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, but in many cases of adult leukemia, the diseases are not curable, and cause disability and eventual death. More than in other cancers, scientists 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 agents to eliminate small numbers of leukemia stem cells 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 leukemia stem cells. Drugs against leukemia cell stems may already exist, or could be simple to make, but there is not an easy current way to identify them.
Recently, physicians and scientists at universities and research institutes have developed tools to isolate and to analyze leukemia stem cells taken directly from patients. By studying the leukemia stem cells, physicians and scientists have learned what molecules these cells need to survive. We have identified key switches that reprogram normal stem cells into leukemia stem cells. The experimental results strongly suggest that it will be possible to destroy leukemia stem cells with drugs or drug combinations, without harming most normal cells. Now we need to translate the new knowledge into practical treatments.
The goal of the CIRM Planning Grant in Leukemia is to forge a team, and to implement a planning process that will bring together highly experienced scientists and physicians who have developed the leukemia stem cell test systems, with our existing collaborators in the vigorous California pharmaceutical industry, who already have drugs, but lack the cells and model systems to assess their efficacy against leukemia stem cells. The requested funds will support the establishment of an interactive group, a review of projects by expert external advisors, the integration of selected projects according to a practical timeline, and the generation of a reporting structure for CIRM. The new CIRM-supported interactive group will have the resources to introduce into the clinic, within four years, new drugs for leukemias and to change the ways that these diseases are treated for the benefit of the citizens of California.
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. The animal models that pharmaceutical companies use for drug testing do not measure the leukemia stem cells, so the companies cannot identify drugs that kill them. Experts in the industry are aware of the problem, but have had difficulties forging alliances with physicians and scientists at academic medical centers who have models for primary human leukemia stem cells needed for drug testing, and systems for assessing efficacy in clinical trials.
The CIRM Planning Grant in Leukemia, if awarded, will provide the initial resources required to implement a new paradigm for drug development, i.e., a focused team approach with participants from academia and industry sharing a common goal, with clear-cut areas of collaboration. The team approach is necessary to find a cure for leukemia, since the current system is inadequate. Since so much scientific knowledge exists about leukemia stem cells, the systems established in the CIRM Disease Specific Planning Grant will also serve as a model for the clinical development of drugs against solid tumor stem cells, which are not yet 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
(3) new alliances between the academic and pharmaceutical sectors in California that lead to new jobs
(4) the deployment of a new drug development team approach that will be applicable to other cancers
(5) Realization of the CIRM mandate to deliver highly effective novel therapies within a short time frame to benefit the health of Californians afflicted with leukemia.
The Principal Investigator (PI) for this proposal plans to assemble a multidisciplinary team of investigators to develop novel, targeted therapies to eradicate leukemic stem cells, which are thought to be the cause of resistance and treatment failures after current cytotoxic therapies. The team assembled by this investigator has identified several potential molecular pathways that are critical in leukemic stem cells. The team plans to overcome major road blocks in translating cancer stem cell therapies for patients with leukemia and lymphoma by combination therapies targeting quiescent cancer stem cells while sparing normal pluripotent, hematopoietic or mesenchymal stem cells.
Reviewers felt that the concept was highly significant and sufficiently mature to warrant a planning effort. The panel recognized that novel approaches are needed to solve the clinical problems of leukemia relapse, resistance to standard therapy and treatment related toxicities from current therapeutics. There was general agreement among the reviewers on the scientific rationale of the proposal and maturity of the concept. Several potential targets for varied leukemias have been identified by the group for exploration which may require multiple strategic approaches. During discussion by the panel, concerns that the broad approach might take more that 5 years to get to the clinic were mitigated by the proposed team’s track record of having already identified one compound that is being prepared for clinical trials.
Reviewers also recognized the experience and track record of the PI in translating basic research findings to the clinic. The PI has extensive experience in oversight of large research organizations, assembling multi-disciplinary research teams, coordinating planning efforts and developing team oriented proposals in partnership with academic and industrial investigators.
The PI has identified a number of areas of expertise needed by the planning team including leukemia, leukemia stem cells, clinical trial support and regulatory affairs. Overall, the planning process is thoughtful, sufficiently detailed and appropriately collaborative. However, it was somewhat unclear how the CIRM Team Planning Award will specifically enhance collaborations and programs that are already well established by this applicant.
Reviewers noted that they would like to see a full application for the Disease Team Research Award from this group. Further, the panel recommended that the details of the compound/s and cell-based assays that will be used for targeting the cancer stem cells and for the functional analysis should be provided in the full disease team award application.
