Innovative Treatments: Search for a Cure

To stimulate the development of more effective treatments, the CBCRP funds a variety of research topics. These include alternative medicines, novel clinical approaches, testing of promising drug and drug target 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 Issue is an extension of their research previously funded under our Priority Issue of Pathogenesis.

We have divided the innovative treatment priority issue into four broad areas of research:

Research Conclusions

Immune Therapy: Mobilizing the Body's Defenses

Engineering Antibodies Specific for Breast Cancer Proteases.

Breast cancer cells produce enzymes called proteases that break down surrounding tissue and allow the cells to migrate to other locations in the body. Jeonghoon Sun, from the University of California, San Francisco, created six genetically-modified antibodies designed to inhibit the action of a tumor protease called MT-SP1. Using support from other funding agencies, he will test these antibodies in breast and prostate tumor models.

New Drug Design: Creative Science

Novel Inhibitors of Rad51-DNA Repair in Breast Cancer.

Both radiation and chemotherapy kill cancer cells (and also normal cells) by damaging the cell DNA. Breast tumors contain elevated levels of DNA repair enzymes that repair the damage caused by radiation and chemotherapy, creating resistance to these treatments. One DNA repair enzyme found at high levels in breast tumors is called Rad51. Anne Vallerga, Ph.D., from Pangene Corporation, Inc., Fremont, found that substances that inhibit Rad51—either by keeping cells from producing Rad51 or by rendering Rad51 ineffective—made breast cancer cells ten times more sensitive to chemotherapy drugs such as cisplatin or doxorubicin. This research could lead to effective breast cancer treatment combining Rad51 inhibitors with much smaller doses of chemotherapy drugs, potentially with fewer toxic side effects.

Arginine Deiminase as an Innovative Anti-Breast Cancer Agent.

Wei-Chiang Shen, Ph.D., at the University of Southern California, Los Angeles, investigated an enzyme, arginine deiminase, which is found in certain bacteria, as a possible anti-breast cancer treatment. The team cloned the enzyme and investigated how it affected several types of cells at the level of interactions between protein molecules. The results suggest that the compound the team cloned, recombinant arginine deiminase, inhibits the growth of blood vessels. It does so by controlling the production of nitric oxide within the cells that line blood vessels, rather than directly stopping the growth of these cells. This research could potentially provide the basis for a therapy based on choking off a tumor's blood supply.

Computer-Aided Discovery of Novel Breast Cancer Therapeutics.

Danni Harris, Ph.D., from the Molecular Research Institute, Mountain View, and Marcia Dawson, Ph.D., from The Burnham Institute, La Jolla, proved that their new method for identifying possible breast cancer drugs works. Their research combines Dr. Harris's previous research in computer modeling of the structure of complex molecules with Dr. Dawson's previous research in the anticancer biology and chemistry of retinoids. Retinoids include both natural and synthetic substances derived from vitamin A. Retinoids cause cells to mature and then die, or simply to die, by undergoing the normal process of cell death. However, retinoids haven't been used to treat breast cancer yet because the doses that must be given also damage normal cells. The research team used a computer program that models the structure of complex molecules in three dimensions. With this program, they determined the structure of a set of retinoid-like compounds, called AHPNs, that work against breast cancer cells that retinoids don't kill. Using the computer program to analyze the AHPNs, the research team found the part of the molecular structure common to them that causes cells to die. This part of a molecule that is active as a drug is known as the pharmacophore. Next, the team searched databases of the molecular structures of known compounds and found 200 with similar properties. Of these, 11 were readily available, and they tried them on breast cancer cells. One worked well against the cells and was under investigation, by another laboratory, as a breast cancer drug. The team then improved the pharmacophore so that it matches fewer compounds that are poor candidates to become drugs. The CBCRP is funding Dr. Dawson to continue these studies to use computer modeling to search for more drug-like molecules that may work against breast cancer.

