Oncology Diagnostics

The main focus of the diaDexus oncology diagnostics program is to develop markers that are elevated in early stage disease when cancer is most likely to be curable. By targeting markers that circulate in the blood stream, diaDexus is developing simple blood tests that can be used by physicians in routine exams to improve the detection and diagnosis of cancer. The diaDexus program is targeting markers that demonstrate a high level of specificity, showing minimal elevation in healthy normals, or patients with benign disease in order to mitigate the issue of false positives that often plague other cancer biomarkers. We have used our large portfolio of proprietary genes that are over-expressed in cancer to develop cancer biomarkers that can detect cancers in the earliest stages of the disease. Currently, we have developed 6 proprietary blood based cancer biomarkers that are being evaluated in 3 cancer programs (ovarian, colorectal and breast). Scientific descriptions of the biomarkers are described below.

diaDexus Oncology Biomarkers

B7-H4 (DD-O110)
For Ovarian Cancer

• Known in the literature as B7-H4, this protein is a new member of B7 family of proteins that are thought to be a negative regulator of T-cell response

Spondin-2 (DD-P108)
For Ovarian and Colorectal Cancer

• Known in the literature as Spondin-2, this protein is a member of secreted F-Spondin superfamily that is thought to be an extracellular matrix protein

DcR3 (DD-C248)
For Ovarian and Colorectal Cancer

• Known in the literature as DcR3 (Decoy Receptor 3), this protein is a secreted form of the TNFR family which blocks FasL-induced cell death

MIC-1 (DD-X065)
For Ovarian, Colorectal and Breast Cancer

• Known in the literature as MIC-1, this protein is macrophage inhibitory cytokine that is a member of divergent transforming growth factor-beta (TGF-β) family

Reg IV (DD-C101)
For Colorectal Cancer

• Known in the literature as Reg IV, this protein is a calcium-dependent member of regenerating gene superfamily that is thought to be involved in tissue regeneration.

TRAIL-R2
For Colorectal Cancer

• TRAIL-R2 (DR5, Death Receptor 5) is a death domain-containing transmembrane receptor for TRAIL ligand.

Clinical Application of diaDexus Diagnostics in Ovarian Cancer
To date, diaDexus has shown that 4 of the biomarkers, B7-H4, Spondin-2, DcR3 and MIC-1, are promising ovarian cancer markers. These markers have been validated in a number of independent studies including collaborative studies with Johns Hopkins, Fred Hutchinson Cancer Research Center and Mount Sinai Hospital. In one study conducted with over 2500 blood samples, diaDexus’ lead ovarian cancer biomarker, B7-H4, was shown to be significantly elevated in serum samples from ovarian cancer patients when compared to normal controls. Furthermore, the elevation of B7-H4 in early stage ovarian cancer was able to complement the traditional CA-125 test, thus, increasing the overall sensitivity of early stage ovarian cancer detection (Simon et al. 2006, Cancer Research 66:1570-1575). The elevation of B7-H4 in early stage ovarian cancer was confirmed in a separate study where B7-H4 elevation was observed in 47% of the early stage ovarian cancer tissue lysates compared to 31% observed CA-125 in the same population. In addition, another study demonstrated differential elevation in patients with ovarian cancer versus those with benign gynecological disease or healthy women. These data again suggest that B7-H4 is an important ovarian marker that may be useful in early detection of ovarian cancer, especially in combination with traditional diagnostic modalities such as CA-125 and TVUS.

In addition to B7-H4, the three other biomarkers, Spondin-2, DcR3 and MIC-1, were also shown to be elevated in ovarian cancer serum samples when compared to normal and benign controls. Currently, these 4 markers are being evaluated in multiple clinical studies to evaluate their utility in early stage ovarian cancer, and preclinical ovarian cancer samples.

Clinical Application of diaDexus Diagnostics in Colorectal Cancer
Four of the diaDexus serum biomarkers, Spondin-2, DcR3, TRAIL-R2 and Reg IV, have been evaluated in a study in collaboration with the Mayo Clinic. The four diaDexus markers were evaluated in 600 serum samples consisting of normal controls, colorectal cancer and benign colon diseases. Data showed that all four markers were elevated in colorectal cancer compared to the normal controls and benign disease, and all four markers had better sensitivity and specificity than the traditional CEA blood test. In a separate study, MIC-1 was also shown to be significantly elevated in colorectal cancer serum samples when compared to healthy controls. These 5 biomarkers are currently being evaluated as a panel with other biomarkers and diagnostic modalities to improve the detection rate of early stage colorectal cancer.

Clinical Application of diaDexus Diagnostics in Breast Cancer
diaDexus breast cancer diagnostics program is at an early stage of development where we are currently evaluating a large pipeline of potential biomarkers for identifying early stage breast cancer. Data from these studies indicate that a number of diadexus blood-based markers are elevated in breast cancer patients when compared to normal controls. Additional studies are ongoing to confirm these results. Ultimately, our goal is to develop a panel of proprietary biomarkers that can we use to detect breast cancer at an early stage via a simple blood test.