Bryostatins are a unique family of chemicals that occur only in a marine organism called Bugula neritina. Bryostatins have a novel mechanism of action. Most cancer drugs kill any rapidly growing cells in the body. This causes serious side effects. Bryostatins work by affecting signaling pathways that direct a cell¿s behavior. Bryostatins have great promise for the treatment of breast cancer, and bryostatin 1 is currently in Phase II clinical trials for the treatment of several cancers, including breast cancer. Bryostatins inhibit many of the processes that contribute to metastasis of tumors. One exciting application of bryostatins is in combination therapy. Bryostatin 1 increases the susceptibility of cancer cells to other drugs, which could permit greater effectiveness or lower doses. Bryostatin 1 is being studied for adoptive immunotherapy. In this treatment, immune cells are harvested from a tumor after it has been removed. These cells, which are targeted to attack tumor cells, are stimulated to grow by treatment with bryostatin 1. They can then be introduced back into the patient to seek out and destroy tiny metastases before they can be detected. In addition, bryostatin 1 enhances immune cell survival during radiation therapy, potentially enhancing effectiveness of radiation treatment by allowing higher doses while protecting the immune system.

There are 18 bryostatins. Why is only bryostatin 1 sufficiently well studied to be included in clinical trials? Bryostatins have been extraordinarily difficult to investigate due to the lack of supply. Bryostatins are present at very low levels in B. neritina. It is possible that bryostatins other than bryostatin 1 have even greater therapeutic value, but we will require a better method for producing them in order to find out.

We propose to solve this problem using an innovative approach combining marine biology, molecular biology, and natural products chemistry. In the case of many drugs from marine invertebrates, including bryostatins, it is known or suspected that they are made by bacterial symbionts. These bacteria live within the animal. They cause no harm and provide something useful to the host. Probably the chemicals the bacteria make protect the animal from being eaten. If we can grow the bacteria and/or clone the genes that make the drug, we can provide an unlimited supply. The specific goal of this project is to solve the problem of supply of bryostatins by cultivating the bacteria and cloning the genes that make the drug to provide an unlimited supply of bryostatins. It also will allow us to make novel chemicals related to bryostatins that may have improved properties. This project also will develop the methods to do the same thing with many other exciting anticancer drug candidates from marine invertebrates that are currently impractical to develop because the animals are rare or difficult to collect.