Phosphatidylinositol-3-kinases (PI3K) are a family of lipid kinases involved in signaling cascades that play roles in various cell functions, including cell growth, division, and survival. Many human cancers have defects in the regulation of this pathway. While a number of cancer drugs function by inhibiting the activities of molecules involved in the P13K signaling pathway, such as the kinase AKT and mTOR, no inhibitors of PI3K are currently approved as cancer drugs. One such agent is now showing promising results in the clinic. PI3K comes in several isoforms that are expressed in different types of cells.
One isoform, P13K-delta, is produced primarily in immune cells. Calistoga Pharmaceuticals has produced an inhibitor for this particular kinase as a potential drug for treatment of hematologic cancers. The company presented preliminary but dramatic results of phase I trials of the drug, dubbed CAL-101, at the 52nd American Society of Hematology Annual Meeting in Orlando, Florida in December 2010. In a trial of patients with chronic lymphocytic leukemia (CLL) who had received prior therapies and had poor prognoses, CAL-101 treatment reduced tumor size in all 51 patients evaluated. The median progression-free survival exceeded 11 months. Similarly, in 30 patients with indolent non-Hodgkin lymphoma (iNHL) who had also received prior therapies, CAL-101 treatment resulted in a median progression-free survival exceeding 11 months. The drug is also effective in combination with standard therapies. For example, 6 of 6 patients with iNHL treated with CAL-101 plus bendamustine had an objective tumor response, with one patient achieving a complete response. In 7 patients with CLL, both patients receiving CAL-101 plus bendamustine and 3 of the 5 patients receiving CAL-101 plus rituximab had an objective response. The company has now advanced CAL-101 into phase II clinical studies. As a testament to these successes, Gilead Sciences purchased Calistoga Pharmaceuticals in February 2011 for $375 million.