Detection, Prognosis, & Treatment: Delivering Clinical Solutions

Overview: The detection, prognosis, and treatment of breast cancer is a constantly evolving landscape where information filtering in from basic scientists is selectively advanced along the 5-to-10 year stepwise “critical path” for translational application. Cancer stem cells (CSCs), first established in 2003 for breast cancer, are already gaining attention as possible novel targets for therapy. The inability to provide a durable cure for breast cancer is thought to be due to the chemo- and radiotherapy resistance of CSCs to current treatments. And, stem cells might even emerge as a delivery vehicle for therapeutics. Better early detection of disease remains a critical need. Using combined imaging modalities aims to improve both sensitivity and selectivity to reduce unnecessary biopsies and facilitate informative disease staging and prognosis. Genetic profiling of patients continues to move in the direction of “individualized therapy.” New targeted therapies that began with the introduction of Herceptin® require validation of novel targets in the clinical setting and technologies to select patients most likely to benefit from these expensive drugs. Advances in nanotechnology promise new methods for detection and tumor-specific delivery to reduce drug side-effects. However, some clinical scenarios, such as “triple-negative” (ER, PR, and Her-2 negative) breast cancers and the “basal-like” gene expression pattern still account for a significant number of new diagnoses that have fewer treatment options.

The CBCRP funded 14 new grants in 2007 to advance our Detection, Prognosis & Treatment priority issue. Two of the CBCRP’s research topics are represented in this section:

Etiology Portfolio Summary:

Two grants in 2007 focus on the breast ductal system, an underutilized access point for the detection, diagnosis, and treatment of breast cancer. A human breast has many lobes, which are highly variable in size and shape, each with one central duct, its peripheral branches and their associated glandular tissues. Nipple aspirate fluid and ductal lavage can be obtained to analyze the cellular and fluid by histological, proteomic, and genetic techniques. Improvements in mammary ductoscopy using a microendoscope allow for the direct visualization the ductal lining of the breast and the retrieval of epithelial cells. A leader in this field is Susan Love at the Dr. Susan Love Research Foundation. The CBCRP funded a Joining Forces Conference Award to Dr. Love to support the 5th International Symposium on the Intraductal Approach to Breast Cancer in Santa Monica, California, March 1-4, 2007. In attendance were more than 120 oncologists, epidemiologists, biostatisticians, surgeons, biochemists, pathologists, radiologists, endocrinologists, and breast cancer advocates. Next, the CBCRP launched a new Translational Research Award in 2007, and the first recipient is Dr. Love for her three year clinical project, Intraductal Therapy of DCIS: a Presurgery Study. DCIS, an early stage, non-invasive breast cancer, is often over-treated with the same methods of surgery, radiation, and hormone medications as more advanced disease. Historical studies show that most DCIS remains dormant and only 30-40% of cases will ever progress to invasive cancer. The aim of Dr. Love’s translational project is to test the practicality and efficacy of a local treatment of the affected breast duct itself. A currently approved drug, called Pegylated Liposomal Doxorubicin, will be introduced directly into the ductal system of women bearing DCIS lesions. If successful, this novel treatment strategy may eventually save countless women from undergoing disfiguring surgery and debilitating systemic chemotherapy.

Four new grants address the topic of breast cancer imaging with the potential for better earlier detection of breast cancer as well as improved diagnosis and staging of existing disease. Magnetic Resonance Imaging (MRI) is a more sensitive method than x-ray mammography to detect smaller tumors and image the “denser” breasts of younger women, but “standard proton” MRI suffers from limited specificity that leads to unnecessary biopsies. Brian Hargreaves at Stanford University received IDEA funding to develop new hardware and pulse sequence software for “multinuclear” MRI to quantitatively detect differences in sodium concentrations between tumors (increased sodium) and normal tissue. Next, ultrasound is an important adjunct to mammography to identify, characterize and localize breast lesions, and it is also not compromised by dense breasts. Ultrasound requires no radiation or compression. However, ultrasound is operator-dependent and this lack of consistency limits more widespread acceptance. Thomas Nelson from the University of California, San Diego, received an IDEA competitive renewal grant to complete construction of a breast ultrasound scanner to image the entire breast. This volume breast ultrasound (VBUS) machine should be an improvement over hand-held devices currently being used. Dr. Nelson will also add blood flow imaging capability to the scanner to facilitate the discrimination between more vascular tumor lesions vs. benign/normal tissues. Next, accurate staging of lymph nodes is a critical parameter in determining whether a primary breast tumor is likely to have metastasized. Nodal staging dictates the therapeutic options for many cancer patients. Although sentinel node biopsy has reduced the need for more extensive lymphadenectomy (multiple node excision), imaging methods such as CT, MRI, and optical have not yet been developed to the point of accurately distinguishing normal and tumor-infiltrated lymph nodes. Ella Jones from the University of California, San Francisco, aims to develop a non-invasive imaging probe based on a nanotechnology-based dendrimer probe (i.e., uniform populations of repeatedly branched, synthetic molecules, like tiny snowflakes) having fluorogenic (light emitting) properties when cleaved by the tumor-specific Cathepsin B protease. If successful, this approach is predicted to selectively “light-up” cancer cell-continuing lymph nodes for fluorescence detection. First, Dr. Jones and colleagues will conduct testing in mice to show “proof of principle” prior to human translational work. Finally, standard neoadjuvant chemotherapy is used for the management of locally-advanced, large (>3cm) breast cancers to reduce the primary tumor size prior to surgery. However, some cancers are resistant to chemotherapy and earlier identification of these “nonresponders” would help patients avoid toxic and ineffective treatments, and expedite the initiation of alternative therapy. Catherine Klifa also at the University of California, San Francisco, will combine two imaging modalities, Diffuse Optical Spectroscopy (DOS) and MRI, using an instrument already developed by Bruce Tromberg at the University of California, Irvine, and Nola Hylton at UCSF. The aim of Dr. Klifa’s clinical study of 30 patients is to predict the neoadjuvant response by detecting changes in tumor physiology by DOS after one round of chemotherapy, which would be too soon to measure reduced tumor size using MRI.

