Detection, Prognosis, and Treatment: Delivering Clinical Solutions

Overview: The .war on cancer. is over 30 years old, yet progress comes slowly despite the many billions of dollars invested. Since President Nixon signed the National Cancer Act into law in 1971, we have seen the emergence of an innovative biotechnology industry, the completion of the human genome project, and Nobel prizes were awarded for the landmark work on (cancer-causing) oncogenes to J. Michael Bishop and Harold Varmus from the University of California, San Francisco. Still, much of this research is awaiting actual translation into human cancer therapy and prevention. Sadly, X-ray mammography, a basic radiology method devised over a century ago, and toxic chemotherapeutic drugs, many in use for decades, remain the frontline weapons in our .war.. Despite the technologies of the .information age., new drug development and clinical testing can take 10-15 years and cost up to $1 billion. A ten-year wait for a new breast cancer .cure. might eventually cost over 50,000 lives in California alone! Fortunately, breast cancer is one disease that has seen the emergence of patient advocates and activists that are willing to ask tough questions to researchers and demand that public research funding seek new avenues for progress.

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.

Funding Data:
 

Proportion of Total

Detection, Prognosis, and Treatment grants awarded in 2004:

5

12%

Funded amount:

$2,185,348

14%

Detection, Prognosis, and Treatment Portfolio Summary:

Two of CBCRP's research topics are represented in this section:

Both of the CBCRP-funded grants in the imaging topic are full Translational Research Collaborations (TRCs) that have a focus on optical imaging. Bruce Tromberg and John Butler at the University of California, Irvine, are teaming with Nola Hylton from the University of California, San Francisco, to expand the clinical potential of previous work by Dr. Tromberg (partially supported by the CBCRP) to develop a non-invasive, optical detection-based Laser Breast Scanner (LBS). In this new project they will find ways to make the functional parameters from optical imaging complementary to high anatomic resolution images derived from the magnetic resonance imaging (MRI) work from Dr. Hylton.s laboratory. In terms of breast cancer prognosis/diagnosis, they will study the impact of menopausal status, hormone replacement therapy (HRT), and neoadjuvant chemotherapy on physiological properties in normal and high risk subjects; and develop Tissue Optical Indices that report on functional parameters related to metabolism, angiogenesis, and cell/matrix density. Dr. Butler is the clinician who will supervise the selection of patient groups and correlation of imaging data with disease parameters. Gregory Faris, a medical physicist at SRI International in Menlo Park, is collaborating with Robyn Birdwell, a clinical radiologist from Stanford University. They are taking an optical (infrared) method, called differential vasoactive optical imaging (DVOI) from animal models of breast cancer to human studies. The DVOI method depends on the metabolic differences in normal breast tissue vs. tumor tissue before and during inhalation of mixtures of oxygen and carbon dioxide. This imaging method works because of (1) tumor blood pooling, and (2) the oxy- and deoxy-hemoglobin-dependant (tumor hypoxia) properties. Besides being non-invasive, the advantages of optical-based detection methods are the low cost and the portability of the basic instrumentation.

Three other funded projects in 2004 are novel treatment strategies. Sylvia Fong at the California Pacific Medical Center Research Institute in San Francisco was awarded a postdoctoral fellowship to study a group of genes, called FKBP, for their potential to alter the angiogenic and metastatic properties of breast cancer cells. The FKBP genes are reduced in expression in aggressive cancers, and Dr. Fong is exploring their connection to metastasis-regulatory genes, such as syndecan-1 and MMP9. In this project the FKBP genes will be surveyed from patient tumor samples. The FKBP genes are good candidates for gene therapy as developed in the lab of Dr. Fong.s mentor, Dr. Robert Debs. Next, Her-2 is recognized as an important oncogene for promoting breast cancer growth, and its presence is a prognostic marker for poor patient survival. However, even after the development of Herceptin® (Trastuzumab) by Genentech, there continues to be much research interest in advancing other therapeutic modalities to treat breast cancer patients with elevated Her-2. Although Herceptin® is a remarkable drug, only about 30 percent of patients eligible for its use will respond well to therapy. Joseph Lustgarten from the Sidney Kimmel Cancer Center is funded to develop a vaccine approach against Her-2 that is based on the use of synthetic peptides from on the Her-2 protein sequence. Using this approach combined with special immune-stimulating .adjuvants., Dr. Lustgarten hopes to avoid the problem of T-cell tolerance, which handicaps many attempts at developing anti-tumor vaccines. Maurizo Pellecchia from The Burnham Institute is funded to study a metabolite of Gossypol, a polyphenol derived from the cottonseed plant used as a male oral contraceptive in China, as a possible new drug to stimulate apoptosis (programmed cell death) in breast cancer. Dr. Pellechia hopes to develop synthetic derivates of Apogossypol that interfere with the biology of the apoptosis inhibitory protein, called Bcl-xl. The goal is to sensitize breast cancer cells to death-inducing stimuli in either a chemopreventive or a therapeutic strategy.

Detection, Prognosis, and Treatment Grants Funded in 2004:

Imaging, Biomarkers, and Molecular Pathology

Differential Optical Mammography
1Gregory Faris, Ph.D. and 2Robyn Birdwell, M.D.
1SRI International and 2Stanford University
Award type: TRC Full
Duration: 3 years
$936,996

Breast Cancer Functional Imaging with Optics and MRI
1Bruce Tromberg, Ph.D., 2Nola Hylton, Ph.D., & 1John Butler, M.D.
1University of California, Irvine, and 2University of California, San Francisco
Award type: TRC Full
Duration: 3 years
$500,000

Innovative Treatment Modalities

FKBP Proteins as Molecular Targets in Breast Cancer Therapy
Sylvia Fong, Ph.D.
California Pacific Medical Center Research Institute
Award type: Postdoctoral fellowship
Duration: 2 years
$89,988

Her-2/Neu Crossreactive Analogs as Targets for Breast Cancer
Joseph Lustgarten, Ph.D.
Sidney Kimmel Cancer Center
Award type: STEP
Duration: 2 years
$372,600

Apogossypol Derivatives for Breast Cancer Therapy
Maurizo Pellecchia, Ph.D.
The Burnham Institute
Award type: STEP
Duration: 2 years
$285,764