Innovative Treatments: Search for a Cure

The clinical translation of promising cancer laboratory discoveries is a time consuming, costly, and inefficient process. Patient advocates often ask why drug discovery and development cannot be improved and why researchers aren’t more cognizant of the human issues of the disease. Mr. Clifton Leaf, writing in the March 22, 2004, issue of Fortune magazine, has thrown down the gauntlet to the federal cancer funding agencies, drug companies, and researchers through his article, “Why we’re losing the war on cancer (and how to win it).” Mr. Leaf and many others have noted a series of fatal flaws in our shortsighted search for the cure. Perhaps the key underlying research issue is the pre-clinical model, which often uses human cancer cell lines grown in special strains of mice. This approach is riddled with problems that are not being solved. The human breast cancer cell lines themselves do not represent common forms of breast cancer, and they often vary from lab to lab. When grown as tumors, these “xenograft mouse models” lack the cellular heterogeneity seen by clinical pathologists when they examine human tumor biopsies. The mice themselves often have defective immune systems, so the drugs to be tested are working in an abnormal setting. The most troubling issue in preclinical testing is that metastatic disease is not the focus. Researchers typically measure drug efficacy in xenograft mouse models by tumor shrinkage, which is not an accurate predictor of benefit for the patient. Taken together, the pitfalls of pre-clinical drug testing and breast tumor modeling in mice has resulted in the development of drugs that extend survival by merely months.

Fortunately the NIH is taking steps to address the issues of animal models of cancer. The NCI’s Mouse Models of Human Cancers Consortium (MMHCC) is “a collaborative program designed to derive and characterize mouse models and to generate resources, information, and innovative approaches to the application of mouse models in cancer research.” Still, there is a critical need for pre-clinical research work on better representation of the human disease in the cell lines chosen for study, and for new approaches that focus on metastatic disease, the real killer.

In the Innovative Treatment research settings supported by the CBCRP, there are continued efforts in key topics. For immunotherapy, researchers are developing new types of antibodies to target the key proteins in breast cancer. As the key growth signaling and apoptosis (cell death) pathways are identified and dissected by researchers, there are parallel efforts to evaluate each new protein and its functional domain as potential new targets for therapy. Alternative medicines based on plant compounds and herbs are being considered in the context of both therapy and chemoprevention. Researchers continue to revisit angiognenesis and other topics with novel technologies. Advances in gene therapy and targeted drug delivery become refined and inch towards clinical translation. Research is being funded that originates from non-cancer disciplines, such as blood clotting and inflammation, because they may have unexplored applications to breast cancer.

At the CBCRP we strive to link new ideas, collaboration, and translation into a synergistic strategy to attract researchers and fund new approaches in the topic of Innovative Treatments.

Research Conclusions

Eighteen grants in the Innovative Treatments priority issues were completed in 2003.

Cell-Based Immunotherapy for Breast Cancer.
Nabila Jabrane-Ferrat, Ph.D., was funded as a New Investigator at the University of California, San Francisco, to develop a method of getting immune-response genes to alter tumor cells and create a “danger signal” in the tumor that will activate the immune system. Her team created tumor cells that produce one of three proteins, CIITA, IFN-gamma, or B7.1, which signal the immune system to attack the tumor cells. They injected these tumor cells into mice that were genetically engineered to produce tumors. Dr. Jabrane-Ferrat’s team found that when the virus carrying CIITA or CD80 was inte-rat neu, which is like the cancer gene Her-2/neu in humans, the vaccine was successful in getting the immune system to wipe out the tumor. Dr. Nelson is going to continue to study rat neu and the VRP approach to stimulating dendritic cells to fight breast cancer. Dr. Nelson and colleagues presented their results at the American Association for Cancer Research annual meeting in
2003.

