Leukemias are cancers of the blood forming cells that afflict both children and adults. Many drugs have been developed to treat leukemias and related diseases. These drugs are often effective when first given, but in many cases of adult leukemia, the disease returns in a form that is not curable, causing disability and eventual death. During the last few years, scientists have discovered that some leukemia cells possess stem cell properties that make them more potent in promoting leukemia growth and resistance to common types of treatment. These are called leukemia stem cells (LSC). More than in other cancers, scientists also understand the exact molecular changes in the blood forming cells that cause leukemias, but it has been very difficult to translate the scientific results into new and effective treatments. The main difficulty has been the failure of existing drugs to eliminate the small numbers of LSC that persist in patients, despite therapy, and that continue to grow, spread, invade and kill normal cells. In fact, the models used for drug development in the pharmaceutical industry have not been designed to detect drugs or drug combinations capable of destroying the LSC. Drugs against LSC may already exist, or could be simple to make, but there has not been an easy way to identify these drugs. Recently, physicians and scientists at universities and research institutes have developed tools to isolate and to analyze LSC donated by patients. By studying the LSC, the physicians and scientists have identified the molecules that these cells need to survive. The experimental results strongly suggest that it will eventually be possible to destroy LSC with drugs or drug combinations, with minimal damage to most normal cells. Now we need to translate the new knowledge into practical treatments. The CIRM Leukemia Team is composed of highly experienced scientists and physicians who first discovered LSC for many types of leukemia and who have developed the LSC systems to test drugs. The investigators in the Team have identified drug candidates from the vigorous California pharmaceutical industry, who have already performed expensive pharmacology and toxicology studies, but who lack the cells and model systems to assess a drug’s ability to eliminate leukemia stem cells. This Team includes experts in drug development, who have previously been successful in quickly bringing a new leukemia drug to clinical trials. The supported interactive group of physicians and scientists in California and the Collaborative Funding Partner country has the resources to introduce into the clinic, within four years, new drugs for leukemias that may also represent more effective therapies for other cancers for the benefit of our citizens.
Thousands of adults and children in California are afflicted with leukemia and related diseases. Although tremendous gains have been made in the treatment of childhood leukemia, 50% of adults diagnosed with leukemia will die of their disease. Current therapies can cost tens of thousands of dollars per year per patient, and do not cure the disease. For the health of the citizens of California, both physical and financial, we need to find a cure for these devastating illnesses.
What has held up progress toward a cure? Compelling evidence indicates that the leukemias are not curable because available drugs do not destroy small numbers of multi-drug resistant leukemia stem cells. A team approach is necessary to find a cure for leukemia, which leverages the expertise in academia and industry. Pharmaceutical and biotech companies have developed drugs that inhibit pathways known to be involved in leukemia stem cell survival and growth, but are using them for unrelated indications. In addition, they do not have the expertise to determine whether the inhibitors will kill leukemia stem cells. The Leukemia Team possesses stem cell expertise and has developed state of the art systems to determine whether drugs will eradicate leukemia stem cells. They have also have access to technologies that may allow them to identify patients who will respond to the treatment. The development plan established by the Leukemia Disease Team will also serve as a model for the clinical development of drugs against solid tumor stem cells, which are not as well understood.
In summary, the benefits to the citizens of California from the CIRM disease specific grant in leukemia are:
(1) direct benefit to the thousands of leukemia patients
(2) financial savings due to definitive treatments that eliminate the need for costly maintenance therapies
This proposal is focused on the development of novel agents to treat leukemia. The applicant team will develop six existing candidate molecules targeting leukemic stem cells (LSCs). These agents, three small molecule drugs and three monoclonal antibodies, will block survival and self-renewal pathways that function preferentially in LSCs as compared to normal hematopoietic stem cells (HSCs). Analysis of these agents will feature a functional xenograft mouse model utilizing primary human cells to test anti-leukemic efficacy and potential side effects on HSCs. Agents will be evaluated for potential therapeutic benefit against both chronic leukemias and acute forms of the disease. Additionally, the applicant team will develop a genomic and proteomic response signature that will allow accurate prediction of therapeutic response to various anti-leukemic agents. Development activities toward IND filings for each of the agents are planned.
