Innovative Treatments: Search for the Cure
Finding a cure for breast cancer is one of the most important goals for CBCRP. The innovative treatment research projects strive to achieve this goal by taking full advantage of current scientific knowledge to design immunologic and hormonal approaches or new surgical technigues.
Research Conclusions
Dr. Michael Samoszuk of the University of California, Irvine was successful in completing his one-year IDEA grant, Blocking Breast Cancer Progression with Radioactive Antibody. The goal of this project was to determine whether the presence of a new marker called eosinophil peroxidase would be produced by women's immune response to breast cancer. Dr. Samoszuk's studies showed that more than 80% of breast cancers in women contain abundant deposits of this new marker. An especially notable finding was the presence of large amounts of this marker adjacent to the new blood vessels and connective tissue that support the growth of the tumor. These results are important for the following reasons: 1) they document the presence of a novel breast cancer marker that can be used as a target for therapeutic radioactive monoclonal antibodies, and 2) they suggest that the host immune response to breast cancer may actually play a role in promoting breast cancer growth. The preliminary findings of this study have led to the funding of a Small Business Technology Transfer Grant from the NCI.
Dr. Chung-leung Chan of the University of California, San Diego completed a 2-year Postdoctoral Fellowship entitled EGFR Structure for Drug Design Targeted to Breast Cancer to study the signaling inside breast cancer cells due to growth factor receptors at the cell surface. These growth receptors, EGFR and erbB2, contain amino acid sequences that provide an essential 'tyrosine kinase activity' for signaling functions inside the cell. Dr. Chan introduced mutations in the tyrosine kinase region in order to probe its functional activity. He reported and published that the 3-dimensional orientation of the 'catalytic loop' in the kinase domain was not important, but that the sequence of amino acids was critical for functional activity. These results are initial steps for subsequent drug design efforts to selectively inhibit the growth of breast cancer cells.
In his grant HSP27 Regulation of Breast Tumor Blood Vessel Growth, Dr. Randolph Piotrowicz of The Scripps Research Institute studied the process of blood vessel growth (angiogenesis) necessary to support breast cancer pathogenesis. A key finding was that estrogen caused endothelial cells, which line blood vessels, to increase their production of HSP27. Then, the HSP27 caused a release of a special form of an angiogenesis-stimulating factor (HMW b-FGF) that also directly stimulates tumor cell growth. Further, he was able to localize HSP27 in the endothelial cells and gain information on how its activity could be regulated. This information is applicable to the specific hormonal and cellular environment of breast cancer.
Dr. Anna M. Wu of The Beckman Research Institute of the City of Hope completed a 1-year IDEA project entitled Engineered Antibodies for Imaging and Therapy of Breast Cancer to develop an innovative monoclonal antibody approach to deliver radioisotopes for detection and therapy of breast tumors. The tumor target is based on an antigen, carcinoembryonic antigen (CEA) found in most breast cancers, and the antibodies are actually protein fragments produced by genetic engineering. The so-called 'minibodies' now in development represent a powerful new technology, since they could be used repeatedly for diagnosis and therapy monitoring. These 'minibodies' avoid the immune response that would normally limit their usefulness.
Research in Progress
Immune therapy: mobilizing the body's defenses
Immunotherapy is an emerging field in breast cancer treatment. Breast cancer is not associated with the development of a strong natural immune response as is seen in certain other tumor types (e.g., melanoma). Dr. Michael Roth at the University of California, Los Angeles is working to enhance the breast cancer patient's own immune response to Her2/neu to determine the regions of the receptor best able to generate a response and the specific cytokines that would be optimal for boosting the immune system. Dr. Thomas Kipps at the University of California, San Diego is developing ways to make the immune system more sensitive to erbB2. He has successfully developed an assay that can detect erbB2 in newly diagnosed breast cancer patients as well as synthetic peptides that can stimulate an antibody-based immune response to erbB2. Dr. Esteban Celis of Cytel Corporation has identified six new peptides targeting HER2/neu, CEA, and MAGE antigens that can be used to develop immune-based peptides. The development of these peptides may make immunotherapy possible for up to 90% of the population. Dr. Malcolm Mitchell at the University of California, San Diego is developing an approach to sensitize the immune system of breast cancer patients to the MUC-1 antibody. He has developed a set of cell culture procedures that will be used to teach the appropriate white blood cells how to recognize the MUC-1 antibody and then select and amplify them. Dr. Joseph Couto of The Cancer Research Fund of Contra Costa is developing novel Ifab2 fragments (pieces of antibodies) that can be conjugated to radioisotopes for targeting breast cancer metastases. He found that in mice the fragments localized to the tumor better than whole antibodies and were cleared from the body just as well. He is now in the process of adapting this system to humans.
New drug design: creative science
Retinoids are agents that have shown some potential in breast cancer therapy. There are a variety of retinoids from different families, with different effects on cell growth. It is therefore important to characterize the actions of different types of retinoids and choose those that show the most promise for use in breast cancer therapy. The process of narrowing down the choices to a manageable number of agents requires some understanding of how retinoids behave. Dr. Anissa Agadir at The Burnham Institute studies the role of the retinoid acid receptors in breast cancer cell growth. She found that RXR retinoids in combination with RAR retinoids can inhibit the growth and induce cell death in retinoic acid-resistant RAR deficient breast cancer cells. Dr. Magnus Pfahl at the Sidney Kimmel Cancer Center has developed novel retinoids that initiate the process of programmed cell death with 24 hour exposure. He has also found that the new retinoids have a more limited pattern of receptor binding, which differentiates them from the non-apoptotic types of retinoids.