Targeted Delivery of an Anti-Breast Tumor Agent.
Continuing research that the CBCRP funded from 1995–2000, Francis Markland Jr., Ph.D., and Noriyuki Kasahara, M.D., Ph.D., from the University of Southern California, Los Angeles, teamed with Gary Fujii, Ph.D., from Molecular Express, Los Angeles to explore how a Copperhead snake venom protein, called contortrostatin (CN), could be used in breast cancer treatment by blocking the formation of tumor blood vessels. Dr. Markland had demonstrated previously that CN could block both blood vessel formation and the spread of breast cancer cells. In addition, he had identified the specific breast cancer and blood vessel “integrin” adhesion receptors that CN blocks. Integrin adhesion receptors, which are found on all types of cells, grated into tumors and the tumors were transplanted into animals, they caused an immune response and grew much more slowly than uninfected tumor cells. This research provides clues that could lead to new breast cancer treatments. Results of this research were published in Molecular and Cellular Biology 22 (2003):5616-25.

A New Genetic Vaccine Therapy for Breast Cancer.
Breast cancer can recur after many years in which there has been no sign of a tumor. This suggests that there are a small number of tumor cells that remain alive after standard treatments. Edward Nelson, M.D., at the University of California, Irvine, is trying to develop a vaccine that could eventually be used after treatment for breast cancer to stimulate the immune system to kill any remaining cancer cells and prevent a recurrence. This vaccine would stimulate the immune system’s most potent cells, the dendritic cells. Dr. Nelson and his team investigated the effectiveness of a method of getting the vaccine to the dendritic cells called VEE Replicon particles (VRP). They found that when they used the VRP approach to immunize rats against portions of serve to anchor cells to their surrounding protein matrix. The next step was to use mice to test methods of getting CN to the tumor site when it is injected into the bloodstream. To that end, the collaborative team explored two drug delivery methods, one in which CN is delivered in protein form, the other in which CN is delivered as DNA (also known as gene therapy.) Both methods proved successful in inhibiting tumor growth. Dr. Markland intends to continue to study the possibility of using CN snake venom protein to treat breast cancer. Several publications resulted from this research, including articles in Biochemistry & Biophysics Research Communications 267 (2000):350, Breast Cancer Research & Treatment 61 (2000):249, and Acta Crystallographica D58 (2002):2122-2124.

Targeting the EphB4 Receptor to Inhibit Breast Tumor.
Novel Anti-Angiogenic Agents for Breast Cancer Therapy.
PPARd Ligands for Inhibition of Breast Cancer Progression.
Three completed CBCRP-funded grants explored non-conventional connections between angiogenesis and cell growth processes. First, EphB4 is a “receptor tyrosine kinase” that is found at high levels in breast cancer cells that spread to other parts of the body. Elena B. Pasquale, Ph.D., of The Burnham Institute, La Jolla, investigated whether the portion of EphB4 that is exposed on the cell surface stimulates the formation of blood vessels that allow a tumor to grow. Dr. Pasquale’s team found that EphB4 signaling activity does not promote tumor cell growth, like other receptor tyrosine kinases do. Instead, EphB4 proteins actually inhibited tumor growth; however, the presence of EphB4 on tumor cells may still promote the growth of blood vessels that feed the tumor. These findings could lead to the development of breast cancer treatments that target EphB4 to inhibit cancer growth. Dr. Pasquale published some of her findings in Oncogene 19 (2000):5614-9.

The connection between angiogenesis inhibition and a group of drugs called selective estrogen receptor modulators (SERMs) was studied by Keith Laderoute, Ph.D., at SRI International, Menlo Park. SERMs, like tamoxifen, are already used to treat breast cancer tumors that are estrogen receptor (ER) positive. Dr. Laderoute found that a novel compound developed by SRI, called SR 16234, not only blocks tumor cell growth in mice, but also blocks the growth of blood vessel cells and the formation of new blood vessels. SR 16234 is now being studied in a Phase I breast cancer clinical trial. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors. PPARs regulate a wide array of biological processes, from cell differentiation to metabolic homeostasis. Brian Murphy, Ph.D., also at SRI International, demonstrated that a protein called PPAR is not only present in breast cancer cells but is found at higher levels in some of the breast cancer cells that have the ability to spread to other body parts. Dr. Murphy interpreted this as an indicator that PPAR helped promote breast tumor growth and spread, and was an opportunity for a new treatment intervention. He studied a drug, called SR 13904, which could attach to and inhibit the PPAR protein and thereby stop breast cancer progression. Dr. Murphy intends to conduct further studies on SR 13904 in animal models. Toxic side effects from a drug like SR 13904 should be minimal because it selectively targets the PPA protein, which has no known critical role in normal tissue.

