Liver cancer, primarily hepatocellular carcinoma (HCC), accounts for ~662,000 deaths each year and is the third leading cause of death from cancer worldwide. The age-adjusted incidence of HCC tripled between 1975 and 2005 in the US, and primary liver cancer mortality rates have increased faster than mortality for any other tumor type. One- and 3-year survival rates were 36% and 17%, respectively, in the Surveillance, Epidemiology and End Results (SEER) registries from 1998 to 2000. HCC is treated by aggressive surgery, liver transplantation, radiation, chemoembolization or chemotherapy. Only one drug (Nexavar/sorafenib) is approved for HCC and this extends life by a modest 4 months. The introduction of new and efficacious therapeutic options is critical for effective management of this disease, particularly in cases where tumor has spread to secondary sites. NovaTarg has established a novel approach to HCC treatment in which biguanides are designed to utilize transporters (OCT1 and OCT3) expressed on hepatocytes. These biguanides are selectively taken up by HCC cells where they activate AMPK and regulate cell growth and energy utilization. It is well established that the LKB1-AMPK pathway plays an important role in tumor suppression; inhibiting both cell proliferation and protein synthesis by regulating the actions of p53, mTOR, p27 and cyclin D1. Metformin, a biguanide known to activate AMPK, has been shown to prevent development of HCC in diabetes patients and to display antitumor activity in vitro and in vivo in tumor models. Importantly, metformin is synergistic with chemotherapy, radiation therapy and is active against cancer stem cells. NovaTarg is improving biguanide potency and targeting them to liver cells for the treatment of HCC. NovaTarg biguanides are derivatives of metformin which are more potent, transporter specific and focused on liver cancer cells. For example an early lead compound, NT1014, potently activates AMPK in liver (OCT1) cells, is ~12x more potent at inhibiting growth of Huh7 cells as compared with metformin and is a promising lead compound that NovaTarg is will optimize to create a drug candidate in this Phase 1 project. Using detailed SAR analysis to inform the design of next generation compounds we will, over a 12 month period, prepare new molecules that both deliver the desired pharmacological profile to HCC cells, as well as building in the physicochemical properties required in a drug molecule. Compounds that meet our selection criteria will be subjected to pharmacokinetic analysis and in vivo evaluation in mouse xenograft models of HCC in order to identify a drug candidate that we will be progressed to drug development in a Phase 2 application. It is worth noting that biguanides, such as metformin, fall into a known drug class which has demonstrated good drug molecule properties and safety in human subjects.
Public Health Relevance Statement:
Public Health Relevance: Hepatocellular carcinoma (HCC) accounts for ~662,000 deaths each year and is the third leading cause of death from cancer worldwide; primary liver cancer mortality rates have increased faster than mortality for any other cancer over the past decade and no effective therapies are available to treat disseminated disease. NovaTarg has discovered a series of liver selective AMPK activators that target HCC cell growth with the potential to provide a new therapeutic approach in an area of serious unmet medical need. In this Phase1 application we plan to identify a drug candidate that will be progressed to drug development.
Project Terms:
Accounting; Adverse effects; Affinity; Age; Animal Model; Area; base; BAY 54-9085; Biguanides; cancer cell; Cancer Etiology; Cancer stem cell; cancer therapy; Cause of Death; cell growth; Cell model; Cell Proliferation; Cells; Cessation of life; Chemistry; Chemoembolization; chemotherapy; Clinical Research; commercialization; Cyclin D1; design; Development; Diabetes Mellitus; diabetic patient; Disease; Disease Management; Dose; drug candidate; drug development; Drug Formulations; Drug Kinetics; effective therapy; Effectiveness; Evaluation; Excretory function; falls; Family; Goals; Growth; Hepatocyte; human FRAP1 protein; human subject; improved; in vitro activity; in vivo; Incidence; innovation; Insulin; Kidney; Lactic Acidosis; Lead; Life; Liver; liver transplantation; Malignant Epithelial Cell; Malignant neoplasm of liver; Malignant Neoplasms; Measures; Medical; Medical Surveillance; meetings; Metabolic Clearance Rate; Metabolism; Metformin; Modeling; Mortality Vital Statistics; mouse model; Mus; neoplastic cell; Nexavar; next generation; Non-Insulin-Dependent Diabetes Mellitus; novel; novel strategies; novel therapeutic intervention; Odds Ratio; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; POU2F1 gene; POU2F2 gene; preclinical study; Preclinical Testing; prevent; Primary carcinoma of the liver cells; Procedures; Property; protective effect; Protein Biosynthesis; public health relevance; Radiation; Radiation therapy; Rattus; Registries; Reporting; Resected; Risk; Role; Safety; Secondary to; Selection Criteria; Series; Site; STK11 gene; Sulfonylurea Compounds; Survival Rate; System; Therapeutic; tumor; tumor growth; Tumor Suppression; Work; Xenograft Model; Xenograft procedure
