph.D, from the Sidney Kimmel Cancer Center, San Diego explored whether blocking a series of protein interactions inside cells (called the JNK pathway) will overcome cell resistance to chemotherapy. Dr. Mercola inhibited JNK by using special "antisense" molecules in order to make breast cancer cells and tumors sensitive to a chemotherapeutic drug, cisplatin. This approach had promise specifically in one type of breast tumor (Her-2/neu-positive), but did not appear effective in another type, estrogen-receptor-positive tumors. Dr. Mercola performed these experiments on human tumor cell lines grown in mice. Several publications resulted from this funding, including a report in Cell Growth & Differentiation 10:545-554 (1999). Matching appropriate therapies to subgroups of breast cancer patients whose tumors interact with specific hormones or other bodily substances is a topic of intense research interest. Also, new approaches are needed to tackle Her-2/neu-positive breast cancer, since the current drug, Herceptin, is successful in only about 30% of patients.
How Indole-3 Carbinol Inhibits Breast Cancer Cell Growth
Liqun Zhang, Ph.D., at the University of California, Berkeley investigated how indole-3-carbinol (I3C), a compound found in cruciferous vegetables such as cabbage and broccoli, inhibits growth in breast cancer cells. She exhaustively studied a series of protein interactions that take place inside cells, the MAPK (mitogen-activated protein kinase) pathway. In a variety of experiments, it appeared that MAPK is not connected with I3C, and her team plans to look at other protein interactions inside cells to understand I3C's growth-inhibiting effect on breast cancer.
Gene Therapy and Other Treatments: New Frontiers
Outpatient Stem Cell Transplants for Breast Cancer
High-dose chemotherapy with bone marrow or stem cell transplant is a treatment option for breast cancer that has spread to other parts of the body or for high-risk breast cancer. Traditionally, it requires prolonged inpatient hospitalization. Kathryn Hollenbach, Ph.D., of the University of California, San Diego compared two groups of women, one who had the treatment as inpatients, and another who had it as outpatients. She compared the groups for (1) cost , (2) the patient's psychological well being, (3) the psychological well being of the family member or friend who acted as caregiver, (4) toxicity associated with treatment, and (5) hospital re-admissions. There were no statistically significant differences between inpatient and outpatient groups on number of days from first date of high-dose chemotherapy to the date the patient returned to the referring oncologist. There were also no differences in toxicity, number of hospital re-admissions, or length of hospital readmission. Adjusting for age and symptom severity, on average, outpatient costs were 71% less than inpatient. No differences in well-being were seen in patients or caregivers at the beginning of treatment or 60 days after treatment. However, after adjusting for age, symptom severity and quality of well being at the beginning of treatment, outpatients had significantly poorer well-being during treatment. Similar differences were not seen for caregivers. There was no difference in well-being between the inpatient and outpatient groups at the end of treatment or at subsequent follow-up. Results demonstrate that this therapy, administered in an outpatient setting, was associated with significant cost savings and no permanent adverse effects. The significant cost savings support consideration of making this therapy widely available. Dr. Hollenbach was co-author of a publication reporting this research, Bone Marrow Transplantation 21:927-32 (1998).
Improved Delivery of Pharmaceuticals to Breast Cancer
Demetrios Papahadjopoulos, Ph.D., (deceased) and Dmitri Kirpotin, Ph.D., at the California Pacific Medical Center Research Institute, San Francisco completed a project with the goal of designing a new way to deliver chemotherapeutic drugs directly to breast tumors. They encapsulated an anti-cancer drug inside liposomes (microscopic fat particles that can enter the cell wall), and targeted the liposomes to the tumor cells through the blood. They also heated the tumor slightly above normal to enlarge tumor blood vessels and maximize the efficiency of delivering anti-cancer drugs. Drs. Papahadjopoulos and Kirpotin found that when they heated a tumor, it took up three times more liposomes. They designed specialized liposomes they called "stealth" liposomes that work especially well with heating tumors. This study has resulted in a Phase I/II clinical trial, where the drug delivery method will be tested for safety and effectiveness in humans. Additional details were published in Pharmacological Reviews 51: 691-743 (1999).