Blood Vessel Markers in Breast Cancer.
Erkki Ruoslahti, M.D., Ph.D., at The Burnham Institute, La Jolla, has developed a novel technology called “phage display” to distinguish blood vessel proteins that are associated only with breast cancers. The identification of such a homing peptide could be the basis of directing the therapeutic drug to a tumor and avoiding side effects to the rest of the body. To date, the group has identified a five-amino acid peptide, which only attaches to the blood vessels of human breast tumors grown in mice. They are in the process of patenting and publishing these findings.

Dietary Indole Effect on Estrogen Urinary Metabolites.
Novel Agents for Treatment of Advanced Breast Cancer.
Two CBCRP-funded projects examined compounds derived from natural sources. Research has shown that diets that include large amounts of foods from the Brassica family, such as cabbage, broccoli, and Brussels sprouts can reduce breast cancer risk. One of the main substances found in these vegetables is Indole-3-carbinol (I3C), which has been shown in the lab to inhibit the growth of human breast cancer cells. The human body converts I3C to Diindolymethane (DIM). In the first project, Gary Firestone, Ph.D.; Leonard Bjeldanes, Ph.D.; and Kathie Dalessandri, M.D., at the University of California, Berkeley, studied what effect DIM capsules, which have been shown to be safe when taken orally, would have on postmenopausal women with early stage breast cancer (Stages 0–2). Nineteen women completed their study. Ten women took DIM capsules daily for 30 days; the other nine received a placebo. The research team tested the women’s urine before and after they took the pills. They found that the women who took DIM had changes in certain chemicals in their urine that could be associated with a reduced risk for breast cancer. This pilot study could lead to future research on the use of DIM supplements for breast cancer prevention and treatment. Medicinal chemists strive to develop more active, stable, and specific derivatives of existing compounds to begin clinical development. Ling Jong, Ph.D., at SRI International, Menlo Park, explored the therapeutic potential of a new class of compounds derived from indole-3-carbinol (I3C). Dr. Jong developed a new drug, called SR13668. When tested in tumors grown in mice and in cells in culture, SR13668 appears able to inhibit both estrogen receptorpositive and estrogen receptor-negative types of breast cancer as well as tumors that no longer respond to the SERM tamoxifen. Successful development of SR13668 for clinical use may bring a new, safe, improved weapon to combat cancer. Dr. Jong was funded by the CBCRP in 2003 to continue this line of research.

Novel Technologies to Identify Tissue-Selective Estrogens.
A critical issue in the clinical development of SERMs, like tamoxifen, are the unwanted estrogen-promoting effects in other organs, like the uterus. Thus, researchers are trying to fine-tune SERMs and develop tests that better distinguish SERM effects in various cells and body organs. Fred Schaufele, Ph.D., at the University of California, San Francisco, is using novel technology to speed the identification of drugs that are organ-specific for breast cancer prevention and treatment. Dr. Schaufele uses a unique fluorescence resonance energy transfer (FRET) technique that allows him to see how a drug affects living cells from tissue (like the uterus) that may respond to estrogen-like drugs.

