Detection, Prognosis, and Treatment

The detection, prognosis, and treatment topics funded by the CBCRP continue to change as novel technologies and approaches come under investigation. CT (computerized tomography) scanning is emerging with new instruments being designed that are dedicated to breast imaging. Also digital tomosynthesis (a new type of mammography), ultrasound, and PET technologies are being used to better image the breast and to allow more accurate excision of tumors. For better disease prognosis, several gene expression profiling tests are coming into both commercial use and clinical testing. The expected benefits of genetic testing performed on tumor samples are to allow individualized therapy to spare women the unnecessary side-effects of treatments with no potential benefit—a common outcome with most non-targeted chemotherapeutics. Cancer therapeutic development continues to evolve with a focus on (i) the validation of novel cell targets and an improved understanding of the disease at the genetic and molecular levels, and (ii) an enhanced ability to match patient subgroups with individual drugs or drug combinations to assess efficacy earlier in pre-clinical testing. Alternative therapies and drugs, especially those derived from plants, engender intriguing areas of investigation.

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.

Two research topics are represented in this section:

Research Conclusions

Breast Stromal Genes Act as Early Markers of Malignancy
The breast epithelial cells—the cells from which breast cancers arise—grow within a matrix of breast stroma. The stroma is made up of fibroblasts, the cells that give rise to connective tissue. The cell-to-cell signaling that takes place between stromal fibroblasts and malignant breast epithelium contributes to the growth and spread of breast cancer. Thea Tlsty, Ph.D., and Stefanie Jeffrey, M.D., of the University of California, San Francisco, studied 36 fibroblast cell lines from breast cancer specimens, normal mammary tissue samples, and breast reduction tissue, to see if they could identify an early marker of malignancy. They found that the fibroblasts in the breast cancer specimens (carcinoma associated fibroblasts or CAFs) stimulated the growth and altered the structure of normal breast epithelial cells. In addition, a complex gene analysis they performed showed that the expression of several proteins that activate white blood cells, called chemokines, as well as a chemokine receptor, was lower in the CAFs than in the other tissue samples. Drs. Tlsty and Jeffrey are now exploring when in a tumor’s development the CAF’s characteristics appear. This work could lead to the discovery of a molecular pattern in the stroma that could be used to not only detect breast cancer at an earlier stage but also to predict the risk of disease progression.

Molecular Imaging of Breast Cancer Using Breast PET/CT
Combining the information obtained from the physiological images derived from positron emission tomography (PET) with the anatomical detail provided by breast computed tomography (CT) could provide physicians with a way to quantitatively assess a breast cancer’s aggressiveness. This could, in turn, aid treatment decisions. Ramsey Badawi, Ph.D., at the University of California, Davis, combined a PET detector system with a CT scanner to create a well-integrated PET/CT system dedicated to breast imaging. Dr. Badawi has received funding from the American Cancer Society to start a human trial in 10 patients with suspected breast cancer to test the accuracy of this new breast PET/CT. Findings from this research were published in Nuclear Science Symposium Record 4(2006)2335 and 3(2005)1524.

Novel Agents for Breast Cancer Therapy
Scientists are trying to identify molecular targets that are specific to cancer cells. This would allow them to develop treatments that could home in on cancer cells and leave normal cells alone. One potential target is a protein called Bcl-xl. It is part of a family of proteins called Bc1- 2, which help regulate programmed cell death (a process known as apoptosis.) Bcl-xl has the ability to help cancer cells proliferate even when targeted by radiation or chemotherapy. Maurizo Pellecchia, Ph.D., at The Burnham Institute for Medical Research, La Jolla, is trying to develop a way to target Bcl-xl. Dr. Pellecchia and his team discovered that Gossypol, a natural product with demonstrated anti-breast cancer activity, works by selectively blocking Bclxl. They then identified and studied a new compound, Apogossypol, and found that it had less toxicity and appeared to be even more effective than Gossypol. This work could lead to the development of more effective breast cancer treatments.

Dietary Indole Analogs Inhibit Breast Cancer Cell Invasion
Up to half of all patients who have a breast cancer recurrence will eventually have metastatic disease. Scientists believe that a cancer recurrence is probably the result of undetectable residual cancer cells left after breast cancer surgery. Ling Jong, Ph.D., at SRI International, Menlo Park, is trying to develop a maintenance therapy that could indefinitely suppress these residual cancer cells and, essentially, cure the cancer. Dr. Jong and his team discovered and developed an oral anti-cancer agent, called SR13668. This agent is similar to indole-3-carbinol, an anti-cancer agent found in cruciferous vegetables. The team had previously found that SR13668 could inhibit phospho-Akt (pAkt) in breast cancer cells in cell cultures and in mice. This is significant because patients that are pAkt-positive are more likely to have a recurrence that involves distant metastasis. This research project, a safety study in rats, found no drug-related deaths or organ toxicity when the drug was administered at a level 30-60 times higher than what has been found to be effective. Based on these findings, the National Cancer Institute has agreed to support additional preclinical studies on this new anti-cancer agent.