Targeted Gene Therapy Using Anti-p185Her2 Immunoliposomes
John Park, M.D., of the University of California, San Francisco developed a way to use liposomes (microscopic fat particles) to deliver genes to breast tumors. The formulation he developed, called anti-Her2 immunoliposomes, contains liposomes, genes or DNA, and an antibody that targets the treatment to breast cancer cells. Dr. Park was able to deliver test genes to breast cancer cells in test tubes and to human breast tumors grown in mice. Most of the targeting systems developed for delivering gene therapy to breast tumors are based on technologies that use viruses. Dr. Park's study has shown the promise of using a non-viral system for delivering gene therapy to breast tumors. This study is discussed in numerous publications, including one in the Annals of the New York Academy of Sciences 886:293-6 (1999).
Mechanism of Radiosensitivity in Breast Cancer Cells
Xiaofei Wang, Ph.D., of The Scripps Research Institute, La Jolla investigated how cells become resistant to radiation and attempted to determine the best way to enhance radiation-induced cell killing. He found evidence that two macromolecules, ATM and Cds1, are required for establishing resistance to radiation in breast cancer. By designing inhibitors to these molecules, it may be possible to develop treatments that will increase the effectiveness of radiation therapy.
Research in Progress
Immune Therapy
Her-2/neu DNA Vaccines for Breast Cancer. The Her-2/neu gene is found in invasive breast tumors, and also in about 50% of cases of DCIS, a precancerous condition of the breast that may turn into cancer. Michael Campbell, Ph.D., from University of California, San Francisco is pursuing a vaccine approach that could prove a powerful preventive agent in women at risk for progressing to invasive disease. Dr. Campbell reports the potential for Her-2/neu DNA-based viral vaccines to elicit an immune response in mice.
Antibody-IL-2 Fusion Protein for Breast Cancer. Fusion proteins are two separate proteins that have been combined to make a single new protein. Joseph Lustgarten, Ph.D., of the Sidney Kimmel Cancer Center, San Diego has found that both heregulin-IL2 fusion proteins and Her-2/neu-IL2 fusion proteins are able to inhibit tumor cell growth in laboratory and experimental mouse models.
New Drug Design
Treating Breast Cancer with Chinese Herbs: A Pilot Study. Debasish Tripathy, M.D., of the University of California, San Francisco is testing whether Chinese herbal extracts can keep cancer cells from growing or kill them. Dr. Tripathy is using cell lines and tumor-bearing mice with cloned genes transferred into their DNA to test the effect of the herbal extracts on cell growth. After testing 76 extracts, the team found several herbal combinations that inhibit cell growth. They will next try to isolate a cell growth-inhibiting compound from these extracts.
Hormone and Chemotherapy Targets
Biologic Determinants of Response to Paclitaxel and Radiation. Silvia Formenti, M.D., and Peter Danenberg, Ph.D., at the University of Southern California, Los Angeles are analyzing the effectiveness of treating patients with either the chemotherapy drug paclitaxel alone or paclitaxel plus radiation before surgery. They are also identifying the features of the breast tumors that predict the response to treatment. They found that 1/3 of the tumors responded to paclitaxel and radiation, but only 1/10 responded to paclitaxel alone. Early results indicate that tumors with a low level of the Her-2/neu protein respond to paclitaxel plus radiation.
Gene Therapy and Other Treatments
Can Molecular Markers Predict Response to Adjuvant Therapy. Tumor-related markers are genes or proteins found in tumors that may provide information on the nature and severity of the disease. Shelley Enger, Ph.D., of Southern California Kaiser Permanente and Michael Press, M.D., Ph.D., at the University of Southern California, Los Angeles are investigating whether some of these markers, including Her-2/neu, p53 and Bcl-2, can be used to predict whether a patient is likely to respond to various therapeutic regimens. It is critical that physicians treating beast cancer patients have new information to better match therapeutics with individual patient tumor markers.
Molecular Mapping of Surgical Margins. Shanaz Dairkee, Ph.D., at the California Pacific Medical Center, San Francisco is investigating genes in breast surgery specimens. She has found that the gene changes present in breast tumors were also detectable in nearby breast tissue that appears to be otherwise normal, and in abnormal non-cancerous lesions. By examining the "normal" cells at the genetic level, it may be possible to better assess a woman's risk of the cancer growing back at the same site after surgery.