Two CBCRP-funded grants explore novel therapeutics. Tumors express antigens that should induce immune-mediated rejection, but rejection of established tumors is uncommon. One reason is that tumors actively defeat host immunity, so researchers are always testing new ways to harness host immunity to battle cancer. One approach to making tumor immunotherapy more broadly applicable is to administer recombinant cytokines to strengthen the immune response and overcome tumor suppressive mechanisms. However, issues such as toxicity, poor drug half-life in circulation, and stimulation of T-regulatory cells (immune suppression) are obstacles to the clinical development of therapeutic cytokines. Ananda Goldrath at the University of California, San Diego, has found that IL (interleukin)-15 may not only offer a more favorable dose-limiting toxicity compared with IL-2, but may differentially affect Tregulatory cells. She will combine IL-15 with its soluble receptor (sIL-15Rα) prior to injection in mouse models of breast cancer. It is hoped that the IL-15/receptor complexes will improve the priming and survival of lymphocytes. Next, the capacity of malignant cells for invasion and metastasis is triggered in part by the metabolic needs of the growing tumor. As the cancer grows, its demand for nutrients and oxygen overwhelms the local blood supply. A low oxygen level, or hypoxia, causes the cell to increase the amount of a DNA-binding protein, called hypoxia inducible factor (HIF). In addition to activating genes involved in blood vessel formation (angiogenesis), recent studies in breast cancer cells have shown that HIF also induces the expression or tumor cell genes directly implicated in invasion and metastasis. John Phillips from the California Institute of Technology received a dissertation award to target HIF using polyamides, a class of synthetic, sequence-specific DNA-binding molecules that can block transcription factor-DNA interactions. Most DNA-interacting drugs damage DNA in a nonselective manner, killing cancerous cells and healthy cells alike. Polyamides, on the other hand, are designed to control cancer-causing genes without DNA damage.

Four new grants focus on new approaches for existing breast cancer targets or to identify patient sub-populations that would receive the most potential benefit from existing therapies. ErbB receptors (e.g., EGFR and Her-2) are displayed on the exterior surface of many breast tumor cells and transmit molecular signals from the extracellular environment to the inside of the cell. In this way, they mediate normal cell processes and functions, but in breast tumors can trigger aberrant cell growth. Jennifer Lahti at Stanford University received a dissertation award to study whether “knottins”, which are mini-proteins with a high potential for drug design, when combined with fragments of natural epidermal growth factor (EGF) ligands can be selected and developed as novel inhibitors of tumor cell signaling and progression. Second, the taxane compounds, paclitaxel (Taxol) and docetaxel (Taxotere) have been important components of chemotherapy regimens to treat metastatic breast cancer. However, a patient’s intrinsic or acquired resistance to these drugs limits their widespread clinical utility. Taxanes specifically target the cellular microtubules, and Tatana Spicakova also from Stanford University will study whether altered levels and/or aberrant modification of microtubule associated proteins (MAP-Tau, MAP4 and MAP2) confer resistance to taxanes. Next, HSP90 (heat shock protein 90) is a molecular chaperone (involved in correct protein folding) and is one of the most abundant cellular proteins. In tumor cells HSP90 can act as a "buffer" for mutated proteins. Cynthie Wong at the Beckman Research Institute of the City of Hope will investigate specific antibiotics, called geldanamycin derivatives, which bind to HSP90. She will test the ability of geldanamycin derivatives to inhibit cell proliferation through known cell cycle and apoptosis pathways in Tamoxifen- and aromatase inhibitor (AI)-resistant breast cancer cell lines. Elucidating the mechanism of how geldanamycins can inhibit the proliferation of drugresistant breast cancers will be beneficial for the development of the next generation of therapies to target endocrine-resistant breast cancers. Finally, DNA repair mechanisms are emerging as promising avenues to target breast cancer, especially since the role of BRCA genes in DNA repair processes have been elucidated. Although only a small percentage of women carry BRCA gene mutations, it is thought that defects in the BRCA1/2 pathways (i.e.,“BRCAness”) are common in sporadic breast cancers. Poly (ADP-ribose) polymerase (PARP) repairs DNA single strand breaks through its activation and recruitment of other DNA repair enzymes. PARP inhibitors may overcome defense mechanisms of tumor resistance against standard chemotherapy. Karlene Cimprich from Stanford University received IDEA funding to“profile” genetic biomarkers of sporadic human breast cancers with the aim of detecting tumors that would be sensitive to PARP inhibitors.

