John Isaacs in an overview this month in BJU of “New strategies for the medical treatment of prostate cancer” brings up:

novel treatments that target prostate-specific antigen (PSA), human glandular kallikrein-2, or prostate-specific membrane antigen. An inactive prodrug with a thapsigargin analogue, a sesquiterpene lactone from the plant Thapsia garganica, is currently under investigation specifically for the targeted therapy of HRPC. Preclinical data suggest the PSA-targeting abilities of this novel therapy are associated with a nearly complete cessation of tumour growth with minimal toxicity.

When a researcher offers this kind of review you can guess it is a pet project. In this case Isaacs ostensibly talks about all available strategies for treating HRPC, but then he zones in on one rather obscure-sounding novel therapy.

John Isaacs has been working with thapsigarin since the 1990s, with the aim of using it to pump excess calcium out of prostate cancer cells and so push the cells into apoptosis. The trouble is, calcium is used by the rest of the body. He and his team had to find a way to target prostate cancer and leave the rest of thebody alone.

What is thapsigargin? Thapsia garganica is a North African and Mediterranean plant, which, although poisonous, was widely used in medicine and as a contraceptive. Some herbalists identify the resin with Siliphion, the most popular contraceptive in the ancient world, though a stronger candidate for that is giant fennel.

Just recently, it appears, the thapsigargins have begun to be synthesized. Researchers at Cambridge University and Danish University of Pharmaceutical Sciences write:

The therapeutic effects of the thapsigargins are well described in that they are recognized as potent histamine liberators and selective and irreversible inhibitors of sarcoendoplasmic reticulum Ca2+ ATPase (SERCA)-dependent pumps at subnanomolar concentrations. Thapsigargin itself penetrates intact cells and binds the SERCA into a conformation that has poor affinity for both Ca2+ and ATP. As such, they have become powerful tools in the study of Ca2+ signaling pathways. In recent times they have been shown to restore apoptotic function in cancer lines … and consequently have been developed as potential treatments for prostate cancer. This approach utilizes a prodrug conjugate that is cleaved and activated by prostate-specific antigen (PSA) . This antigen is an enzyme, the normal function of which causes the breakdown of seminal gel proteins; however, increased levels of PSA are used as a specific diagnostic for prostate cancer. There is also evidence that PSA plays an important part in tumor cell growth and their later metastasis, and consequently they have become targets for potential antitumor drugs .

Most of their references in the above are to John Isaacs work, some of which he did with these same Danish chemists — including their joint publication Prostate-Specific Antigen-Activated Thapsigargin Prodrug as Targeted Therapy for Prostate Cancer (JNCI, 2003).

What they have done is couple a chemically modified form of thapsigargin, L12ADT, “to a peptide carrier that is a substrate for the prostate-specific antigen (PSA) protease to produce a soluble, cell-impermeant latent prodrug that is specifically activated extracellularly within metastatic prostate cancer sites by PSA.”

Investors are already flapping about it. Bioportfolio in a piece titled Prostate cancer specific derivatives of thapsigargin
says:

Given the slow rate of proliferation of prostate cancer cells, the identification of apoptotic drugs remains one of the highest priorities for the treatment of prostate cancer. Despite considerable efforts few apoptotic candidates have progressed through to advanced stages of development. One particularly exciting target for apoptosis is the calcium signaling pathway, in particular store-operated calcium channels (SOCs) which are responsible for maintaining calcium levels in intracellular organelles. Restricted prostatic expression of the novel SOCs-related protein CaT1 has been demonstrated and linked to tumor progression. Strong evidence exist to suggest that inhibitors of CaT1 may induce apoptosis in a wide range of prostate cancer phenotypes; reduce the development of androgen-independence; and have activity in androgen-resistant cells (Click here for an overview of this target). Although blocking SOCs offers one approach to depleting intracellular calcium, this end-point can also be achieved through the use of thapsigargin and its derivatives which target intracellular stores directly to induce apoptosis in prostate cancer cells. Thapsigargin is not however selective to the prostate and to avoid the risk of side-effects, Danish researchers in collaboration with Johns Hopkins Oncology Center have developed a series of inactive Thapsigargin prodrugs that can be activated by PSA. The prodrugs thus synthesized demonstrated prostate cancer specificity suggesting that they may represent novel therapeutic candidates for this disease.