HepTide™ Drug-targeting to the Liver: Hepatocellular Carcinoma
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Hepatocellular carcinoma (HCC), often referred to as primary liver cancer, has a very high incidence and mortality rate, both in the U.S. and worldwide (see sidebar). The incidence of HCC is highest in areas with endemic viral hepatitis, such as Asia and Southern Europe.
In the U.S., cirrhosis of the liver is the 10th most common cause of death in adults and is present in 80% of patients diagnosed with HCC. Both cirrhosis and viral hepatitis are considered major risk factors for developing HCC. Additional important risk factors in the U.S. are smoking and increasingly, obesity.
Learn more about HepTide™:
HepTide™ Targeting Behavior
Drugs currently used to treat primary liver cancer are often toxic to other organs and tissues. We believe that the pharmacokinetic behavior of RAP (i.e., the determination of the fate or disposition of RAP once administered to a living organism) may diminish the non-target toxicity and increase the on-target efficacy of attached therapeutics.
In preclinical studies of our radio-labeled HepTide™ (a variant of RAP), HepTide™, our proprietary drug-targeting peptide, was shown to distribute predominately to the liver. Radio-labeled HepTide™, which was tested in a preclinical research model of HCC, at the National Research Council in Winnipeg, Manitoba, Canada showed 4.5 times more delivery to the liver than the radio-labeled control, which did not include HepTide™ (Isbell, Haslam, Zankel 2007b). Another study of radio-labeled HepTide™ in a non-HCC preclinical model, showed 7 times more delivery to the liver than the non-HepTide™ radio-labeled control, with significantly smaller amounts of radio-labeled HepTide™ delivery to other tissues and organs (Isbell, Haslam, Dennis 2007).
HCC is caused by the malignant transformation of hepatocytes, epithelial cells lining the vascular sinusoids of the liver, or their progenitors. HepTide™ has been shown to bind to lipoprotein receptor-related protein (LRP1) receptors on hepatocytes (Isbell, Haslam, Zankel 2007a). The pharmacokinetics and systemic toxicity of a number of potent anti-tumor agents may be controlled in this way.
There are additional factors that favor the suitability of RAP as an HCC targeting agent:
- RAP is captured efficiently by hepatocytes, primarily on arterial first-pass.
- Late-stage HCC is perfused exclusively by the hepatic artery, while the majority of the liver is primarily perfused through the portal vein.
HepTide™ Conjugates as a Potential Liver Cancer Treatment
Our studies have shown that the RAP receptor, LRP1, is well-expressed on human HCC and underexpressed on non-cancerous, but otherwise diseased, hepatocytes (Isbell, Haslam, Zankel 2007b). Also, high levels of LRP1 expression are maintained on metastasized HCC. These factors will favor delivery of RAP peptide-conjugated anti-tumor agents to tumor cells, whether in the liver or at metastasized sites.
Raptor is evaluating conjugates between HepTide™ and other molecules for testing in vitro and in appropriate preclinical models for the potential treatment of HCC and other liver diseases.
Learn more about Raptor's other preclinical programs:
- NeuroTrans™ for the potential delivery of therapeutics across the blood-brain barrier
- WntTide™ for the potential treatment of breast cancer
Facts about Hepatocellular Carcinoma (HCC)
U.S. (source: National Cancer Institute)
- 20,000 patients diagnosed annually
- 10th most common cause of cancer-related death
Worldwide (source: Schutte K, Bornschein J, Malfertheiner P. Dig Dis 2009:27(2):80-92)
- 1,000,000 patients diagnosed annually
- 5th most common solid tumor
- 3rd most common cause of cancer-related death