Lead Project

The Orion Colorectal Cancer Risk Test is a simple blood test that detects an epigenetic abnormality, the loss of imprinting of the cancer-associated growth gene, IGF2 (“IGF2 Biomarker”). Our test is being developed to identify people at increased risk of developing colorectal cancer (“CRC”) who will benefit from early CRC screening. Screening allows physicians to identify and remove precancerous polyps and prevent future colon cancer. Preclinical studies suggest that individuals who are positive by our test may also benefit from treatment with a novel class of drugs in development.1 When clinical trials are completed, we will market the Orion CRC Risk Test to the 81.6 million people in their 20’s and 30’s in the United States and to the primary care physicians who treat them.

Clinical Need - Colorectal Cancer in the United States

CRC is the third most common cancer with 142,000 new cases in 2013 2
CRC is the second most deadly cancer resulting in 50,000 deaths in 2013 2
61% of CRC cases are first detected after the disease has spread 2
One in three patients with the disease will not survive the next 5 years 2
No test exists to identify people at risk for sporadic CRC, the most common form of the disease

Clinical Impact of Our Test

Between 65% and 85% of all colorectal cancer cases are sporadic (non-heritable) and occur in people who are not being aggressively screened and who are classified as having an average risk of developing colorectal cancer according to the existing stratification criteria.3 Currently, risk tests on the market today are only able to identify people at risk of developing rare hereditary colorectal cancer syndromes, which are responsible for only 1-3% of all CRC cases. We are developing the Orion CRC Risk Test to help physicians identify patients who are at risk of developing sporadic CRC. Orion has a worldwide exclusive license to a broad estate of issued and pending patents covering imprinting abnormalities of the insulin-like growth factor II gene (“IGF2”) from The Johns Hopkins University School of Medicine.

The IGF2 Biomarker and Colorectal Cancer

40% of colon tumors have loss of imprinting of IGF2 (the IGF2 Biomarker) 4-7
CRC patients are 21 times more likely to carry the IGF2 Biomarker in their blood 8
CRC and adenoma patients are 5 times more likely to carry the IGF2 Biomarker 8, 9
7-10% of the population carry the IGF2 Biomarker in their blood 8, 10, 11
A large prospective study is underway of the Prostate, Lung, Colorectal and Ovarian Trial
Over 80 publications on the role of the IGF2 Biomarker in cancer 12 since its discovery in 1993 13
IGF2 Biomarker has been associated with more than 20 different cancer types 12

Adapted from Falls, et al AJP 154, 635-647 (1999)

List of Cancer Types Demonstrating Loss of Imprinting of IGF2

Childhood CancersAdult Cancers
Novartis Molecular Diagnostics Bladder Chronic Myelogenous Leukemia
Rhabdomyosarcoma Breast Esophageal
Ewing’s Sarcoma Cervical Lung
Hepatoblastoma Choriocarcinoma Medulloblastoma
Wilms’ Tumor Colorectal Mesothelioma
Gastric Adenocarcinoma Ovarian
Glioma Prostate
Hepatocellular Renal Cell Carcinoma
Acute Myelogenous Leukemia Testicular Germ Cell

What is Loss of Imprinting?

Genomic imprinting is a rare but important mechanism of gene regulation where one copy of the gene (an “allele”) is normally expressed and the other allele is silenced through epigenetic marks of parental origin.14 For example, the imprinting of a gene can be maternal, resulting in the expression of the paternal allele and silencing of the maternal allele. IGF2 is normally imprinted in human tissues. In 1993, scientists at the Johns Hopkins University School of Medicine discovered that normally imprinted genes including IGF2 can “lose their imprint” resulting in the expression of both copies of the gene, and this can lead to human disease.13 IGF2 is a growth promoting gene, and evidence is mounting that individuals whose peripheral blood leukocytes (“PBL”) exhibit loss of imprinting of IGF2 (the IGF2 Biomarker) may be at elevated risk for developing colorectal cancer.8, 9

  1. Kaneda A, et al. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. PNAS 104, 20926-31 (2007).
  2. American Cancer Society. Cancer Facts & Figures 2007. Atlanta: American Cancer Society: 2007.
  3. Burt RW. Colon Cancer Screening. Gastroenterology 119(3):837-53 (2000).
  4. Kinochi Y, et al. Relaxation of imprinting of the insulin-like growth factor II gene in colorectal cancer. Cancer Letters 107, 105-108 (1996).
  5. Cui H, et al. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nature Medicine 4-11, 1276-1280 (1998).
  6. Nishihara S, et al. Multipoint imprinting analysis in sporadic colorectal cancers with and without microsatellite instability. Int. Jour. Oncol. 17, 317-322 (2000).
  7. Nakagawa H, et al. Loss of imprinting of the insulin growth-like factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. PNAS 98-2, 591-596 (2001).
  8. Cui H, et al. Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk. Science 299, 1753 (2003).
  9. Woodson K, et al. Loss of Insulin-Like Growth Factor Imprinting and the Presence of Screen Detected Colorectal Adenomas in Women. JNCI 96-5, 407-410 (2004).
  10. Sakatani, et al. Epigenetic Heterogeneity at Imprinted Loci in Normal Populations. Bioch. and Biophys. Res. Comm. 283, 1124-1130 (2001).
  11. Vorwerk, et al. Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia. Leuk Res. 27(9):807-12 (2003).Falls, et al. Genomic Imprinting: Implications for Human Disease. AJP 154, 635-647 (1999).
  12. Rainier S, et al. Relaxation of imprinted genes in human cancer. Nature 362, 747-749 (1993).
  13. Barlow DP. Gametic imprinting in mammals. Science 270, 1610-1613 (1995).