Targeting Class I PI3Ks in the Treatment of T-Cell Acute Lymphoblastic Leukemia

Cancer is the most common cause of nonviolent death for children in the United States. In fact, one in 300 children will be diagnosed with this disease by the age of 20 years, with acute leukemia accounting for the majority of cases. Despite the dramatic improvement in survival of children with leukemia, 10 to 15% will develop an aggressive form known as T cell acute lymphoblastic leukemia (T-ALL), rendering them less responsive to intensive therapies and bone marrow transplantation, underscoring the urgent need to develop more effective anti-leukemic drugs. Sadly, as the total number of new pediatric cancer diagnoses is miniscule compared with the total number of new adult cancer diagnoses, pharmaceutical companies hesitate to invest in cancer treatments for children due to economic reasons and the potentially serious toxic side-effects. Case in point: high expectations were placed on newly developed gamma-secretase inhibitors (GSI) that block a pathway important in the development of T-ALL and possibly the survival of leukemic cells in the body. However, severe gastrointestinal toxicity was reported in clinical trials, limiting its potential use in patients. Thus, if we are to see improved treatment outcomes in T-ALL, industry and academic centers must focus research efforts towards finding new and potentially safer agents specifically for use in children stricken with this deadly disease. By combining the expertise of the Diacovo and Ferrando labs at the Irving Cancer Research Center at Columbia University Medical Center and utilizing their close partnership with Calistoga Pharmaceuticals, this group of investigators is poised to develop a novel and potentially less toxic therapy to treat T-ALL based on selective inhibition of class I phosphoinositide 3-kinase (PI3K), which play a key role in the development, function, and survival of T cells from which T-ALL originates. This therapy would not only benefit children, but also adults as 25% of cases of acute leukemia in this older age group are due to T-ALL.

What is a class I PI3K and how would blocking its activity be beneficial in treating T-ALL?

Class I PI3Ks are a group of proteins found within our cells that permit them to respond to their local environment by generating chemical signals that regulate cell growth, proliferation, and survival. There are 4 family members that have distinct expression patterns and function. PI3Kalpha and PI3Kbeta are found in tissues throughout the body, play a key role in glucose metabolism, and are critical for the growth and development of the mammalian embryo. PI3Kgamma and PI3Kdelta, on the other hand, are expressed mainly in white blood cells (WBC) where they regulate the ability of these cells to participate in an immune response. They are not known to be important in mammalian development nor play a significant role in glucose metabolism, which would make them an ideal drug target. Relevant to this proposal is the observation by this group of investigators that the combined activities of PI3Kgamma and PI3delta are essential for T cell development and survival as evidenced by the dramatic reduction in T cell numbers in the circulation of mice lacking these proteins due to increased cell death. Importantly, other than the expected defect in immune function, there is no reduction in life span, no known development abnormalities in vital organs, or perturbation in blood glucose levels in mice lacking these particular PI3Ks. Based on these observations, we asked whether PI3Kgamma/delta deficiency would protect animals from developing T-ALL typically caused by genetic abnormalities in proteins that regulate gene expression (i.e. NOTCH1) or the activity of PI3Ks (i.e. PTEN). Indeed, this was the case as absence of PI3Kgamma and PI3Kdelta dramatically slowed or prevented the development of the disease.

Can one actually develop a drug that inhibits the activity or both PI3Kgamma and PI3Kdelta , and will it in work in humans with T-ALL?

Based on the above observations, we have now begun work with our colleagues at Calistoga Pharmaceuticals to development a drug that can block the function of both PI3Kgamma and PI3Kdelta (CAL-130). In fact, treatment of human T-ALL cells with this dual inhibitor significantly reduced their survival. Importantly, this drug has no observable toxicity when administered at high concentrations to animals, and it does not block the activity of other important cellular pathways critical to our survival. Thus, we believe the work outlined in this proposal will not only improve our understanding of the mechanisms that contribute to the development and maintenance of T-ALL, but will also lead to a less toxic strategy to treat the disease. We also anticipate within the next 3 to 5 years that it should be feasible to begin a Phase I Clinical Trial if we continue to demonstrate drug efficacy. Funding of this proposal will allow us to achieve this goal and hopefully save the lives of children, our most precious resource.