Role of p14ARF in Metastatic Breast Cancer.
A protein found in normal cells and tumor cells, p53, triggers a cell’s death after it has been damaged by chemotherapy or radiation. Another protein normally found in the cell nucleus, p14ARF, binds to and stabilizes p53 to allow maximum function. Some breast tumors have defective p53, but many of those with normal p53 appear to be missing p14ARF. And when the p14ARF protein is not present, the cancer cells lack the ability to trigger their own death. Ruth Gjerset, Ph.D., at the Sidney Kimmel Cancer Center, San Diego, found that p14ARF is generally missing from breast cancer specimens. She explored whether restoring p14ARF with gene therapy would make cells more sensitive to therapy that depends on the action of the p53 protein. She found that re-introducing p14ARF to cells slowed breast cancer cell growth, even when p53 is not present, and that it added to the effectiveness of chemotherapy. In addition, p14ARF had a “bystander effect”; adjacent cells were affected even if they didn’t take up the gene therapy treatment. These findings could lead to the development of gene therapies that could be useful in treating women with metastatic breast cancer. Results from this research were published in Cancer Gene Therapy 9 (2002):830-9.

A Patient Decision Support Framework for Breast Cancer.
Physicians seek better methods of predicting successful treatments for breast cancer. C. Anthony Hunt, Ph.D., from the University of California, San Francisco, is developing a computerized process called a “decision support framework” to help physicians choose the dose of chemotherapy that will provide the greatest benefit with the least amount of harmful side effects. Working with collaborators at the University of Michigan Cancer Center, Dr. Hunt has been exploring the role of the Erythromycin Breath Test (EBT) in determining individual chemotherapy dosage. The EBT, which is quicker and easier than taking a blood sample, measures how quickly the antibiotic erythromycin is metabolized in the body by an enzyme called CYP3A4. Dr. Hunt has found that measuring this patient-specific rate of metabolism, combined with other standard dose selection procedures, is an improvement over the current method, which determines dosage based on a woman’s body size. He is continuing to fine-tune his informatics/computer software approach for choosing the best chemotherapy dosage, with the goal of providing women with individualized breast cancer treatment.

Can Molecular Markers Predict Response to Adjuvant Therapy?
Tumor-related biomarkers are genes or proteins that may provide information on the best choices for therapy and likely clinical outcome. Shelley M. Enger, Ph.D., of Southern California Kaiser Permanente, and Michael F. Press, M.D., Ph.D., at the University of Southern California, Los Angeles, investigated whether some of the markers that can be found in tumor tissue—including estrogen receptors (ER), Her-2/neu, p53, BCL-2, and BAX—could be used to predict whether a patient is likely to respond to various treatments. If these markers could predict response, then they might be used to determine the best treatment options. Drs. Enger and Press completed medical reviews of 1,465 breast cancer patients. They found that women whose tumors were ER-negative or HER2/neu-positive had a greater risk of dying of their disease than did women whose tumors were ER-positive or Her2/neu-negative. However, a woman’s risk of death did not appear to be influenced by whether her tumor contained p53, BCL-2, or BAX, and preliminary data suggest that expression of HER2/neu molecules may be associated with risk of death mainly among patients who did not receive doxorubicin as part of their initial treatment. Drs. Enger and Press will continue to follow these patients so that they can examine long-term outcomes associated with these different tumor markers. These findings have the potential to lead to more personalized and effective treatment regimens.

New Radiation Therapy for HER-2-overexpressing Breast Cancer.
Richard Pietras, M.D., Ph.D., of the University of Southern California, Los Angeles, explored what happens at the molecular level when Herceptin and radiation therapy are combined. Studies have shown that tumors are able to survive radiation by stimulating DNA to repair the damage that has occurred. Dr. Pietras found that Herceptin appears to keep this from happening by interfering with the DNA repair mechanism by altering a protein, p21WAF1, that plays an important role in DNA repair. Noting that recent studies have found that combining Herceptin with new treatments that keep tumors from developing new blood vessels also appears to make radiation more effective, Dr. Pietras concluded that understanding precisely how Herceptin and other cancer treatments work together at the cellular level may lead to new treatments for women whose tumors make too much of the HER2/neu protein. Results of the study were published in Endocrine 2001 Apr;14(3):417-27.

