EXECUTIVE SUMMARY

Biomarkers for Breast Cancer

SUMMARY:  Dr. Kiran Madura in the Department of Biochemistry at the University of Medicine & Dentistry of New Jersey (UMDNJ) has identified several protein biomarkers in tumor tissue of patients with breast cancer.  The expression levels of these proteins are strongly correlated with the incidence of breast cancer.  Because the levels of multiple proteins can be simultaneously examined, the veracity of the readout is correspondingly strengthened.  Studies are underway in collaboration with a clinical oncologist to compare blood and tissue obtained from breast cancer patients to determine whether the same biomarkers can be detected in blood.  Siuta Consulting has been retained by UMDNJ to identify potential partners for these biomarkers that have potential application: (1) for the early diagnosis of breast cancer; (2) to discriminate between different types and stages of breast cancer; and (3) for monitoring breast cancer patients who are undergoing therapy.

BACKGROUND:  The current methods for early detection of breast cancer include self-examination and routine mammography.  However, a typical-self examination is imprecise and normally reveals a growth of approximately one inch.  While a mammogram can reveal smaller masses, it is considered to be an invasive method.  Because early detection is critical for improving the prognosis for the patient, the availability of diagnostic methods that can identify abnormal growth at an early stage and distinguish between cancer and non-malignant growth is crucial.  The two methods that are currently available are based on the polymerase chain reaction (PCR).  One of these can identify mutations in the BRCA1 gene present in familial forms of breast cancer which affects 5% of patients.  The second method measures expression levels of the Her2 gene which is indicative of increased potential for developing breast cancer but is only representative of a minor fraction of patients.  Since most breast cancers occur spontaneously without a genetic/familial origin, a proteomic method that can reveal altered expression of specific proteins, rather than genetic alterations would be more desirable. 

TECHNOLOGY:  Dr. Madura's laboratory has examined the mechanistic aspects of the ubiquitin/proteasome pathway (UPP) of protein degradation.  This pathway plays a central role in regulating normal growth of all mammalian cells.  Defects in this pathway have been implicated in a variety of abnormal cellular conditions, including most cancers and neurodegenerative diseases.  Discoveries previously reported from Dr. Madura's laboratory have shown that a number of components of this pathway are expressed at high levels in breast cancer. 

It is envisioned that the identification of specific biomarkers of the UPP in breast and other cancers will fill an unmet need in the medical diagnostics field.  In particular, the development of a high-sensitivity assay for early detection of breast cancer, before the appearance of clinical symptoms, is considered of extremely high value.  The broad applicability of this methodology, which can specifically interrogate the UPP system, is not only novel and targeted, but highly likely to yield informative biomarkers because most, if not all, key regulatory factors in the cell are degraded by this proteolytic system.

Dr. Madura has created a start-up company, CellXplore, to validate these biomarkers.  While previous studies showed that ~ 93% of primary breast cancer tissue specimens contained elevated levels of the specific biomarkers, ongoing studies will determine if the same biomarkers can be detected in the blood.  Studies are underway in collaboration with a clinical oncologist to compare blood and tissue obtained from breast cancer patients.  Tissue collection involving almost 1,000 patients is in place and it is likely that the biomarker analysis can be refined to determine the stage of breast cancer as well as determine its cellular origin.  Moreover, the efficacy of treatment will be monitored (before and after treatment), to determine if the levels of the biomarkers are altered.  This assay would provide one of the first direct biochemical readouts on clinical effectiveness of chemotherapy and radiation therapy.  Based on the outcome of this analysis, CellXplore will further fractionate blood cells to identify the cellular fractions that provide the most sensitive biomarker detection assay.  Current assays in the laboratory have been sufficiently refined to detect UPP function in as few as ten lymphocytes.

A second phase of inquiry will examine other cancers such as melanoma, colon, esophageal and leukemia.  Preliminary studies of melanoma patients using primary tissues have been very promising. 

PUBLICATIONS:  Details of this research can be found in the following publication:

L. Chen and K. Madura, Increased Proteasome Activity, Ubiquitin-Conjugating Enzymes, and eEF1A Translation Factor Detected in Breast Cancer Tissue, Cancer Res., 65 (13), 5599-5606 (2005).

PATENT STATUS:  United States and PCT applications have been filed.

LICENSE TERMS:  UMDNJ and CellXplore are seeking partners to collaborate on the further development of these biomarkers.