Hormone and Chemotherapy Targets: Improving Today's Arsenal

Targeted Chemotherapy to Treat Breast Cancer.

Liposomes are laboratory-synthesized microscopic particles with a fatty outer layer and a water-soluble center. Liposomes can circulate in the blood and carry chemotherapy drugs, genes, or other therapeutics to selected locations. Francis Szoka, Ph.D., at the University of California, San Francisco, attempted to increase the ability of drug-carrying liposomes to locate and bind to breast cancer cells, but not to normal cells. This would isolate the drug from the body until it is absorbed by breast cancer, minimizing side effects. Dr. Szoka attempted to target liposomes by incorporating into them special sugar molecules that bind to a protein, CD44, found on breast cancer cells. The team's initial approach did not work, and an alternate method only partly succeeded. However, the team developed a human breast tumor system in mice, and all elements are in place to continue this project in the future. The initial phase of this project was published in Cancer Research 61:2592-2601 (2001).

Biologic Determinants of Response to Paclitaxel and Radiation.

Locally-advanced breast cancer is defined as a lump larger than 2 inches that has spread to the lymph nodes. This type of breast cancer may also have features of aggressive tumors. The tumor may make the skin swell, form a sore on the breast, or be stuck to the chest wall. The chance that locallyadvanced breast cancer has spread to other body parts is high; the chance of surgically removing the entire tumor is low. This type of breast cancer is particularly common among minority women with little access to medical care. Silvia Formenti, M.D., and Peter Danenberg, Ph.D., at the University of Southern California, Los Angeles, tested a new way of giving treatment to 82 women with locally advanced breast cancer, 90% of them minority women. Instead of administering chemotherapy or radiation after the women's breast tumors were removed, they administered these treatments first. Then, after the tumors were surgically removed, the research team tested the tumor tissue to see whether the previous treatment had any effect. The chemotherapy drug paclitaxel alone was effective against 12% of the tumors; paclitaxel plus radiation worked against 40%. These treatments were most effective against tumors with low levels of the HER2/neu and estrogen receptor proteins. This research provides information on how to individualize treatments for locally-advanced breast cancer based on the characteristics of tumors.

A New Class of Drugs to Treat Breast Cancer.

Tamoxifen, the leading drug to treat breast cancer, works on breast cancers that need the hormone estrogen to grow. It ties up the protein that cells use to combine with estrogen, the estrogen receptor. Thomas Robertson, Ph.D., of the University of California, San Francisco, used computer modeling in an attempt to design compounds that would block the growth of breast cancer in a different way from tamoxifen, in order to overcome limitations such as drug resistance and side effects. The team identified a group of chemicals that may inhibit breast cancer growth. All of these chemicals shared part of their chemical structure, so the team tried to synthesize this part, but did not succeed.

Research in Progress

New Drug Design: Creative Science

Interaction of PPARν and Retinoid Ligands in Breast Cancer.

Compounds derived from Vitamin A (retinoids) show promise for prevention and treatment of breast cancers that depend on hormones to survive and grow, but not for hormone-independent breast cancers. Sharon James, Ph.D., of The Burnham Institute, La Jolla, is testing compounds that may make one class of retinoids more effective against hormone-independent breast cancers. The researchers have found that a type of retinoid, RXR retinoids, combined with two drugs—one called a PPAR specific drug and the other called trichostatin A—make cells produce an enzyme called RAR beta. RAR beta allows cells to take up retinoids and makes treatment with retinoids more effective against hormone-independent breast cancer. The team is currently investigating whether a protein called COUP must also be present in the cells for the combination of drugs and retinoids to work.

Blood Vessel Markers in Breast Cancer.

