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Biomarkers for risk assessment in colorectal cancer patients

Technology
We have developed an ELISA-based immunoassay that measures the levels of two proteins in the blood, Mortalin/GRP75 and HSP70, identifying colorectal cancer patients at high risk of poor survival.
Mortalin/GRP75, is a ubiquitous mitochondrial chaperone related to the cytosolic heat shock protein 70 (HSP70). We have conducted a clinical trial, collecting and analyzing blood samples from 175 colorectal cancer patients. We demonstrated, for the first time, the presence of circulating mortalin in blood of cancer patients. We have found that circulating Mortalin and extracellular soluble HSP70 (sHSP70) are independent risk factors for poor survival of the patients. Taken together, analysis of these two biomarkers provides a highly significant prognostic value to identify colorectal cancer patients at high risk of poor survival.
Experiment highlights:

  • Cox regression analysis indicated that high mortalin (>60ng/ml) is a risk factor for poor survival. 
  • Serum levels of sHSP70 and mortalin in patients were independent variables. 
  • Concurrence of high sHSP70 and mortalin was associated with rapid disease progression (HR=4, 2.04-8.45, P<0.001). Addition of high sHSP70 and mortalin to a baseline model of age, sex and TNM stage, significantly (P<0.001) enhanced the risk score to 8 (3.26-20.46). 
  • Increased risk was demonstrated in the different disease stages (unpublished data).
  • Patients with high levels of both biomarkers showed a significantly lower (16.7%) 5-year survival then patients with low levels of both biomarkers (69.6%).

The Need
Colorectal cancer is the third most common cancer in men (746,000 cases, 10.0% of the total) and the second in women (614,000 cases, 9.2% of the total) worldwide. The American Cancer Society estimates that 136,830 people will be diagnosed in 2014 and that 50,310 will die from colon cancer in the United States.
Mortality rates for colorectal cancer have declined in both men and women over the past two decades. These decreases reflect declining incidence rates and improvements in early detection and treatment.
A key challenge in the clinical management of newly diagnosed colorectal cancer patients is the choice of correct treatment. With the growing availability of treatment options and protocols, the correct determination of the patient’s prognosis is key in selecting the proper adjuvant therapy following surgery. With the limited data available today, many patients are subjected to unnecessary aggressive and expensive treatments, while others are under treated, increasing their risk of poor survival.
The technology we have developed may provide critical information for correctly selecting the personalized medicine for these patients.

Potential Application
An In-Vitro Diagnostic (IVD) kit that measures the levels of circulating mortalin and HSP70 biomarkers in blood samples, identifying colorectal cancer patients at high risk of poor survival.
Stage of Development
The ELISA tests have been developed and used to provide proof-of-principle clinical findings, calibrating risk cut-off for each biomarker.
A blinded validation clinical trial is underway, aimed at analyzing the levels of both biomarkers in an independent set of ~240 colorectal cancer patients.

Patents
PCT patent application PCT/IL2013/050817 filed in October 2013
Supporting Publications
Perri Rozenberg, Judit Kocsis,  Moran Saar, Zoltán Prohászka, George Füst and Zvi Fishelson, Elevated levels of mitochondrial mortalin and cytosolic HSP70 in blood as risk factors in colorectal cancer patients. Int. J. Cancer 133(2) 514–518 (2013)