HER3 Infidelity and Resistance to Tyrosine Kinase Inhibitors
The human epidermal growth factor receptor (HER) family is known to play a role in cancer progression. The family has four members, HER1-4. The most well known in breast cancer is HER2. There is evidence to suggest that HER2-positive cancers should respond to drugs that inhibit an enzyme called HER2 kinase. However clinical trials of HER family tyrosine kinase inhibitors (TKIs) have not found these drugs to be effective. Mark Moasser, MD, at the University of California, San Francisco, and colleagues discovered previously that HER family TKIs effectively inhibit HER1, HER2, and HER4 but not HER3. This is a problem because HER3 works with HER2 in cancer tumors. This study allowed Dr. Moasser’s team to explore why HER3 does not respond to these therapies. They discovered that the HER2-HER3 partnership is protected by specific feedback signaling mechanisms that allow HER3 to continue to function when targeted by TKIs. They also discovered that although cancer cells can survive when HER2 is weakened, they are unable to survive when it is completely inactivated. Dr. Moasser is now developing and testing inhibitors that can completely inactivate HER2 in preclinical models. This work could lead to the development of new treatments for women with HER2-positive breast cancer. Findings from this research appeared in Nature 445(2007)437.

ID4: a Prognostic Factor of Breast Cancer Metastasis
Metastasis of breast cancer to regional lymph nodes is one of the most important factors in predicting disease outcome. David Hoon, M.Sc., Ph.D., at the John Wayne Cancer Institute, Santa Monica, and colleagues discovered that when a gene, called ID4, is inactivated, the tumor is likely to have metastasized to the sentinel lymph node (SLN). To validate this finding, Dr. Hoon and his team analyzed primary breast tissue and SLN samples to see whether ID4 inactivation correlates with cancer progression. They also studied the cancer cells to learn more about how ID4 functions. If the team finds that ID4 is predictive of tumor metastasis to the SLN, it could be used to determine which breast cancer patients needs SLN surgery, which could help improve survival and disease management.

Inhibition of Brain Metastases in Breast Cancer
Up to 30 percent of breast cancer patients will have their cancer metastasize to the brain. Because current treatments for breast cancer metastases are not very successful, new approaches are needed. Brunhilde Felding-Habermann, Ph.D., at the Scripps Research Institute, La Jolla, and colleagues have created new human breast cancer cell models and analytical systems that allow them to follow the development of breast cancer brain metastases step-by-step and evaluate treatment response. This work led them to identify a new molecular target on metastatic breast cancer cells. The target is a cell adhesion receptor, called the activated conformer of integrin avß3. The team found that this receptor promotes breast cancer cell metastases to the brain and central nervous system. They also showed that treatment with antibodies against activated avß3 could reach target organs of breast cancer metastasis, including the brain. This work could lead to the development of a new therapy for brain metastases in breast cancer patients. Findings from this work were published in Clinical Cancer Research 13(2007)1656.

cAMP Antagonists of Protein Kinase as Breast Cancer Drugs
Mounting evidence suggests that an enzyme called cAMP-dependent protein kinase (PKA) plays a role in breast cancer. But since this enzyme also plays a role in many normal cell processes, it’s not a good drug target. There is however, a subunit of PKA, called RIalpha, that cell and animal models have established is a good target, and phase II cancer clinical trials testing a therapy that prevents RI synthesis are now underway. Sanjay Adrian Saldanha, Ph.D., first at Scripps Research Institute, La Jolla, and then at the University of California, San Diego, is trying to identify a small molecule that would target RIalpha and provide an alternative way to target PKA. Dr. Saldanha and his team developed a new assay for the identification of PKA agonists or antagonists that could help them identify this molecule. They tested a series of drug-like small molecules and marine natural products, but only found that those that were analogs of cAMP were active towards PKA. These findings lay the groundwork for future studies to validate PKA as a drug target.