Reviewer One Comments
Effective stem cell-directed therapy must kill or differentiate quiescent cells, must not destroy normal pluripotent, hematopoietic or mesenchymal stem cells, and a combination of therapies may be needed. The concept of leukemia stem cells is well-established and the need to develop therapies targeting them is well-justified. Thus, the proposal is of high significance. The team assembled by this investigator has identified several potential molecular pathways that are critical in leukemic stem cells, including the Wnt pathway regulator GSK-3ï¢ in drug-resistant CML, Jak2 mutations in myeloproliferative diseases, the Wnt pathway component expressed by CLL cells, and the ability of demethylating agents to induce the differentiation of AML progenitors into leukocytes. Thus, potential targets have been identified and the concept is mature. Existing collaborations and/or service agreements with pharmaceutical companies have already led to development of some of these drugs. A major activity that is in need of further development is analysis of normal embryonic and tissue-specific stem cells in the context of the chosen combination therapies prior to clinical trials. Thus, the development of a multi-faceted drug regimen to treat leukemic stem cells is needed and the studies are of high significance. It is somewhat unclear how the CIRM Team Planning Award will enhance collaborations and programs that are already well established by this group.
Dr. Carson has a strong track record of translating his basic research findings to the clinic. He discovered that leukocytes have high deoxycytidine kinase activity and thereby developed the drug 2-chlorodeoxyadenosine. He supervised preclinical development and early-stage clinical trials of this drug, which shows 75% efficacy in inducing long-term remission of hairy-cell leukemia. He is currently developing inhibitors of the Wnt pathway as well as TLR agonists for vaccination and TLR antagonists for use in autoimmune diseases. Thus, he has a strong history as a translational researcher. He currently serves as director of the Moores UCSD Cancer Center and is former director of the Sam and Rose Stein Institute on Aging at UCSD. Thus, he has extensive experience in oversight of large research organizations. He has assembled multi-disciplinary research teams, coordinated planning efforts and developed team-oriented proposals. These include the UCSD Center of Cancer Nanotechnology Excellence proposal that was funded by the NCI is 2005. He also coordinated the recent resubmission if the UCSD NCI-funded Cancer Center Support Grant. He established an office of industrial relations at UCSD Moores Cancer Center in 2003 to promote partnerships with pharmaceutical and biotechnology companies and promote drug discovery research. Thus, he has outstanding experience at assembling teams of academics, basic scientists, clinicians and members of the pharmaceutical industry for drug development.
The goal of the planning grant is to forge a team and implement the planning process that will bring together academic scientists from UCSD, the Ludwig Institute, the Salk Institute, and the J Craig Venter Institute, who have developed leukemia stem cell test systems, with existing collaborators in the pharmaceutical industry. While the industry collaborators may already have effective drugs, they lack the expertise to assess the efficacy of their drugs against leukemia stem cells. The requested funds will support the establishment of a cohesive team, a review of projects by expert external advisors, the integration of selected projects according to a practical timeline, and planning for the implementation of early phase clinical trials. A number of areas of expertise needed by the planning team have been identified, including leukemia, leukemia stem cells, animal models for leukemia, normal pluripotent stem cells, clinical oncology/clinical trials, clinical trial support, and regulatory affairs. The PI will establish an external advisory board, identify projects and project leaders, identify core resources and core leaders, and establish cooperative agreements with industry partners for the development of diagnostics and therapeutics. The team assembling process has begun and planning meetings have been scheduled. Overall, the planning process is thoughtful, sufficiently detailed and appropriately collaborative.
Reviewer Two Comments
The goal of this planning grant for this PI is to bring together a team of investigators who are skilled in identifying, isolating and testing “leukemia stem cells” with the long term goal of developing novel, targeted therapies to eradicate these cells which are thought to be the cause of resistance and treatment failures after current cytotoxic therapies currently in practice. The group of investigators assembled by the PI has previously demonstrated progress in this area in the study of “stem cells” in CML, MPD and CLL, laying the foundation for a team of experts to develop targeted therapies for patients with these diseases. The problem of leukemia relapse, resistance to standard therapy and treatment related toxicites from current therapeutic approaches are all critical, relevant and in need of novel approaches. The group is likely to make progress in 5 years, but the diversity of diseases will require multiple strategic approaches and will likely require the attention of specialized research teams for several decades.
Dr. Dennis Carson is highly qualified to lead this team. He has a long and established track record as an investigator in the field of leukemia and drug development and his highly aware of the challenges of this field.
The planning process is reasonable and likely to lead to a competitive application for a Disease Team Research Award.