Innovation: Therapeutics—small-molecule inhibitors of a specific cancer-promoting protein
Targeted Cancer(s): Liver cancer
Scientific Leadership: Paul. B. Fisher, M.Ph., Ph.D.; Webster Cavenee, Ph.D.
Stage of Project: Matching fund application in progress


PDZ1i is a proprietary small-molecule that is an effective inhibitor of the ultimate and most lethal stage of cancer progression: metastasis. This novel drug candidate binds specifically to the PDZ1 domain of the pro-metastatic gene MDA-9/Syntenin, blocking essential protein-protein interactions regulating critical cancer signaling properties. Based on the relevance of MDA-9/Syntenin to cancer development, metastasis and patient-survival, as well as the broad-spectrum anti-cancer activity of PDZ1i, bringing this lead agent into the clinic carries potentially profound implications for patients.

In animal and other laboratory studies, PDZ1i has shown profound anti-invasive and anti-metastatic activity in multiple cancers, including melanoma, glioblastoma, neuroblastoma and carcinomas of the breast, liver, lung, pancreas and prostate. PDZ1i inhibits retention of tumor cells in the lungs, restricts lung metastasis formation, suppresses breast and prostate metastases, blocks metastatic cancer cell attachment and dissemination and inhibits invasion, thereby prolonging survival following xenograft implantation into nude mice. Additionally, when combined with other modes of therapy, including chemotherapy, radiotherapy and immunotherapy, therapeutic outcomes are significantly enhanced.

Unmet Medical Need

  • It is estimated that nearly 90% of patients with advanced cancers die as a result of complications associated with tumor cell invasion into normal tissue and metastatic spread from primary tumor sites to secondary locations in the body, including lung, liver, bone, brain and other organs.
  • Hepatocellular carcinoma (HCC), the first disease to be targeted, is the most common form of liver cancer in adults.
  • Liver cancer has more than tripled since 1980, and its death rates have increased by almost 3% per year since 2000. The 5-year relative survival rate for HCC and intrahepatic bile duct cancer is 31% for localized disease, 11% for regional disease and 2% for distant disease.


  • By targeting mechanisms of motility that lead to disease spread, synergizing with two standard-of-care HCC therapies (radiation and sorafenib, a drug approved by the U.S. Food and Drug Administration (FDA)) and inhibiting tumor angiogenesis, PDZ1i has promise to significantly improve survival.
  • Since PDZ1i also modulates the cancer “stemness” and stem cell survival, responses of patients would also be expected to be durable.
  • Small-molecule drugs offer significant advantages in terms of use and cost improvements over cell-therapy based disease approaches.

Asset Profile & Development Plan

  • Potency and Duration of Action: Potential anti-cancer and anti-metastatic effects of PDZ1i in several animal models, as well as a favorable half-life (the rate at which the molecule is eliminated from the body), support using daily or weekly dosing in humans
  • Proof of Concept: PDZ1i is efficacious in multiple metastatic cancer models, including liver: In animal studies, it has been shown to prevent metastatic spread of cancers after surgery and, when in combination with sorafenib, has been shown to display profound activity against liver cancer in models containing human HCC xenotransplants
  • Safety and Tolerability: No remarkable safety concerns for PDZ1i in studies of absorption, distribution, metabolism, and excretion (ADME), genotoxicity or safety pharmacology; the drug candidate exhibits an extended half-life (over 10 hours) in mice and greater than 90% bioavailability; synthesis of the molecule is well established and its formulation is standard
  • Intellectual Property: Exclusive licenses of a full portfolio around PDZ1i (along with MDA-9/Syntenin) patents are held, and additional applications are underway
  • Clinical Development Plan: Investigational New Drug-enabling toxicology design has been discussed and awaits funding before submitting application to the FDA