Antiproliferative Activity of Microsclerodermins

Application

Microsclerodermins are cyclic peptides derived from marine sponges, which can inhibit cancer cell growth and growth of cells caused by autoimmune and inflammatory diseases.

Problem

In the US, cancer is responsible for 25% of all deaths. Death from cancer is primarily due to overgrowth and metastasis of cancer cells to other organs followed by secondary tumor formation throughout the body. Despite improved treatment options, cancer remains a devastating illness. Anticancer drugs directed against the microtubule, including taxanes and vinca alkaloids, have been the backbone of many chemotherapy regimes for decades. However, these drugs have significant limitations to improving patient treatment response including hypersensitivity reactions, neurotoxicity, and the emergence of drug resistance, which have prompted the need for novel microtubule targeting agents. Ideally, novel agents would bind with enhanced tumor specificity, be insensitive to chemoresistance, and reduce neurotoxicity.

Technology

The inventors have isolated a new class of naturally occurring microsclerodermins from marine sponges of the Lithistid (Theonella, Microscleroderma, and Amphibleptula genera) and Pachastrellidae families. These cyclic peptides posses unusual amino acids, which can inhibit cancer cell growth (microsclerodermin F) as well as unwanted cell growth related to autoimmune disorders and inflammation. Specifically, they may inhibit growth of tumors in the breast, colon, CNS, liver, lung, as well as leukemia or melanoma cells. They may also be active against ovarian, uterine, renal, pancreatic, and prostate cancer. These compound block mitosis of tumor cell lines and have a number of cellular effects including disruption of the tubulin matrix. They can be readily modified into analogs, derivatives, and salts under a variety of reaction conditions.

Competitive Advantage

Lithistida sponges produce a diverse array of structurally complex compounds such as microsclerodermins with potent and unique biological activities. Potentially bioactive molecules isolated from living organisms such as marine life are commonly recognized as being more effective than those obtained through combinatorial synthetic chemistry. With synthetic libraries, there are a limited number of synthetic reactions resulting in a lack of structurally diversity and exploration of the biological space. Marine natural products are often enzymatically engineered and biologically validated and may represent a higher quality product. Recent technical advances in the synthesis of these compounds have furthered their development into promising therapeutic agents. The marine-derived microsclerodermin F technology has potent anti-proliferative activity against tumor cells, as it completely inhibits mitosis at low Ic50 concentrations and shows pronounced changes in normal microtubule arrangement in A549 lung cancer and Hct-116 colon cancer cells. Microsclerodermin F has a highly unusual amino acid sequence and probable unique mechanism of action making it highly useful in the treatment of Taxane or drug-resistant tumors. It also belongs to the class of cyclic peptides, which have immense therapeutic utility due to their intrinsic, enhanced protein binding affinity and metabolic stability.

Opportunity

Many marine-derived compounds such as microslerodermin F were discovered over a decade ago, however their low recovery from sponges limited their development. Recent technical advances in the synthesis of these compounds have furthered their development into promising therapeutic agents. This technology has tremendous applicability, as it can be used to treat a variety of solid tumors and leukemia and also can cross the blood-brain barrier to treat CNS tumors. Similar to other anti-tumor marine-sponge derived compounds, microsclerodermin F can be used individually or in combination with lower doses of other standard chemotherapy regimes. It has multifaceted biologically activity, as it also can inhibit the growth of cells caused by autoimmune and inflammatory diseases. The proliferative nature of the immune response is generally controlled with immunosuppressive drugs. An alternative method of treatment such as microsclerodermin F may allow for cell growth control without the side-effects associated with a compromised immune system. Treating a variety of conditions with one class of compounds represents a huge cost savings in clinical development. Lastly, since microsclerodermins also affectively absorb UV rays, they can be used industrially as ultraviolet screeners in the plastics.

Stage of Development

• Collection of sponge source material
• Isolation of Microsclerodermins by fractionation and chromatography
• Cell culture assays (Ic50 values were obtained)
  • Effect of the compounds on cell proliferation was assessed in A549 lung cancer and P388
    murine leukemia cell lines. * Tumor cell growth inhibition was also assessed in an enriched fraction (AW-21-51.2) containing
    a mixture of four microsclerodermins (15% microsclerodermin F)
• Immunofluorescent detection of microtubule matrix effects in A549 lung cancer cells
• Formulation and dosage administration considerations

Patent Status

A patent has been issued for the Microsclerodermins technology. The inventors at the Harbor Branch Oceanographic Institution in Fort Pierce, Florida are looking for a partner for further development and commercialization of this technology through a license.

Issued: May 7, 2002

U.S. Patent 6,384,187 B1

Researchers

Amy Wright, Ph.D. (UC, Riverside) has been working in the field of Marine Natural Products Chemistry for over 24 years. Her primary research interests focus on the purification and structure identification of naturally occurring compounds, which may have utility in treating cancer. Much of the research focuses on the investigation of deep-sea invertebrates collected using the Johnson-Sea-Link human- occupied submersibles. She has over 150 Peer Reviewed publications. Her past partnerships with large and small biotechs, Sanford Burnham, Moffitt Cancer Center, with funding from NIAID, MIGMS, MCCAM, & NOAA. Through her research, she has access to a vast (5,000+) natural marine compounds library http://dorsrv1.fau.edu/CEBMB/Libraries.aspx. Dr. Shirley Pomponi, Ph.D is Research Professor and Executive Director of the NOAA Cooperative Institute for Ocean Exploration, Research, and Technology at Harbor Branch Oceanographic Institute, Florida Atlantic University, in Fort Pierce, Florida. She received her Ph.D. in Biological Oceanography from the University of Miami. Her research focuses on marine biotechnology, in general, and sponge systematics, cell and molecular biology, in particular. She has authored or co-authored more than 100 peer-reviewed scientific publications and is co-inventor on several patents. a Research Professor at Florida Atlantic University’s Harbor Branch in Marine Biomedical and Biotech Research. Dr. Ross E. Longley, Ph.D. is an Associate Professor of Microbiology and Immunology at Lake Erie College of Osteopathic Medicine in Erie, Pennsylvania. He has authored over 37 peer-reviewed publications. Dr. Richard Isbrucker, Ph.D is a Senior Research Scientist at the Center for Biologics Research Health Canada. He has authored over 15 peer-reviewed publications.

Field

Oncology, drug discovery, natural marine products, immunology