Two newly funded grants have a focus on stem cells, an emerging topic of great importance in cancer research over the past few years. First, Brunhilde Felding-Habermann at the Scripps Research Institute received a renewal of previous CBCRP IDEA funding for a project to inhibit breast cancer brain metastases by harnessing neural stem cells (NSCs), the body’s own mechanism for healing and regeneration in the brain. As a shielded “sanctuary site”, the brain may harbor breast cancer cells that resist current treatments and can develop into metastases, long after chemo-, radiation- or immuno-therapies have been applied. In Dr. Felding- Habermann’s unique approach, NSCs are “armed” with cytosine deaminase, and then allowed to migrate to sites of tumor growth. At this point they have the potential to kill nearby proliferating breast cancer cells by converting non-toxic 5-fluorocytosine into highly toxic 5-FU. Lastly, a major reason for failures in cancer therapy is the incomplete elimination of a special type of cell, termed cancer stem cells (CSCs). The CSC model argues that tumors arise from small population (1-2% of the tumor) of cells that retain the properties of adult stem cells, particularly for their ability to self-renew and differentiate into multiple cell types, commonly seen as the heterogeneity of tumor cell types in patient samples. Frank Pajonk from the University of California, Los Angeles, received IDEA funding to explore ways to increase the radiation therapy sensitivity of a type of CSC, called the breast cancer initiating cell population (BCIC). In fact, breast cancer stem cells exhibit increased radioresistance, such that ionizing radiation interferes with the stem cell “niche” (i.e., the local environment of cells that are important for their regulation) resulting in inhibition of asymmetric cell division, thereby increasing the number of cancer stem cells responsible for treatment failure. Dr. Pajonk hopes to elucidate the signaling pathways, especially radiation-induced “Notch” activation, of the BCIC stem cell population to point the way for potential novel therapies.

Detection, Prognosis, & Treatment Grants Funded in 2007:

Exploring the Role of PARP Inhibitors in Breast Cancer
Karlene Cimprich, Ph.D.
Stanford University
Award type: IDEA
$157,750

Neural Stem Cell Therapy for Breast Cancer Brain Metastases
Brunhilde Felding-Habermann, Ph.D.
Scripps Research Institute
Award type: IDEA-competitive renewal
$360,277

Novel Cytokine Immunotherapy for Breast Cancer
Ananda Goldrath, Ph.D.
University of California, San Diego
Award type: IDEA
$150,000

Multinuclear MRI of Breast Tumors
Brian Hargreaves, Ph.D
Stanford University
Award type: IDEA
$236,771

Molecular Imaging of Metastatic Lymph Nodes in Breast Cancer
Ella Jones, Ph.D.
University of California, San Francisco
Award type: IDEA
$150,000

Breast Cancer Treatment Monitoring Combining MRI and Optics
Catherine Klifa, Ph.D.
University of California, San Francisco
Award type: IDEA
$149,927

Engineering EGFR Antagonists for Breast Tumor Targeting
Jennifer Lahti
Stanford University
Award type: Dissertation
$75,992

Intraductal Therapy of DCIS: a Presurgery Study
Susan Love, M.D., M.B.A.
Dr. Susan Love Research Foundation
Award type: Translational Research
$851,559

Symposium on the Intraductal Approach to Breast Cancer
Susan Love, M.D., M.B.A.
Dr. Susan Love Research Foundation
Award type: Joining Forces Conference
$25,000

Early Breast Cancer Detection Using 3D Ultrasound Tomography
Thomas Nelson, Ph.D.
University of California, San Diego
Award type: IDEA-competitive renewal
$225,000

Modulation of Breast Cancer Stem Cell Response to Radiation
Frank Pajonk, M.D., Ph.D.
University of California, Los Angeles
Award type: IDEA
$150,000

Polyamide HIF Inhibitors to Block Breast Cancer Metastasis
John Phillips
California Institute of Technology
Award type: Dissertation
$76,000

Determinants of Response to Microtubule Stabilizing Drugs
Tatana Spicakova, Ph.D.
Stanford University
Award type: Postdoctoral Fellowship
$90,000

Mechanisms of HSP90 Inhibitor Action in Breast Cancer
Cynthie Wong
Beckman Research Institute of the City of Hope
Award type: Dissertation
$67,871