Dr. Francis Markland of the University of Southern California is continuing promising studies in mice using a snake venom-derived protein that arrests both tumor growth and spread, which indicates how these processes are related. He is now pursuing gene therapy to produce this snake venom inhibitor directly at the tumor site.
Hormone/chemotherapy targets: improving today's arsenal
Dr. Paul Webb at the University of California, San Francisco is looking at the mechanism of tamoxifen action by examining its interaction with AP-1 (a set of proteins responsible for cell growth and implicated in cancer). He has found that the estrogen receptor (ER) binds to AP-1 in the presence of tamoxifen by way of a “molecular sandwich” in which ER binds the coactivator p160, which binds the coactivator CBP, which binds AP-1. Tamoxifen causes ER to stimulate the activity of p160 component of the sandwich. This cascade partially explains the estrogen-like effect of tamoxifen on cell growth. Recently an additional form of ER was discovered and named ERb.
Dr. Richard Pietras at the University of California, Los Angeles has developed anti-phosphotyrosine proteins targeted against the estrogen receptor (ER) that block ER coupling and, therefore, action. The next step for estrogen to generate a cell response is the estrogen receptor complex must bind to another series of proteins (coactivators) and only then can it turn on the other genes required for cell growth. Dr. Pietras has also found that overexpression of HER2 (which shows some correlation with tamoxifen resistance) regulates the variants of ER differently. Dr. Cara Marks at the University of California, San Francisco is using both monoclonal antibody and biophysical/molecular approaches to study the more external regions of the receptor involved in dimerization. Dr. Marks is working towards a detailed ‘map’ that shows the ErbB (HER2) domains involved in dimer formation.
Gene therapy and other treatments: new frontiers
Several investigators are looking at ways to improve drug delivery and gene therapy. Dr. John Park at the University of California, San Francisco is using liposomes (microscopically small, membrane-enclosed sacs made in the laboratory) to introduce genes into target cells. For these experiments he is using antibodies that recognize HER2/neu. In test tube experiments, these liposomes can deliver test genes specifically to cells with high levels of HER2/neu, while delivery to cells with low levels of HER2/neu is reduced. The next year of studies will test these observations in animal studies. Dr. Demetrios Papahadjopoulos at the University of California, San Francisco is looking at new ways to deliver drugs to the sites of breast cancer by using targeted, specially designed liposomes in combinations with hyperthermia (heat). He has found a liposome composition and protocol for combining liposome administration and heat that leads to a two and a half to three fold enhancement of delivery to the breast cancers grafted to mice. These studies lay the groundwork for clinical trials with the newly approved liposomal Doxorubicin. Dr. Orhan Nalcioglu at the University of California, Irvine is investigating the delivery of drugs to the tumor site in combination with use of a contrast agent for magnetic resonance imaging (MRI). He is obtaining critical information on the degree of 'leakiness' associated with the tumor vasculature in breast cancer. New approaches to understand this 'leakiness' and control it could be important for both optimal detection and therapy options as MRI gains more acceptance.
CBCRP also funded grants that are examining the therapeutic properties of other agents. Dr. Robert Stern at the University of California, San Francisco finds that a blood enzyme, hyaluronidase, can neutralize components on the breast cancer cell surface. He is studying how this has an impact on the tumor cell, and finds initial evidence that hyaluronidase will induce apoptosis, make cells susceptible to immune attack, and directly inhibit tumor growth.
Progress has also been made in CBCRP grants aimed at improving surgical aspects of breast cancer treatment. Dr. Silvia Formenti at the University of Southern California is developing an alternative to radiation therapy through radiosurgery. Radiosurgery exposes the affected area of the breast to a highly concentrated, precise dose of radiation that can deliver the same dosage in one hour as six weeks of conventional radiation therapy. She has demonstrated that the technique is feasible and has begun to analyze the effects of radiosurgery by treating tumors, removing them and analyzing them for microscopic signs of cell death. Dr. Boris Rubinsky at the University of California, Berkeley is performing pre-clinical studies to optimize cryosurgery for the treatment of breast cancer and to determine the parameters required for complete destruction of the tumor. He has found that mouse tumors that were frozen to 40oC at a rate of 5oC/min still had surviving cells after one freezing cycle. The implication for treatment of human tumors is that multiple freezing cycles would be necessary in order to achieve optimal cell killing.
Recently Initiated Research
In 1997, 16 new grants were funded to investigate innovative treatment modalities, including finding ways to boost the immune system to fight breast cancer; developing methods to deliver genes and/or drugs to cancer cells, and to overcome resistance to drugs; developing drugs to prevent the spread of breast cancer; and exploring ways to tailor therapy to the individual characteristics of tumors. Several studies are exploring different ways to boost the body's immune system to prevent any breast cancer cells that form from developing into an invasive cancer. Some of these studies are developing methods by which the immune system can be augmented or guided to kill tumor cells. Other studies are using new knowledge gained in recent years about the ways in which cancer cells grow and spread to develop new drugs to intervene in the process.
