Venture capitalists aren't funding early stage drugs these days. And even if they were, it still wouldn't be for multiple myeloma.

Myeloma, or cancer of the bone marrow, is a comparatively rare cancer, and so its fewer than 50,000 U.S. sufferers face a cruel calculus. For drug developers, it makes more sense to spend limited resources on other indications.

Nevertheless, multiple myeloma patients stand to be among the first to benefit from a new class of anticancer therapy. Semafore Pharmaceuticals plans to enter Phase I trials with its PI3 kinase inhibitor SF1126 for myeloma only a few months after initiating Phase I trials in relapsed solid cancers. The trials "are basically starting at the same time," said Derek Small, Semafore's director of corporate development.

The reason is money again: in this case, a specific grant from the Multiple Myeloma Research Foundation (MMRF). After grants from the Cancer Treatment Research Foundation, and another from the state of Indiana, the MMRF's award in early December marked the receipt of nearly $4 million worth of grants over the past nine months for the Indianapolis-based biotech firm.

Small told BioWorld Today that SF1126 looks like it will be the first PI3 kinase inhibitor with "clear, potent antitumor activity" to enter clinical trials, but it almost certainly won't be the last. In a paper published in December on Science magazine's online Signal Transduction Knowledge Environment, researchers from Harvard University's Dana-Farber Cancer Institute recap the PI3 kinase's history. When they were first discovered, PI3 kinases were widely believed to be a purification artefact, but those days are over. Now, the authors say, "a search for small-molecule inhibitors of PI3K activity is currently a major effort of the pharmaceutical industry."

Small noted, "Everyone in pharma is trying to come up with something."

Semafore's compound, or at least a close relative, has an unusually wide paper trial. Its precursor, LY294002, was originally synthesized by Indianapolis-based Eli Lilly, but was never patented by the company. A Medline search gives nearly 3,500 papers on LY294002.

SF1126 is basically LY294002 conjugated to an RGD peptide that binds to integrins specifically expressed in neovasculature. This means the compound homes to tumor vasculature, where it is cleaved and enters tumor cells.

At the Society of Hematology annual meeting in December, Donald Durden, professor of pediatric oncology and hematology at Atlanta's Emory University who is also the chairman of Semafore's scientific advisory board, presented data on SF1126's effects in multiple myeloma. That included data to show that it appears to be a synergistic relationship with Millennium Pharmaceuticals Inc.'s multiple myeloma drug Velcade (bortezomib).

The core rationale for using SF1126, Durden explained, is that "central nodal intercept points exist to coordinate and control signaling cascades." PI3 kinases and their complementary phosphatase, PTEN, are one such node. PTEN is deleted in many cancers, and because it opposes the cell growth signals that PI3 kinases respond to, the PTEN deletion leads to excessive proliferation. Certain types of PI3 kinases also can be overexpressed in cancer cells, though that is not universal.

Durden told BioWorld Today "Nature has told us that a lot of [cancer] therapies are failing" because of the PI3K/PTEN checkpoint. Resistance to Genentech's breast cancer drug Herceptin (trastuzumab), for example, appears to be due to loss of PTEN.

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