Reviewers were highly enthusiastic about this well crafted and balanced proposal to develop novel anti-leukemic agents. The central rationale for the proposed approach is based on the cancer stem cell hypothesis, the theory that a small population of leukemic cells possesses stem cell-like properties, displays particular resistance to standard chemotherapeutic agents, and drives tumor reappearance and growth. The rationale for each of the proposed agents in targeting key components of cellular signaling pathways in leukemic cells was well established and convincing. Reviewers recognized the value of testing the development agents against putative LSCs isolated from a variety of tumor samples. Although several reviewers questioned the validity of the cancer stem cell hypothesis, there was widespread agreement that new therapeutic agents preferentially targeting leukemic cells over HSCs could provide valuable and novel approaches for treatment of leukemias.
The proposed project addresses a compelling medical need as half of adults diagnosed with leukemia will die of the disease. Substantial evidence supports the concept that recurrence and persistence of many leukemias stem from the relative resistance of LSCs to therapeutic agents currently in use, so the development of novel agents that preferentially target LSCs may be particularly valuable in attacking both lymphoid and myeloid malignancies. Furthermore, a successful demonstration of targeted therapy against leukemic stem cells will support further studies towards targeting of cancer stem cells in general.
Reviewers judged the proposed project to be extremely mature and supported by compelling preliminary data. The research team has developed methods for the isolation and assay of primary LSCs, and they have ready access to an extensive collection of primary human tissue specimens. Reviewers felt that the applicant provided convincing data to support the proposed therapeutic approach (albeit within the limitations of the xenograft mouse model). In addition, reviewers praised the highly sensitive cell labeling and imaging techniques that have been established to monitor in vivo LSC migration, survival and self-renewal.
Reviewers considered the proposed research plan to be logical and largely achievable. Although multiple agents will be evaluated against four different indications (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, and chronic lymphoid leukemia), the unified experimental approach and the applicant’s focus on primary leukemia samples were viewed as particular strengths of the proposal. There was some concern about limitations of the xenogenic murine model and whether efficacy observed with this system will accurately predict therapeutic efficacy in patients with leukemias. Additionally, some reviewers questioned the value of the extensive genomic and proteomic analyses and suggested that this component of the study will not be required for obtaining drug approval. However, the simultaneous development of multiple agents, as well as adequate plans for alternative strategies if developmental failures are encountered, bolstered reviewer confidence that some of the proposed therapies will progress to IND filing. Plans to test combinations of therapeutic agents were viewed as an additional strength of the proposal.
The proposal stipulates a clear series of measurable milestones with appropriate go/no-go decision points. Reviewers judged the project timeline to be reasonable and feasible. Submission of one or more INDs within the project’s four years was viewed as extremely likely.
Reviewers considered the proposed research team to be a particular strength of the application. The PI and Partner PI are leaders in the fields of cancer research and treatment and possess many years of successful leadership of large research teams. The PI has extensive experience in the development of drugs and IND filings and has demonstrated previous success in bringing therapeutic agents to the clinic. Other team members provide appropriate expertise for each of the targeted diseases. The investigators’ commitments to the project were viewed as appropriate. The leadership plan was adequately described. There were some concerns that several aspects of the budget were excessive, yet reviewers acknowledged the high potential cost of the extensive animal studies and the need for a large number of personnel for this multifaceted study.
Reviewers recognized enormous synergy in the highly collaborative effort derived from complementary strengths of the PI, Co-PI, and Partner PI. This collaboration was viewed as absolutely necessary to facilitate the proposed application of cutting-edge technologies and accumulation of needed resources for accomplishing the study goals. Reviewers cited the outstanding research environments, important established collaborations with pharmaceutical and biotechnology companies, and the superb group of co-investigators and consultants as contributing to an exceptionally strong proposal.
The proposed project constitutes a highly coordinated and multifaceted effort to develop novel anti-cancer agents that target leukemic stem cells. Strengths of the proposal include an exceptionally experienced and qualified collaborative team, use of in vivo functional assays and cells from leukemic patients to assess agent efficacy, compelling preliminary data, and the maturity of the project overall. The project is likely to result in one or more IND filings within four years.
- Andrew Balber
- Ivar Mendez