Erkki Ruoslahti, M.D., Ph.D., at The Burnham Institute, La Jolla, is engineering small pieces of protein called peptides that are placed on viruses. These proteins allow the viruses to bind to other specific proteins found on breast tumor blood vessels, but not on normal blood vessels. Eventually, these “homing peptides” could be designed to carry chemotherapy drugs. So far, the research team has identified a breast tumor vessel homing peptide, which they have named BCRP-1. When this peptide is attached to a fluorescent marker molecule, a large amount of fluorescence appears in the tumor, and little or none in normal tissues. The fluorescent molecule has a chemical structure similar to drug molecules, so a drug coupled with the peptide would also become concentrated in the tumor. This could lead to a new way to target chemotherapy to tumors, with fewer toxic effects on normal tissues.

Enhanced HER-2 Directed Liposomal Therapeutics.

Daryl Drummond, Ph.D., from the California Pacific Medical Center, San Francisco, is formulating liposomes (microscopic fat particles) which contained a chemotherapy drug. On their surface, the liposomes have a HER-2 antibody that convenes on tumor cells. The chemotherapy drug is not released until the tumor cells take it up, which should minimize side effects. The researchers are systematically overcoming formulation problems with this method of delivering chemotherapy. They are attempting to formulate liposomes that allow more of the drug to reach the cancer, which would reduce the total amount of the drug that needs to be administered. They are working on ways to maximize the amount of time the liposomes circulate in the blood, ways to maximize the number of liposomes the tumor retains, and ways to allow the drug to be released inside the cancer cells.

Hormone and Chemotherapy Targets: Improving Today's Arsenal

Role of p14ARF in Metastatic Breast Cancer.

A protein found in 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 normally found in the cell nucleus, 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, has found that P14ARF is generally missing from breast cancer specimens. She has found that restoring p14ARF with gene therapy will make cells more sensitive to therapy that depends on the action of the p53 protein. In addition, p14ARF has a “bystander effect”; adjacent cells are affected even if they don't take up the gene therapy treatment. Results from this research have published in Cancer Gene Therapy 9:830-9 (2002).

Novel Technologies to Identify Tissue-Selective Estrogens.

Estrogen-dependent breast tumors contain a specific protein (the estrogen receptor) that binds to the hormone estrogen. This binding causes tumors to grow. Fred Schaufele, Ph.D., at the University of California, San Francisco, is using novel technology to test many proteins in living cells in order to identify a drug that will block estrogen in the breast, but preserve the beneficial effects of estrogen in other organs. The research team has so far adapted the necessary technology so that a large number of chemical interactions in living cells can be analyzed quickly at low cost.

Gene Therapy and Other Treatments: New Frontiers

In Vivo Effects of Chinese Herbal Extracts on Breast Cancer.

Michael J. Campbell, Ph.D., at the University of California, San Francisco, is testing extracts of Chinese herbs that have traditionally been used to treat cancer. Dr. Campbell's team is identifying the compounds in various herbs that are most active against breast cancer in lab cultures. Next, they are feeding these substances to mice with tumors, or injecting them into mice with tumors, to see if the tumors shrink. So far, one herb, Scutellaria barbata, inhibits tumor growth when injected, but not when given orally. The team is currently testing several compounds derived from this herb and from another herb, Vaccaria segetalis.

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 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, are investigating whether some of these markers—including Her-2/ neu, p53 and Bcl-2—can be used to predict whether the patient is likely to respond to various treatments. To date, they have collected data from medical records of 1,517 breast cancer patients. They have found that the presence of tumor markers is not related to whether the tumor was found early or late, but that some tumor markers are more common in tumors that have one type of structure (lobular tumors) or in another (ductal tumors). The team is currently analyzing data to determine if any of the markers can predict response to treatment.

Chinese Herbal Therapy (CHT) for Symptom Management.