Breast Cancer Gene Expression Using Amplified Core Biopsies. Stefanie Jeffrey, M.D., from Stanford University, Palo Alto successfully amplified small surgical samples of tumors from needle core biopsies to get a genetic profile previously thought possible only with larger tumor samples. Tumors are composed of cells with varying degrees of malignancy and genetic makeup. Dr. Jeffrey is pursuing amplification to see if it can be used to detect genetic differences between various cells in a single tumor.
Bispecific Antibodies for Radiotherapy of Breast Cancer. Michele Winthrop, Ph.D., from the University of California, Davis is developing antibodies that simultaneously carry a radiochemical (90Y-DOTA), and a recognition site for tumor cells (Muc-1) to make the antibody interact with tumor cells, but not normal cells. This approach promises advances in both the detection and the treatment of breast tumors by delivering radiation through the blood, rather than external radiation focussed on the tumor site. Progress on this project was recently published in the Quarterly Journal of Nuclear Medicine 44:284-295 (2000).
New Radiation Therapy for Her-2-overexpressing Breast Cancer. Richard Pietras, M.D., Ph.D., of the University of California, Los Angeles is using a mouse model to determine the best schedule for combining the chemotherapy drug Herceptin (used with tumors containing a high level of the Her2/neu protein) and radiation treatments. They have found that close timing maximizes the effectiveness of these two therapies. Dr. Pietras is also investigating the underlying mechanism for this synergistic effect.
Research Initiated in 2000
Immune Therapy
Cell-Based Immunotherapy for Breast Cancer. Nabila Jabrane-Ferrat, Ph.D., of the University of California, San Francisco will incorporate 'danger signals' (HER-2/neu with CIITA, CD80 or interferon gamma) into vaccines. These danger signals are proteins present in tumor cells at higher levels than in normal cells or with a structure slightly different from the protein in normal cells. The goal is to stimulate the immune system to produce a type of white blood cell that will recognize the danger signal and attack the tumor as a foreign body.
New Drug Design
Targeted Delivery of an Anti-breast Tumor Agent. Francis Markland, Ph.D., and Fred Hall, Ph.D., from the University of Southern California- Keck School of Medicine, Los Angeles and Gary Fujii, Ph.D., at Molecular Express, Inc., Los Angeles are teaming up for a cross-disciplinary project. They are in the early stage of developing a novel drug to block tumor blood vessel formation (angiogenesis). The drug is based on contortrostatin (CN), a protein found in a snake venom. CN works in simple tests on tumor cells in culture, now they are working on a way to deliver CN to tumors via the blood following an injection, using animal model systems.
Novel Anti-Angiogenic Agents for Breast Cancer Therapy. Keith Laderoute, Ph.D., at SRI International, Menlo Park will investigate the mechanism of action of a novel selective estrogen receptor modulator (SERM). SERM blocks tumor cell growth, and also appears to selectively inhibit the growth of human tumor blood vessel cells and antagonize the formation of new tumor blood vessels.
Computer-Aided Discovery of Novel Breast Cancer Therapeutics. Gilda Loew, Ph.D., at the Molecular Research Institute, Menlo Park and Marcia Dawson, Ph.D., from the Molecular Medicine Research Institute, Menlo Park, are teaming up from two complementary disciplines. The first is computer software design that generates 3-dimensional models of sections of proteins in cells that could potentially interact with drugs; the second is breast cancer biology. They will work on vitamin A compounds, called retinoids, that regulate cell differentiation and proliferation. The goal is to use retinoids as an anti-breast cancer chemotherapy that would be less toxic than current drugs.
Arginine Deiminase as an Innovative Anti-Breast Cancer Agent. Wei-Chiang Shen, Ph.D., at the University of Southern California, Los Angeles will investigate an enzyme, arginine deiminase, which is found in certain microorganisms, and can inhibit new blood vessel growth. It works by interfering with the production of the amino acid arginine, thereby altering the regulatory balances within the cell. Dr. Shen will explore the feasibility of using this newly-discovered agent as a breast cancer therapy.
