Targeting SIRT1 in leukemia stem cells
Cancer stem cells are the root of disease for leukemias and certain solid tumors. Conventional chemotherapy kills the bulk of cancer cells, but fails to eliminate cancer stem cells. These cells will become an important source for disease recurrence. This is best exampled by chronic myelogenous leukemia (CML). CML is a lethal hematological malignancy resulting from transformation of a hematopoietic stem cell by an oncogene called BCR-ABL. The potent BCR-ABL inhibitor Gleevec (imatinib) inhibits its activity, induces remission and prolongs survival of CML patients. However, Gleevec fails to eradicate CML leukemia stem cells (LSC) that persist as a reservoir of disease and potential source of relapse after cessation of imatinib treatment. Patients need continuous treatment to prevent disease relapse with potential risk of side-effects, non-compliance and a high financial burden. Similarly, inability to eliminate LSC contributes to the subsequent disease relapse of acute myelogenous leukemia (AML), and is a major limitation of current treatments for AML. Development of an effective agent to target LSC will be a major advance in leukemia treatment.
SIRT1 is a mammalian protein deacetylase that modifies cellular protein functions by removing an acetyl group from its substrate. SIRT1 is present in many cells, but is over-abundantly present in a variety of human cancer including AML. High levels of SIRT1 promote cancer cells survival under various stress and hostile environmental conditions, such as chemotherapy and radiation therapy. Inhibition of SIRT1 can render cancer cells sensitive to treatments. We found that SIRT1 promotes survival, growth and genetic mutations in LSC of CML and AML. The objective of this proposal is to develop a potent drug to inhibit SIRT1 activity to target and eliminate LSC, and to improve results of clinical treatment of these leukemias. We have already identified certain promising lead compounds that can inhibit functions of this gene. We propose to further optimize these lead compounds into a potent drug targeting SIRT1 for eradicating LSC. We will use computational modeling and biochemical approaches to modify the lead compounds. The modified compounds will be analyzed using functional tests in cells and potency tests in animal models of CML and AML, and by studying the toxicity, safety and pharmacological profiles in animals. Successful completion of these studies will result in development of novel means to target and eliminate LSC resulting in improved treatment outcomes and cures for patients with leukemia.
California has the highest leukemia incidence in the United States, according to Cancer Facts 2010 of American Cancer Society. It is estimated that 4,460 new leukemia cases will be diagnosed in California for year 2010, representing over 10% of new leukemia cases in the nation. For chronic myelogenous leukemia, about 5,000 new cases of CML a year occur in the United States. Due to increased survival after imatinib treatment, it is projected that there would be 250,000 CML patients in the United States, and about 25,000 CML patients in California by year 2040 . Since Gleevec does not cure the disease, patients need continued treatment to prevent disease relapse with potential risk of side-effects and non-compliance. Besides, a high financial burden is evident for controlling CML by Gleevec, with current average cost of $44,400-$46,800/year for each patient. The state-wide cost is estimated to be $1.1-1.2 billion per year using current drug price for the projected 25,000 patients in 2040 in California. Besides, an estimated 13,000 new cases of AML were seen in the US in 2009. Failure to eradicate leukemia stem cells also poses a major challenge for AML therapy. Therefore, development of an effective agent to target leukemia stem cells to eliminate these diseases will not only improve patients' life, but also financially benefit patients, the state of California and the nation significantly.