Hope S. Rugo, M.D., of the University of California, San Francisco, is conducting a Phase III clinical trial (the final trial before a medication can be approved for use) initiated by Debasish Tripathy, M.D. The purpose of the trial is to investigate whether Chinese herbs will relieve the side effects caused by chemotherapy. So far, 28 women receiving chemotherapy treatment with doxorubicin and cyclophosphamide have taken part. Half the women are also being given a 21-herb combination designed by experienced acupuncturists, and half a placebo. It is not clear yet whether the Chinese herbal combination reduces side effects overall, but a small number of the women taking the Chinese herbal combination and a small number taking the placebo have experienced serious side effects.

Research Initiated in 2002

Immune Therapy: Mobilizing the Body's Defenses

PPARν Modulators as Apoptosis Sensitizers for Breast Cancer.

John Reed, M.D., Ph.D., of The Burnham Institute, La Jolla, is testing substances called PPARν modulators for their ability to enable the natural process of cell death in cancer cells. Some PPARν modulators are drugs currently used to treat other diseases, others occur naturally in the human body.

New Drug Design: Creative Science

Novel Retinoids with Enhanced Anti-Breast Tumor Efficacy.

Marcia Dawson, Ph.D., at The Burnham Institute, La Jolla, is attempting to improve the effectiveness of a compound derived from vitamin A, called an AHPN, that may be able to stop the growth of breast cancer cells without undesirable side effects.

Regulation of SXR and Drug Resistance in Breast Cancer.

Jennifer Murray at the Beckman Research Institute of the City of Hope, Duarte, is studying a gene involved in the production of SXR, a protein that allows cancer cells to resist drug treatment and often thwarts chemotherapy.

Retinoids in Combination Therapies Against Breast Cancer.

Francisco Javier Piedrafita, Ph.D., at the Sidney Kimmel Cancer Center, San Diego, is testing combination therapy for breast cancer in cells grown in cultures and in animals. The combinations of medications include compounds derived from Vitamin A (retinoids) along with medications that choke off a tumor's blood supply or stimulate the body's immune system.

MMP-Directed Synthesis of Invasive Breast Cancer Blockers.

MMPs are proteins that cancer cells secrete in order to invade the surrounding tissue and move to new parts of the body. Researchers have developed drugs to block MMPs. However, because these drugs also inhibit MMPs involved in normal body processes, they have bad side effects. Vito Quaranta, M.D., at The Scripps Research Institute, La Jolla, will use a new chemistry method to “instruct” MMPs involved in breast cancer to synthesize substances that block only those particular MMPs.

Potential New Drug therapy for Breast Cancer.

Jack Youngren, Ph.D., at the University of California, San Francisco, is testing compounds that block the action of IFGIR, 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.

TR3-Based Peptides for Apoptosis in Breast Cancer.

Xiao-kun Zhang, Ph.D., at The Burnham Institute, La Jolla, is investigating how a protein called TR3 destroys cancer cells. The research team, who previously discovered TR3, is also looking for the part of the protein responsible for its anticancer action.

Hormone and Chemotherapy Targets: Improving Today's Arsenal

Chemotherapy-Induced Ovarian Damage: Prevention and Impact.

When young women with breast cancer receive chemotherapy treatment, it generally damages their ovaries and makes them unable to have children. 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 medicine called GnRH-analogues that shuts down the ovaries. They will give this treatment to 32 women ages 35-44 during chemotherapy to see if it protects the women's ovaries and fertility.

Gene Therapy and Other Treatments: New Frontiers

Drug Dose Tailoring Based on Patient-Specific Factors.

The optimal dose of a chemotherapy drug would be strong enough to eliminate the tumor, but not so strong that it is toxic to the rest of the body. Christine Case, Ph.Dc., at the University of California, San Francisco, is developing a method for creating the optimal dose of the chemotherapy drug docetaxel for individual patients, based on a profile of the patient's blood proteins, liver enzymes, and other factors.

Clotting Breast Cancer.

Michael Samoszuk, M.D., at the University of California, Irvine, is attempting to activate a normal blood clotting mechanism in a tumor blood supply to starve breast cancer. The research team is trying the concept on cells grown in lab cultures and on mice with tumors.