Diagnosis and Treatment: Delivering Clinical Solutions

Overview: Early detection does not guarantee a cure. The limitations of mammography require women to undergo unnecessary biopsies and emotional strain. Ultimately patients and physicians have too few options for treatment. New breast cancer-specific and patientindividualized therapies require investigation. The CBCRP encourages lab researchers and clinicians to engage in more cross-disciplinary research projects to link discovery efforts with the clinical issues important to breast cancer.

Two of CBCRP's Priority Issues are represented in this section:

Funding Data:

    Proportion of Total
Diagnosis & Treatment grants awarded in 2003:

11

20%
Funded Amount:

$1,883,348

16%

Diagnosis & Treatment Portfolio Summary:

The past decade has offered many challenges for researchers working in the fields of breast cancer early detection and treatment. Screening mammography has been a success in terms of access with annual screening rates of 70-80%. Despite this, there is debate and uncertainty over the degree of benefit and what technology might replace mammography in the future. The screening mantra of “smaller is better” has reached practical limits. We know that many breast cancers as small as 1-2 mm already have the physiological means to metastasize. Conversely the number of biopsies that turn out to be things other than cancer needs to be reduced to spare women the trauma of a “suspect lesion.” The CBCRP funded two grants in 2003 that address the Earlier Detection priority issue. First, we teamed with the Susan Love MD Breast Cancer Foundation to co-sponsor their 3rd Symposium on the Intraductal Approach to Breast Cancer in Santa Barbara held in March 2003. This symposium brought together more than 120 researchers, scientists, doctors, and advocates from throughout the world, including many from California. The meetings were multidisciplinary, including clinicians, bench scientists, and the lay public. Pilot grants were funded to further support and encourage research on fluids and cells collected from the breast ducts to allow earlier detection and analysis of breast cancer. Next, we funded a dissertation project at the Beckman Laser Institute, University of California, Irvine, to Sean Merritt in Bruce Tromberg's laboratory to explore the potential of combining ultrasound with their pre-clinical development of an infrared, optical imaging of breast cancer. This technology employs a portable, hand-held device that allows tumor detection without radiation or breast compression.

The discovery and development of effective new treatments for breast cancer remains an elusive goal. 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. Indole 3-carbinols (I3C) are compounds derived from certain vegetables (e.g. Brussels spouts) that were initially studied for prevention of cancer cell growth through modulation of the cell cycle, but are now being studied for possible inhibition of cell invasion properties. Christine Brew and her mentor Gary Firestone at the University of California, Berkeley, are funded though separate grants to study I3C's role in regulation of metalloproteinase genes and to identify the cellular target for the I3C derivative DIM, respectively. Ling Jong 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. By understanding the mechanism of action and cellular targets, these natural compounds have the potential to become anti-cancer agents.

There is the concern that widespread use of alternative and complementary therapies might alter the effectiveness of Western medicines. Michael Campbell at the University of California, San Francisco, was awarded an innovative STEP 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. First, Joseph Lustgarten at the Sidney Kimmel Cancer Center is 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 at the University of California, Irvine, received an IDEA (innovative) 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 light focused on the tumor. Dr. Nelson is evaluating whether marrow-derived dendritic cells might work to enhance this therapy. Margaret Huflejt also from the Sidney Kimmel Cancer Center received an IDEA 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.

Peter Vogt from the Scripps Research Institute 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. Finally, Robert Cardiff at the University of California, Davis, received Joining Forces Conference Award to support a special conference on improving animal models in pre-clinical research on breast cancer. Too many drug discovery efforts either fail at the stage of animal studies or yield promising results that do not translate into successful human trials.

Diagnosis & Treatment Grants Funded in 2003:

Earlier Detection Priority Issue

3rd Symposium on the Intraductal Approach to Breast Cancer
Susan Love
Susan Love MD Breast Cancer Foundation
Joining Forces Conference Award
1 year; $25,000

Combined Optical and Ultrasound Imaging for Breast Cancer
Sean Merritt
University of California, Irvine
Dissertation Award
2 years; $58,304

Innovative Treatment Modalities Priority Issue

Inhibition of Breast Cancer Cell Invasion by Natural Indoles
Christine Brew
Postdoctoral Fellowship Award
2 years; $80,000

Chinese Herb/Chemotherapy Interactions in Breast Cancer
Michael Campbell
University of California, San Francisco
STEP Award
2 years; $200,000

Preclinical Trials for Breast Cancer
Robert Cardiff
University of California, Davis
Joining Forces Conference Award
1 year; $25,000

Novel I3C Regulated Cell Cycle Factor in Breast Cancer Cells
Gary Firestone
University of California, Berkeley
STEP Award
2 years; $150,000

Lactulosamines: Novel, Non-toxic Therapies for Breast Cancer
Margaret Huflejt
Sidney Kimmel Cancer Center
IDEA
1 year; $192,600

Dietary Indole Analogs Inhibit Breast Cancer Cell Invasion
Ling Jong
SRI International
STEP Award
2 years; $388,491

Cryptic Peptides-Based Vaccines for Breast Tumor Treatment
Joseph Lustgarten
Sidney Kimmel Cancer Center
STEP Award
2 years; $385,200

Pilot Studies of Breast Cancer Immunophototherapy
Edward Nelson
University of California, Irvine
IDEA
1 year; $99,834

Inhibitors of Myc: Novel Drugs for Breast Cancer
Peter Vogt
Scripps Research Institute
STEP Award
2 years; $278,919