Hormone and Chemotherapy Targets
Novel Agents for Treatment of Advanced Breast Cancer. Ling Jong, Ph.D., at SRI International, Menlo Park will explore the therapeutic potential of a new class of compounds derived from indole-3-carbinol (I3C), a compound found in cruciferous vegetables such as broccoli and Brussels sprouts. I3C also interferes with estrogen action. Dr. Jong will optimize the effect of these drugs using cells in culture, and then evaluate their action on breast tumors grown in animals.
Identifying the Breast Cancer Target for Indole-3-Carbinol. Urmi Chatterji, Ph.D., at the University of California, Berkeley is also studying I3C. Because I3C appears to inhibit tumors that respond to estrogen (which can be treated with the drug tamoxifen) and tumors that don't respond to estrogen (which are resistant to tamoxifen), Dr. Chatterji is trying to discover the protein within cells that initially binds with I3C. If she succeeds, this information could lead to a common strategy to combat the two major variants of the disease.
A New Class of Drugs to Treat Breast Cancer. Most anti-estrogen therapies involve blocking the binding of estrogen to its receptor (a protein inside the tumor cell). Thomas Robertson, Ph.D., of the University of California, San Francisco will use computer modeling to design compounds that selectively block the estrogen receptor before it has a chance to turn on other genes in the cell.
Role of p14ARF in Metastatic Breast Cancer. A protein found in both normal cells and tumor cells, p53, triggers death of tumor cells after they have been damaged by chemotherapy or radiation. Some breast tumors have defective p53, but many of those with normal p53 appear to be missing another protein, p14ARF. The tumor cells without p14ARF appear to have lost the ability to initiate cell death. Ruth Gjerset, Ph.D., at the Sidney Kimmel Cancer Center, San Diego plans to use gene therapy to introduce p14ARF into breast tumors. She wants to see whether there is a 'bystander effect,' where altered cells kill neighboring tumor cells. Any success to validate the bystander process would be exciting, since gene therapy approaches are often limited by low efficiency.
Targeted Chemotherapy to Treat Breast Cancer. Breast cancer cells frequently have a sugar-binding molecule on their surface, called CD44. Sugar containing molecules, called hyaluronans, will bind CD44 with poor affinity. However, when the hyaluronans are formulated into microscopic fat droplets, called liposomes, the cancer cell binding increases dramatically. Francis Szoka, Ph.D., at the University of California, San Francisco will explore the potential for this novel technology by incorporating a chemotherapeutic drug, doxorubicin, into liposomes that contain hyaluronan.
Gene Therapy and Other Treatments
Wnt Signaling in Breast Cancer. The large family of Wnt proteins are secreted by cells to control diverse aspects of development in organisms ranging from fruit flies to mammals. An extensive body of evidence suggests these proteins are essential for both normal development and tumor formation. Randall Holcombe, M.D., Marian Waterman, Ph.D., and Lawrence Marsh, Ph.D., (co-PIs) from the University of California, Irvine plan to measure the amounts of Wnt in tumor and normal cells, along with associated genes, using two technologies, differential display and analysis with gene microchip arrays. They also plan to study the role of Wnt and associated proteins from patients with known genetic predisposition to breast cancer, such as those with BRCA1 and BRCA2 mutations.
Stress Protein Induction and Drug Resistance in Human Breast Cancer. In solid tumors, such as breast cancers, there are regions of low oxygen concentration. Low oxygen starves cell metabolism and leads to the production of special stress proteins. Amy Lee, Ph.D., at the University of Southern California, Los Angeles will investigate stress proteins in breast cancers, and the potential for blocking their function as a novel method of therapy to overcome drug resistance.
Thrombosis for Anti-angiogenic Therapy of Breast Cancer. Tiny tumor blood vessels are leaky and prone to becoming plugged with blood clots. Tumors appear to overcome this by creating their own system to prevent blood from clotting and maintain the blood flow essential for cell survival. Min-Ying (Lydia) Su, Ph.D., from the University of California, Irvine will explore the possibility of inhibiting this tumor-based anti-clotting system as a novel means to attack breast cancer that has spread to other parts of the body.
Chinese Herbal Therapy (CHT) for Symptom Management. Debasish Tripathy, M.D., of the University of California, San Francisco will conduct a Phase III clinical trial (the final trial before a medication can be approved for use) to investigate whether Chinese herbs will relieve the side effects caused by chemotherapy.