Wnt Signaling in Breast Cancer: Translational Studies.
Wnt proteins are a family of evolutionarily conserved, secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. In cancer, they are of interest because of their connection with catenin proteins that regulate the cell-cell associations that are critical for forming the epithelial monolayer structure of the breast ducts. Randall Holcombe, M.D., Marian Waterman, Ph.D., and Lawrence Marsh, Ph.D., from the University of California, Irvine, explored the role of the Wnt proteins and ligands that are part of its signaling system in breast cancer. They found that there was less of the family member Wnt7b and more of LEF1 protein in breast cancer tissue than there was in normal tissue. And they found that the amount of the LEF1 protein was influenced by estrogen in breast cancer cells. They also showed that high levels of the LEF1 protein were not linked to high levels of the Her2/neu protein, and that abnormalities in the Wnt signaling pathway were separate from abnormalities in the Her-2/neu signaling pathway.

Stress Protein and Drug Resistance in Human Breast Cancer.
In solid tumors, such as breast cancer, there are regions of low oxygen concentration (hypoxia). Low oxygen starves cell metabolism and leads to the production of response proteins. These so-called “stress proteins” may influence the sensitivity of the tumor cells to chemotherapy. Amy Lee, Ph.D., at the University of Southern California, Los Angeles, established that when cancer cells produce a lot of a stress protein, called GRP78, they become more resistant to certain types of chemotherapy drugs, such as doxorubicin (Adriamycin) and cisplatin. To see if this holds true for human breast cancer cells, Dr. Lee is studying whether decreasing the production of GRP78 will make breast cancer cells more likely to respond to (and be killed by) chemotherapy treatments. She is also looking at whether the tumor’s estrogen receptor or p53 status influences the effect that GRP78 has on breast cancer cells. This research was published in Journal of Biological Chemistry 278 (2003):20915-24.

Clotting Breast Cancer.
Thrombosis for Anti-angiogenic Therapy of Breast Cancer.
Anyone who has watched a cut heal notes the inflammatory redness, which is associated at the cellular level with cell growth, division, differentiation, and healing. But as noted in the February 23, 2004, issue of Time, “The Secret Killer: the surprising link between inflammation and heart attacks, cancer, Alzheimer’s, and other diseases,” there is much to be learned about the link between healing and cancer. Is cancer a result of an injury that does not heal? Two CBCRP-funded projects examined blood clotting, immune mast cells, and angiogenesis events in breast cancer. Michael Samoszuk, M.D., from the University of California, Irvine, noted that tumors had endogenous anticlotting mechanisms in place to prevent clots from blocking their blood supply. Dr. Samoszuk wanted to see what would happen if these anti-clotting mechanisms were blocked. Using four different drugs—sodium cromolyn, which is used to treat allergies; heparinase enzyme, which is being tested as a treatment for people who overdose on blood thinner; gabexate mesylate, which is used in Europe to treat patients with bleeding disorders; and imatinib mesylate (Gleevec), which is approved for the treatment of chronic myelogenous leukemia—he found that all of the treated mice had evidence of blood clotting in their tumors while none of the untreated mice had blood clotting occur. He also found that the tumors in the treated mice were larger than those in the untreated mice. Thus, Dr. Samoszuk concluded that allergic cells may play an important role in regulating blood clotting in breast cancer and promoting the growth of breast cancer, that drugs that stop the allergic cells can lead to blood clotting in breast cancer, and that this blood clotting is associated with increased tumor growth and decreased oxygen levels in tumors. Results from this research were published in International Journal of Cancer 107 (2003):159-63, International Journal of Cancer 106 (2003):647-52, and Thrombosis Research 25 (2003): 109:153-6.

