Early Translational II
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.
Statement of Benefit to California:
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.
This Development Candidate (DC) proposal aims to develop small molecule inhibitors of sirtuin 1 (SIRT1) to target human leukemia stem cells (LSC). SIRT1 is an enzyme that becomes over expressed in a variety of human cancers, including acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). The applicants will perform a structure activity relationship (SAR) analysis on analogues of existing SIRT1 inhibitors and test them for their effects on an in vitro model of CML-LSC. Next investigators plan to determine how compounds interact with SIRT1 to guide chemical optimization. This will be accomplished by modeling SIRT1 based on existing structural knowledge for related proteins and by generating a platform for SAR. Investigators also plan to determine the specificity of candidate SIRT1 inhibitors by performing microarray analysis of inhibitor-treated CML-LSC. Next, investigators will test the ability of their optimized SIRT1 inhibitors to eradicate CML-LSC in a mouse model of CML, and to kill CML-LSC and AML-LSC isolated from human patients. They will also test signaling pathways affected by in vivo inhibitor treatment. Finally, investigators plan to perform pharmacology and safety studies. LSC are believed to resist leukemia treatment, accumulate mutations and lead to relapse and poor patient outcomes. Reviewers agreed a successfully developed drug that could ablate these cells addresses an unmet medical need and would definitively impact disease. However, the panel expressed mixed opinions regarding the rationale for the proposed approach. The applicant provides data that suggest SIRT1 is an interesting molecular target for intervention. However, reviewers noted the existence of drugs that already down-regulate activity of the SIRT1 pathway and they questioned whether targeting that pathway further would improve disease outcome. Furthermore, the group questioned the inclusion of CML as a disease target, as the LSC population is better characterized in AML than CML. Reviewers highlighted the application’s over-reliance on mouse CML models for SIRT1 inhibitor efficacy evaluation. Despite serial transplants, the short murine life span cannot accurately model the indolent and unpredictable course of CML in humans and complicates clinical efficacy assessment. Also, the product description confused reviewers as to whether SIRT1 inhibitors would be administered as a first- or a second line therapy after imatinib failure. In the latter case, CML patients’ prior imatinib treatment could confound analysis of clinical samples. For these reasons, it was suggested that AML is a better disease target for future SIRT1 inhibitor development. Reviewers agreed that the plan proposed by the principal investigator (PI) would not achieve a development candidate within three years, since the scope of the proposed work was too broad. Reviewers considered the proposed development of the platform for SAR to be a time-consuming research effort that should have been completed prior to the onset of translational studies and thus distracts from the goal of achieving a DC. Some reviewers even questioned whether the proposed platform was required for achieving a DC. Furthermore, some of the alternative plans require re-initiation of early stage activities and their late implementation would not enable completion of the project within the award period. Reviewers also believed that too many compounds were being studied, and the PI does not present an adequate plan to select a single development candidate for preclinical studies. Overall, reviewers appreciated that the preliminary data in both the application and the literature suggest SIRT1 as a potential target for cancer therapy. However, preliminary data with inhibitors and SIRT1 knockdown left reviewers unconvinced selective inhibition of SIRT 1 could efficiently ablate LSCs, and led them to question whether SIRT1 was adequately validated as a target. The lack of validation data for the secondary assays and cell-based assays further eroded reviewers’ confidence. Taken together, these issues led reviewers to conclude that the proposed project was too immature to be fully responsive to the RFA. Reviewers commented that the PI is well trained and has published a number of papers relevant to the proposal. Together, the PI and co-PI are pioneers in studying the role of SIRT1 activity in CML resistance. The PI has assembled a multi-disciplinary team with significant research expertise. However, the medicinal chemist’s commitment to the project is inadequate and the team appears to lack critical drug discovery and development experience. Reviewers praised the collaborative environment and excellent resources of the host institution although letters of support were absent. In summary, this application is focused on the development of small molecule SIRT1 inhibitors to target human LSCs. Although the proposal addresses a serious unmet medical need, reviewers did not recommend this application for funding because of feasibility concerns with the overly broad research plan and because current evidence was not sufficient to convince them that inhibition of the target would impact disease. PROGRAMMATIC REVIEW A motion was made to consider moving this application to the Development Candidate Feasibility (DCF) category, since SIRT1 is an interesting novel target that deserves exploration. A reviewer cautioned that the DCF Award should not be treated as a research grant, and this RFA specifically excludes target validation. Other reviewers reiterated feasibility issues. The proponent of the motion conceded that this application did not address a sufficiently validated target and therefore was too early stage for DCF funding. The motion was withdrawn.