Grants in Progress: 2007

An Approach to Antiestrogen Resistance in Breast Cancer
Oksana Tyurina
University of California, San Diego

Artemisinin Disrupts Estrogen Receptor-Alpha and Cell Growth
Gary Firestone
University of California, Berkeley

Breast Cancer Functional Imaging with Optics and MRI
Bruce Tromberg, Nola Hylton and John Butler University of California, Irvine and University of California, San Francisco

Breast Tumor Inhibition by Vitamin D in a Mouse Model
David Feldman
Stanford University

Chemical Inhibitors of Hsp70 for Breast Cancer
Chung-Wai Shiau
The Burnham Institute of Medical Research

Combined Imaging Modalities for Breast Cancer
Gultekin Gulsen
University of California, Irvine

Differential Optical Mammography
Gregory Faris and Christopher Comstock
SRI International and University of California, San Diego

Early Breast Cancer Detection Using 3D Ultrasound Tomography
Edward Nelson
University of California, Irvine

Factors Influencing Breast Cancer Screening Among Older Thai
Bulaporn Natipagon-Shah and Mary Jo Clark
Thai Health and Information Service and University of California, San Diego

ID4: A Prognostic Factor of Breast Cancer Metastasis
Dave Hoon
John Wayne Cancer Institute

In Vivo MRS for Cancer Diagnosis and Treatment Monitoring
Hyeon-Man Baek
University of California, Irvine

Inhibition of the BRCA2-RAD51 Interaction in Breast Cancer
Jiewen Zhu
University of California, Irvine

Inhibition of Brain Metastases in Breast Cancer
Brunhilde Felding-Habermann
Scripps Research Institute

Inhibition of Breast Cancer Aggressiveness by Cannabidiol
Sean McAllister
California Pacific Medical Center Research Institute

Intraoperative Assessment of Surgical Lumpectomy Margins
Armando Giuliano
John Wayne Cancer Institute

Molecular Imaging of Breast Cancer Using Breast PET/CT
John Boone
University of California, Davis

Neural Stem Cell Therapy for Breast Cancer Brain Metastases
Brunhilde Felding-Habermann
Scripps Research Institute

New Technology to Enhance PET Imaging of Breast Cancer
Craig Levin
Stanford University

Nur77-derived Peptides as a Novel Breast Cancer Therapy
Xiao-kun Zhang
The Burnham Institute of Medical Research

rADDs: Novel Disintegrins Targeting Breast Cancer
Stephen Swenson
University of Southern California

Real-Time 3D Ultrasound Image-Guidance for Breast Surgery
Michael Bax
Stanford University

Removing Respiratory Artifacts in Nuclide Breast Imaging
Brian Thorndyke
Stanford University

Sulforaphane: Its Potential for Treatment of Breast Cancer
Olga Azarenko
University of California, Santa Barbara

A Targeted Therapy for Wound-like Breast Cancers
Howard Chang
Stanford University

Topoisomerase-IIa as a Predictor of Anthracycline Response
Michael Press
University of Southern California

Vascular Targeting Therapy for Breast Cancer
Albert Deisseroth
Sidney Kimmel Cancer Center

Research Initiated in 2007

Breast Cancer Treatment Monitoring Combining MRI and Optics
Catherine Klifa
University of California, San Francisco

Determinants of Response to Microtubule Stabilizing Drugs
Tatana Spicakova
Stanford University

Early Breast Cancer Detection Using 3D Ultrasound Tomography
Thomas Nelson
University of California, San Diego

Engineering EGFR Antagonists for Breast Tumor Targeting
Jennifer Lahti
Stanford University

Exploring the Role of PARP Inhibitors in Breast Cancer
Karlene Cimprich
Stanford University

Intraductal Therapy of DCIS: a Presurgery Study
Susan Love
Dr. Susan Love Research Foundation

Mechanisms of HSP90 Inhibitor Action in Breast Cancer
Cynthie Wong
Beckman Research Institute of the City of Hope

Modulation of Breast Cancer Stem Cell Response to Radiation
Frank Pajonk
University of California, Los Angeles

Molecular Imaging of Metastatic Lymph Nodes in Breast Cancer
Ella Jones
University of California, San Francisco

Multinuclear MRI of Breast Tumors
Brian Hargreaves
Stanford University

Neural Stem Cell Therapy for Breast Cancer Brain Metastases
Brunhilde Felding-Habermann
Scripps Research Institute

Novel Cytokine Immunotherapy for Breast Cancer
Ananda Goldrath
University of California, San Diego

Polyamide HIF Inhibitors to Block Breast Cancer Metastasis
John Phillips
California Institute of Technology

Symposium on the Intraductal Approach to Breast Cancer
Susan Love
Dr. Susan Love Research Foundation