A colleague of Dr. Samoszuk was funded independently to study this process in animal models using magnetic resonance imaging to visualize the tumor vasculature during drug treatments of tumors grown in mice. Min-Ying (Lydia) Su, Ph.D., from the University of California, Irvine, explored the possibility of using blood clotting as a novel way to treat breast cancer. Using mice and rats, her group tested two drugs that stimulate blood clotting and are intended to stop tumors from creating blood vessels or to damage those that have already been created. This treatment, however, was not successful: tumors grew at the same rate in the mice and rats treated with the drug as they did in the untreated mice and rats. Even so, the techniques developed in this study can be applied in future studies of drugs now in development. These results were published in the American Journal of Pathology 159 (2001):245 and NMR in Biomedicine 15 (2002):106.

Research in Progress

A number of ongoing CBCRP grants in the topic of Innovative Treatments reported substantial progress in 2003.

PPARg Modulators as Apoptosis Sensitizers for Breast Cancer.
Every cell contains a suicide mechanism that tells it when it is time to die. This programmed cell death is called apoptosis. Cancer results, in part, from a cell not getting its suicide message. John Reed, M.D., Ph.D., of The Burnham Institute, La Jolla, is investigating a class of plant compounds called triterpinoids (there are over 5,000 triterpinoids in nature) to see if they can restore apoptosis functions in breast cancer cells. Dr. Reed is focusing on the ability of triterpinoids to bind to and activate a gene modulator called PPAR?, which can get the suicide message to cancer cells. Results from this research were published in the Journal of Biological Chemistry 277:22320-22329. This research is being conducted in collaboration with Michael Sporn, M.D., at Dartmouth University.

Regulation of SXR and Drug Resistance in Breast Cancer.
A major problem in the treatment of advanced breast cancer is that, at some point, the tumor will become resistant to the chemotherapy drug that is being used. Jennifer Murray, at the Beckman Research Institute of the City of Hope, Duarte, is studying the SXR protein as well as the proteins—called coactivators and corepressors—that control its activity. This research could lead to a greater understanding of drug resistance and a new way to predict if it will occur. Ms. Murray, who is a graduate student in the laboratory of Dr. Susan Kane, presented her research at the American Association of Cancer Research annual meeting in 2003.

Retinoids in Combination Therapies against Breast Cancer.
Compounds derived from vitamin A (retinoids) have been shown to have the ability to kill cancer cells; however, high doses of vitamin A may cause severe side effects. Francisco Javier Piedrafita, Ph.D., at the Sidney Kimmel Cancer Center, San Diego, is testing whether combining retinoids with medications that choke off a tumor’s blood supply or stimulate the body’s immune system would create a more effective breast cancer treatment. These experiments are being done in breast cancer cells grown in cultures and in animals. If this combination is found to be effective, it will allow the use of lower doses of retinoids, which would minimize potential side effects.

Potential New Drug Therapy for Breast Cancer.
New drugs are needed to treat breast cancer patients whose tumors do not respond to traditional treatments. Jack Youngren, Ph.D., at the University of California, San Francisco, is testing compounds that block the action of IGF-IR, a protein that appears to play a key role in initiating the growth of breast cancer cells. The research team will test whether these compounds stop breast tumors in mice. One compound they have tested, small molecules known as diarylureas (DAU), has been found to be effective in blocking IGFIR. The team also demonstrated that these small molecules stop another known target in breast cancer cells, and that they are not toxic in mice. Their future research will explore how these compounds affect breast cancer cells, how they stop cell growth, and their potential to be developed as new cancer treatments.

Patient-Individualized Chemotherapy in Breast Cancer.
Not all tumors will respond to all types of chemotherapy. Using a form of positron emission tomography (PET) scanning, called microPET imaging, Daniel H. Silverman, M.D., Ph.D., at the University of California, Los Angeles, is developing a test that would show if an individual patient’s tumor will respond to a particular chemotherapy drug. His team is currently exploring whether the PET scans can detect very small, non-toxic amounts of chemotherapy as it enters and passes through human breast tumors and normal tissues in mice. The hypothesis is that the way the small doses of the drugs distribute themselves in the tissues will predict which chemotherapy will work most effectively against a particular tumor. If this technique is successful, women could be pre-tested with small amounts of chemotherapy drugs to see which drugs would work and which would be ineffective.

Chemotherapy-Induced Ovarian Damage: Prevention and Impact.
When young women with breast cancer receive chemotherapy, it can damage their ovaries, leaving them unable to have children. Their chemotherapy treatment also typically puts them into early menopause, which can cause accelerated bone loss, hot flashes, and vaginal dryness. Hope S. Rugo, M.D., of the University of California, San Francisco; Lynn Westphal, M.D., of Stanford University; and Lucy Berlin, M.S., of Young Moms with Breast Cancer, Sunnyvale, are testing a GnRH-analogue called triptorelin which stops estrogen production and induces temporary menopause and may protect the ovaries during chemotherapy. They gave this treatment to 32 women ages 35–44 before and during chemotherapy. They are also surveying 130 young women with breast cancer about chemotherapy, fertility, and how their breast cancer treatment affected their quality of life. This research will raise awareness of the impact chemotherapy has on young women and may motivate development of new treatments that are less damaging to the ovaries.

Research Initiated in 2003

The CBCRP funded nine new grants that focus on Innovative Treatments. Seven of our newly funded grants focus in two areas that have attracted advocacy attention: (1) less toxic treatments that might also be useful in chemoprevention and (2) harnessing the immune response. Christine Brew, Ph.D., and her mentor Dr. Gary Firestone at the University of California, Berkeley, were funded though separate grants to study I3C’s (indole-3-carbinol) role in regulation of metalloproteinase genes and to identify the cellular target for the I3C derivative DIM, respectively. Ling Jong, Ph.D., from SRI International, received an award to evaluate novel I3C derivatives using assays for cell signaling pathways associated with apoptosis (programmed cell death) and angiogenesis. Many natural compounds have potential as anti-cancer therapeutics, but the mechanism of action and cellular targets need identification prior to clinical development. Next, there is the concern that widespread use of alternative and complementary therapies might alter the effectiveness of Western medicines. Michael Campbell, Ph.D., at the University of California, San Francisco, was awarded a grant to investigate how Chinese medicinal herbal preparations work in combination with the traditional chemotherapeutic drugs, doxorubicin and paclitaxel. Dr. Campbell’s study will be done in cell culture systems, but promising results might quickly be translated to human trials.

Three newly-funded CBCRP awards focus on research questions related to immunotherapy of breast cancer. Joseph Lustgarten, Ph.D., at the Sidney Kimmel Cancer Center, San Diego, was funded to study a novel group of “non-self” protein fragments (peptides) for their potential to establish immune responses against the Her-2 oncogene. The normal immune response to Her-2 is weak, so Dr. Lustgarten’s approach of directly activating T-cells might circumvent the immune tolerance exhibited by most patients. Edward Nelson, M.D., at the University of California, Irvine, received an award to explore a novel immunophototherapy approach. This is based on the injection of a precursor molecule, uptake by tumor cells, and metabolic production of a photosensitive killer compound. The “photo” element involves activation by laser list focused on the tumor. Dr. Nelson is evaluating whether marrowderived dendritic cells might work to enhance this therapy. Margaret Huflejt, Ph.D., also from the Sidney Kimmel Cancer Center, received an award to explore how best to neutralize immunosuppressive galectins produced by tumor cells. Galectins are carbohydrate-rich cell surface proteins that are thought to mask tumor cells from immune detection. Two newly-funded CBCRP projects focus on novel drug development and a special conference to explore better pre-clinical models for breast cancer. Peter Vogt, Ph.D., from the Scripps Research Institute, La Jolla, will explore a new approach to screen drugs targeting Myc, an oncogene that is elevated in most breast cancers and serves to de-regulate many genes that are associated with aggressive tumors. Dr. Vogt is searching for compounds that block the key Myc-Max protein interaction, and he plans to evaluate lead compounds by their potential to block anti-estrogen resistance in cultured cells. Robert Cardiff, M.D., Ph.D., at the University of California, Davis, received a Joining Forces Conference Award to partially support a special conference on improving animal models in pre-clinical research on breast cancer.